Neurobiology of Behaviour Visual Summary Issue
University of Toronto
Winter 2015
HMB300H1F 2015 University of Toronto
Table of Contents Summaries by:
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
Vaisny Balamurali Saadia Esat Xin Yue Kou Soonji Kwon Alexandra Kubica Daniel Derkach Vanessa Ferlaino Floriana Ferri Sonja Ing Ricky Ng Jessica Gosio David Giang Akua Obeng-Dei Mie Andersen Madli Vahtra Pranay Siriya Alana Brown Chuqi Sandy Wang Vanessa Bracaglia Vivian Liu Bernie Longange Dong-Eun (Raquel) Lee Vonny Pui Ying Wong Ola Taji Ashima Agarwal Ariba Alam Samin Alikhanzadeh Megan Cabral Sammy Cai Chun-Chi Chu Chantel George Patrick Hornlimann Shikha Kuthiala Shonali Rajesh Lakhani Victor Lee Ella Lew Yi Xuan Li Rose Ly Tong Mai Fazila Malek
4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82
41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.
Catherine Matolcsy Lucy McPhee Arinda Muntean Yuki Nishimura Miranda Nong Hyun Park Maryna Pilkiw Joravir Singh Riar Ashkan Salehi Husain Shakil Arman Shekari Jaclin Simonetta Olivia Singh Eugene Tang Jiawei Zhang
56. Yidong Zhan
84 86 88 90 92 94 96 98 100 102 104 106 108 110 112
114
57. Nimara Dias-Karunaratne 116 58. ZiTeng Li 118 59. Man Lai Ho 120 60. Sylvia Jennings 122 61. Melissa Colaluca 124 62. Divya Mamootil 128 63. Padmanabhan Ramanujam 130
4 Summary of:
Accumulation of amyloid in cognitive impairment after mild traumatic brain injury
Authors: Shun-Tai Yang, Ing-Tsung Hsiao, Chia-Ju Hsieh, Tung-Hsiao Chiang, Tzu-Chen Yen, Wen-Ta Chiu, Kun-Ju Lin, Chaur-Jong Hu Background/Introduction: Mild traumatic brain injury (mTBI) can occur after mechanical force/ impact is applied to the head, usually occurring in accidents and/or sports related injury. Biochemical and physical changes occur within the brain as a result of mTBI, these changes can result in a semi-permanent or permanent decline in cognitive, physical and/or psychological function. Many studies analyzing the consequences of mTBI have shown patients having Alzheimer’s Disease (AD) like pathology; patients showed increased accumulation of Aβ plaque formation, tau proteins and neurofibrillary tangles (NFTs). This study aims to examine the effects of mTBI and look at the role of the APOE4 gene in Aβ plaque formation as well as the effectiveness of using amyloid positron emission tomography (PET) as a diagnostic tool.
Materials and Methods:
A total of 37 participants were used in this study, there were 10 controls. 27 participants were former mTBI patients found in the Taiwan TBI Database, 6 of the 27 mTBI subjects were former mTBI patients with obvious cognitive impairment/ dementia. All study participants underwent questionnaire screening to assess cognitive function. Participants were administered the AD8 questionnaire and Mini Mental Status Examination (MMSE). Apoliprotein E genotyping was done on all participants using the PCR-PFLP method. Aβ plaque, tau proteins and neurofibrillary tangles (NFTs) accumulation was analysed through amyloid PET and normalizing images to an MRI template. MRI images where then used to examine brain volumes of following 7 regions: cerebellum, bilateral frontal, occipital, temporal, precuneus, striatum and posterior cingulate.
Major Results:
Amyloid accumulation scores of 1.83± 0.75 (mTBI with dementia),0.86± 0.65 (mTBI without dementia), 0.60 ± 0.52(control) demonstrated increased amyloid presence in mTBI patients with dementia. Patient’s cognitive function scores through the AD8 tests showed similar trends to that of the amyloid accumulation scores as increased dementia showed increased AD8 scores (0.3 control, 1.6 mTBI without dementia and 3.3 mTBI with dementia). While compiling AD8 scores and amyloid accumulation scores with patient’s other information including Initial Loss of Consciousness (ILOC) researchers found ILOC was a risk factor to increased AD pathology. Odds Ratio of ILOC was 12.5 for patients to acquire dementia. Amyloid PET analysis showed the amyloid burden in participants. mTBI participants with dementia showed the most uptake of radioactivity in brain regions ( bilateral striatum, temporal, frontal and parietal lobes) thus they had the highest amyloid burden, amyloid burden were very low to absent in controls and mTBI participants without dementia. Genotype comparison to amyloid accumulation and post mTBI consequences showed that the APOE4 allele was associated with higher incidence of amyloid plaque formation and dementia. A significant correlation was seen in participants upon a linear regression anaylysis of APOE4 genotype and their amyloid burden.
Conclusions:
This study’s findings are consistent with existing literature as it demonstrated that mTBI does have a role in increasing risk in developing AD like pathology resulting in cognitive decline. It was also able to confirm that the APOE4 allele increases risks to develop Aβ plaque formation. Most importantly this study successfully uses a novel technology (amyloid PET) to demonstrate these findings. This should open pathways to increasing amyloid PET use in a variety of other neurological studies as well as for a more indepth analysis of AD pathology specifically in mTBI patients on a larger scale. Further examination in the pathology/biochemistry of how mTBI increases AD pathology on a larger scale can be very helpful to finding a preventative or curative treatment.
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Sources for images: http://www.autoaccidentattorneyinfo.com/category/brain-injuries/, https://mybiomedart.wordpress. com/tag/beta-amyloid-plaques/, http://www.nature.com/news/dna-data-storage-breaks-records-1.11194
Yang, S.T. et al. (2015). Accumulation of amyloid in cognitive impairment after mild traumatic brain injury. Journal of Neurological Sciences, 341, 99-104.
Summary by: Vaisny Balamurali
6 Summary of:
Hippocampal Neurogenesis Regulates Forgetting During Adulthood and Infancy
Authors: Katherine G. Akers,Alonso Martinez-Canabal, Leonardo Restivo, Adelaide P. Yiu, Antonietta De Cristofaro, Hwa-Lin (Liz) Hsiang, Anne L. Wheeler, Axel Guskjolen, Yosuke Niibori, Hirotaka Shoji, Koji Ohira, Blake A. Richards, Tsuyoshi Miyakawa, Sheena A. Josselyn, Paul W. Frankland Background/Introduction: During adulthood and infancy, it is evident that as neurogenesis occurs, memory persistence decreases. The presence of neurogenesis was monitored using GFP tagging in the dentate gyrus and CA3 neurons. When adult and infant mice were fear conditioned, then tested 1 day later, there was equal freezing time. However as the delay increased up to 28 days (and increased neurogenesis in infant mice) the infant mice showed less freezing time, indicating that the initial conditioning was being forgotten. The reason that infant mice were compared to adult was due to the high amount of neurogenesis occurring in infants, allowing for more visible results, if any. It is hypothesized that if neurogenesis occurs, then other hippocampus-dependent memories will be forgotten to accommodate for the new neuronal connections.
Materials and Methods: Multiple versions of the method to test the hypothesis were carried, however a large focus was on two sections with two subsections of experimentation. The first was with mice who had the option of voluntary running compared to a control who did not have that option. GFP was administered after 4 weeks, and further ZnT3 was used as a counter-stain to compare the presence of new and old neurons in the dentate gyrus and CA3. Additionally a comparison was done between transgenic TK+ mice to wild type, who were administered GAN to prevent neurogenesis. On both groups fear conditioning through foot shocks was done, and they were tested against controls weeks later to see if the contextual fear conditioning had remained. This was done with both adult and then with infant mice.
Major Results: With the first set of experiments mentioned above, it was evident with the counter-stain that new and old neurons were found in close proximity to each other. Additionally, after fear conditioning had occurred, 1 day later the mice were tested and both groups showed equal amounts of freezing. However, after four weeks when mice were tested, those who had access to a running wheel showed a reduction in the conditioned fear context. In the second set of experiments, after the first day, both sets of mice displayed equal freezing during the test. Although, after six weeks, the TK+ transgenic mice showed the same reaction as WT mice who did not has access to a running wheel (they had not forgotten the fear). The WT mice that had access to a running wheel froze less than the TK+ mice at this time.
Conclusions: The study suggests that not only is the hippocampus required for consolidating memories, but the presence of neurogenesis there suggests that it also plays a role in the forgetting of information through rewiring the DG-CA3 circuits as new memories arise. This suggestion is evidence for long term degradation in the hippocampos, a concept necessary to balance long term potentiation. The most frequently activated patterns of activity is remembered, where older contexts are forgotten.
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Fig. 2 Voluntary running increases neurogenesis and promotes forgetting in adult mice. http://www.sciencemag.org.myaccess.library.utoronto.ca/content/344/6184/598/F2.large.jpg
Akers, K. (2014), et al. Hippocampal Neurogenesis Regulates Forgetting During Adulthood and Infancy. Science, 344(6184), 598-602. Retrieved February 9, 2015, from http://www.sciencemag.org. myaccess.library.utoronto.ca/content/344/6184/598.full
Summary by: Saadia Esat
8 Summary of:
Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer’s disease with plaques and tangles
Authors: Antonio Di Meco, Yash B. Joshi, Domenico Pratico Background/Introduction:
Increasing cases of Alzheimer’s disease (AD) in the elderly, and with no definite cure, is becoming a serious public health issue worldwide. From previous understandings, the development of AD is due to a combination of genetic and environmental factors, where one of the potential environmental risk factor is chronic stress. Chronic stress can cause widespread effects within body systems, one of them being the sleep cycle. Interestingly sleep deprivation (SD) have been found in previous studies to play a role in many neurodegenerative diseases, including AD. Studies have shown that in AD transgenic mouse model where it seems that the disease related plaque caused by amyloid-beta is associated with SD. However no further studies have looked at the relationships between SD and other AD features, hence this study is set to examine the correlation between chronic SD and AD phenotypes such as tau metabolism and other causes of cognitive impairments.
Materials and Methods:
This experiment examined several aspects of AD using 3xTg mice that expresses mutant amyloid precursor protein, the human mutant PS1 knockin as well as the transgeneic form of tau. At age 8month, the 18 mice were divided into two random groups, where one group was introduced to SD, and the other group had normal light/ dark cycle as control. During the protocols the mice were assessed behaviourally using the Y-maze (to measure the mice’s spontaneous will to explore new areas), fear conditioning through foot shock and sound cues, as well as the Morris water maze. After scarification at 10month of age, the mice brain were dissected for examination, half for biochemistry assays, and the other half for immunohistochemistry studies.
Major Results:
For results on cognitive function, SD mice showed no difference on Y-maze activity, an insignificant decrease of freezing in cued recall for fear conditioning and an significant decrease in remembering the target platform zone, as well as longer travel distance in the Morris water maze. Biochemically, amyloid-beta peptides did not differ significantly. In terms of tau metabolism, SD mice exhibited a decrease in phosphorylation at several epitopes, potentially due to an significant decrease of the kinase, cdk-5 activity in the brain. There was also a significant increase in insoluble tau as compared to control, this also corresponded to the increase in immunoreactivity of the MC-1 antibody, which is a marker for tau conformation change in AD brain. Western blot and immunohistochemistry shows that PSD95 in SD mice decreased significantly, indicating decreased post-synaptic integrity. SD mice also showed a greater expression of the astrocytosis marker, glial fibrillary acidic protein (GFAP), as microglia and astrocytes are typically active in AD brains. Lastly, even though there was no change in the total CREB level, but its phosphorylated form p-CREB was significantly reduced in SD mice, and this change did not affect any other related factors such as BDNF and cFos.
Conclusions:
We see that sleep deprivation in AD mouse model definitely correlate to cognitive impairments such as spatial memory deficits, as well as changes biochemically in tau metabolism. Tau protein is typically found hyperphosphorylated in the AD brain, in this paper the results of decreased tau phosphorylation and cdk5 activity infer that there may be other kinases responsible for the phosphorylation of tau in the AD phenotype, although body temperature could have acted as a confound which was not acknowledged for. The correlation between increase in MC-1 and insoluble tau suggesting that tau conformation change could mark initiation of AD progression, however still controversial as previous studies suggests otherwise. Overall this study demonstrates that SD causes chronic stress that are not only associated to AD as a progressive marker but in fact likely contribute to the development of AD.
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Di Meco, A., & Joshi, Y. B., & Pratico, Domenico. (2014). Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer’s disease with plaques and tangles. Neurobiologi of Aging, 35, 1813-1820.
Summary by: Xin Yue Kou
10 Summary of:
Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states.
Authors: Little JW, Ford A, Symons-Liguori AM, Chen Z, Janes K, Doyle T, Xie J, Luongo L, Tosh DK, Maione S, Bannister K, Dickenson AH, Vanderah TW, Porreca F, Jacobson KA, & Salvemini D. Background/Introduction:
Most effective treatments of chronic pain typically involve endogenous opioids, adrenergic and calcium channels. These clinical treatment methods however, have detrimental side effects. This study highlights the potential of using an agonist of a G protein-coupled adenosine receptor (AR) subtype A3 in reversing pathogenic pain. Although there have been developments in the analgesic uses of other AR subtype agonists, specifically A1AR and A2AAR agonists, there were cardiovascular side effects. Interestingly, A3AR is highly expressed in cells important in carrying out neuroprotective effects, such as inflammatory cells and peripheral sensory nerves. Additionally, there are already clinical trials using A3AR agonist IB-MECA [N6-(3-iodobenzyl)adenosine-50-N-methyluronamide] as a means to decrease pain caused by chemotherapeutic agents and constriction of sciatic nerve without serious side effects. However, activation of A3AR at spinal and supraspinal (rostral ventromedial medulla (RVM)) sites show promising signs of becoming a more effective treatment of chronic pain without side effects.
Materials and Methods:
A total of 301 rats and 63 mice were used to test various neuropathic pain models, such as chronic constriction injury (CCI), spared nerve injury, spinal nerve ligation, chemotherapyinduced peripheral neuropathy, and cancer-induced bone pain. The mice were classified into two major groups: wild-type and A3AR -/- mice. Dosage effects and motor coordination were tested using the Rotarod motor test. Tail flick and hot-plate latency were used to test if normal nociception was affected by administration of A3AR agonist, MRS5698. Instinctual behaviours such as flinching and guarding were examined in animals with cancer-induced bone pain. Since an important site of A3AR activation is the RVM, various systemic microinjections were employed to test for any differential effects. Additionally, the second important site of A3AR activation is the spinal cord, specifically L4-L5 segments, where post-spinal nerve ligation was conducted.
Major Results: CCI neuropathic pain model involved systemic administration of ABT-702, a selective adenosine non-nucleoside kinase inhibitor. This elicited a long-lasting decrease in flinching and guarding behaviors, indicative of reversing cancer-induced bone pain. Conversely, both pre- and postadministration of MRS1523, a selective A3AR antagonist, diminished the anti-nociceptic effects of ABT-702. The results are similar in A3AR -/- mice. The most effective treatment of neuropathic pain is the administration of MRS5698, a highly selective A3AR agonist. As a result of higher selectivity over A1AR and A2AAR, its effects are fast and even comparable to morphine and IBMECA. Unlike morphine, MRS5698 does not lead to tolerance upon repeated administration. However, it is most effective when given in different types of systemic injections: intraperitoneal, subcutaneous, intravenous. Mechano-allodynia is a specific type of pain induced by stimulation of a low-threshold afferent nerve that is mechano-sensitive. Not only does MRS5698 alleviate mechano-allodyna, it reverses many other pain models, such as spared nerve injury, spinal nerve ligation and cancer-induced pain. Future implications of MRS5698 treatment method may most notably be due to the fact that it is already in its clinical use as an anti-cancer agent. Additionally, endogenous opioid and cannabinoid pathways were entirely independent of the effects of this A3AR agonist. To ensure normal nociception is not compromised, the tail flick and hot-plate methods were used. To locate the optimal injection sites, A3AR mRNA transcript and protein levels were measured and compared by Western blot. Thus, the spinal cord and supraspinal (RVM) sites were both found to be important sites for A3AR activation and therefore, nociception processing as well.
Conclusions: Recent advancements have developed A3AR agonist IB-MECA as anti-nociception treatment however, there were some side effects associated with its use. Alternatively, the use of the highly selective A3AR agonist, MRS5698, did not lead to the development of side effects to date. The most exciting implication of MRS5698 is the possible dual treatment of cancer as well as chronic neuropathic pain.
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Little JW, Ford A, Symons-Liguori AM, Chen Z, Janes K, Doyle T, Xie J, Luongo L, Tosh DK, Maione S, Bannister K, Dickenson AH, Vanderah TW, Porreca F, Jacobson KA, & Salvemini D. (2014). Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain. doi: 10.1093/brain/awu330.
Summary by: Soonji Kwon
12 Summary of:
Decoding Neural Circuits that Control Compulsive Sucrose Seeking
Authors: Edward H Nieh, Gillian A Matthews, Stephen A Allsop, Kara N Presbrey, Christopher A Leppla, Romy Wichmann, Rachael Neve, Craig P Wildes, & Kay M Tye
Lateral hypothalamus (LH) has been found to be responsible for inducing feelings of hunger. Ventral tegmental area (VTA) has been found to be a part of the reward centre of the brain. This LH-VTA pathway has been found electrically and optically, however, how the pathway works corresponding to food reward and addiction has not. The researchers wanted to show that the pathway existed for specifically compulsive sucrose eating, and not just a pathway for eating in general, to the point of addictions like drugs where the substance is still sought after even through negative consequences. The neurons of the pathway that projected from the LH to the VTA and the ones that were received by the LH from the VTA were found using optogeneticmediated phototagging while observing neural activity during reward seeking behaviours. Once these neurons were identified, the mice had an optic fibre inserted over the VTA that shone either blue or yellow light. Then the mice were injected in their LH with either ChR2 which activated the loop with blue light, NpHR which inhibited the loop with yellow light or a control of eYFP. Conditioned mice learned to go to a port when they saw a cue in order to obtain sucrose. The port was on the other side of a shock grid. Then the mice went through 3 different trials each one having 20 cues and was either paired with no shocks, shocks, or shocks but the optic fibres were used at the same time. They also wanted to show that the GABA neurons were not what was causing the compulsive sucrose seeking or an increase in hunger. Vivo patch-clamp experiments were used to identify the glutamate and GABA neurons projecting from the LH to the VTA. The same sucrose-shock experiment was used to understand the role of activation and inhibition of these neurons and their effects on feeding behaviour. As well the researchers wanted to see that the activation of the pathway was not inhibiting the feelings of pain by comparing inhibited and activated mice in hot water tail withdrawal reaction times. By finding how this pathway affects behaviour it can lead to therapies and techniques to deal with high sucrose cravings that lead to obesity and food addictions.
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Cell (2015) doi: http://dx.doi.org/10.1016/j.cell.2015.01.003 Published online January 29, 2015
Summary by: Alexandra Kubica
14 Summary of:
Transient Maternal IL-6 Mediates Long-Lasting Changes in Neural Stem Cell Pools by Deregulating an Endogenous SelfRenewal Pathway
Authors: Denis Gallagher, Andreea A. Norman, Cameron L. Woodard, Guang Yang, Andrée Gauthier-Fisher, Masashi Fujitani, John P. Vessey, Gonzalo I. Cancino, Nadia Sachewsky, Knut Woltjen, Michael P. Fatt, Cindi M. Morshead, David R. Kaplan, Freda D. Miller Background/Introduction:
Current research is unable to explain the mechanism controlling the formation or size of adult stem cell pools. However, it is known that variations in neural precursor cells (NPCs) directly influence neurogenesis in adult mammalian brains. Moreover, human gestational stresses have long-term effects on cognitive function of offspring, possibly correlating to disturbances in the formation of adult NPC pools. This study examines this prospect by analyzing a maternal cytokine surge of interleukin-6 (IL-6) during gestation. IL-6, which is upregulated in infected mothers, is believed to be responsible for certain behavioral aberrations in mice, such as autism spectrum disorder and schizophrenia. Maternal IL-6 enters the fetal circulation and crosses the blood-brain barrier, possibly affecting longterm neural function. This study hypothesizes that this maternal cytokine surge causes long-term changes in NPC pools and seeks to probe into the mechanism responsible for such changes.
Materials and Methods:
IL-6 was injected intraperitoneally in pregnant mice on gestational day 13.5 (G13.5) in experimental groups. Negative controls included mice with no maternal IL-6 infection, or infection with interferon-γ (IFNγ) or IgG. Other experimental groups included mice with IL-6 receptor (IL6R) knockdown via IL6R siRNA and IL-6-/- (knockout) mice, with wild-type positive controls. BrdU and Ki67 were used as proliferation markers. Sox2 was used as a precursor marker. Satb2 was used as a marker for newborn (differentiated) neurons. Hoechst stained for DNA (less toxic than DAPI). BIII-tubulin was used to label neurons. GFAP was used to label astrocytes. Enhanced GFP (EGFP) was transfected in either cortical or ventral ganglionic eminence cells (ventral GE) of embryos using the piggyBac transfection method to track location of these precursor cells in adults. Other techniques used include culturing and passaging of neurospheres, RT-PCR, Western blot analyses, cytokine antibody arrays, as well as various culturing/clonal programs and software for imaging.
Major Results: Intraperitoneal injection of IL-6 into pregnant mice resulted in ~2 times more BrdU-positive subventricular zone (SVZ) cells (Fig. 1A/B) and ~1.5 times more SVZ neurosphere-initiation (Fig. 1H) in 2 month-old (adult) mice. Maternal IL-6 injection also resulted in ~1.5-fold more olfactory bulb neuron birth in adult mice (Fig. 1J). Postnatal (2 weeks-old) EGFP-positive SVZ cells were Sox2-positive (representing proliferation) after electroporation of embryonic cortex with EGFP reporter (Fig. 2B/D), and newborn neuroblasts in the rostral migratory stream (RMS) of adult mice continued to be EGFP-positive (Fig. 2E), illustrating persistence of NPCs from embryo to adulthood. In addition to an increase in BrdU-positive cells (signifying proliferation; Fig. 3C), maternal IL-6 injection resulted in an almost 2-fold increase of embryonic cortical precursors (Fig. 3E) and ventral GE precursors (Fig. 3M) that formed neurospheres at clonal densities 2 days after injection. IL-6 treatment resulted in larger multicellular clonal bodies (Fig. 5A-C), showing enhancement of self-renewal (i.e. cloning). IL-6 treatment also resulted in a ~2-fold increase in mixed clones (BIIItubulin + other, Fig. 5E; GFAP + other, Fig. 5F), as opposed to uniform clones. In vivo analysis showed a significant increase in SVZ neurosphere initiation (Fig. 5G). IL-6 knockout mice (IL-6-/-) showed greatly reduced proliferation of embryonic cortical precursors compared to WT controls (Fig. 6G/H). 3 days after EGFP transfection in IL6R knockdown mice, embryonic cortical radial cells exhibited a composition of fewer precursors (Sox2-labeled) and increased quantities of differentiated neurons (Satb2-labeled; Fig. 7D-G). Similarly, 3 days after BrdU injection in IL-6-/- mice, embryonic cortical radial cells exhibited a composition of fewer BrdU-positive precursors and increased quantities of differentiated neurons (Fig. 7J-M).
Conclusions: This study shows that gestationally increased maternal IL-6 levels increases proliferation and size of adult forebrain NPC pools. The evidence outlined in this study elucidates this conclusion in 2 ways. Firstly, increased embryonic IL-6 exposure enhances SVZ NPC self-renewal and preserves clonal multipotency in these precursor cells. Secondly, this study establishes that IL-6 interacts with its receptor IL6R to uphold NPC levels and to defer neuronal differentiation. This evidence is valuable to neuroscience research because it adds to the foundation for understanding the mechanisms that control the size of NPC pools and their multipotency.
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Figures adapted from Gallagher et al., 2013, p. 566, 572, 574.
Gallagher, D., Norman, A. A., Woodard, C. L., Yang, G., Gauthier-Fisher, A., Fujitani, M., Vessey, J. P., Cancino, G. I., Sachewsky, N., Woltjen, K., Fatt, M. P., Morshead, C. M., Kaplan, D. R., & Miller, F. D. (2013). Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway. Cell Stem Cell, 13(5), 564-576. doi:10.1016/j.stem.2013.10.002
Summary by: Daniel Derkach
16 Summary of:
Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease
Authors: Gwenn S. Smith, PhD; Adrian W. Laxton, MD; David F. Tang-Wai, MDCM, FRCPC; Mary Pat McAndrews, PhD; Andreea Oliviana Diacomescu, PhD; Clifford I. Workman, BS; Andres M. Lozano, MD, PhD, FRCSC. Background/Introduction:
PET imaging studies suggest that neural circuitry changes correlated with decreased cerebral glucose metabolism leads to cognitive defects and neuropsychiatric symptoms associated with Alzheimer’s Disease patients. A recent study investigating alternative treatment methods based on this discovery used deep brain stimulation (DBS) to stimulate the Fornix for 1 year resulting in sustained, increased cerebral glucose levels. The authors investigated this study and predicted that increased glucose levels in parietofrontal and hippocampal/parahippocampal-parietal networks would result from DBS after 1 year, and that this increased glucose metabolism would be associated with better clinical outcomes.
Materials and Methods:
The sample consisted of 5 patients, who had all been taking a steady dose of cholinesterase inhibitors for a minimum of 6 months. Two weeks after surgical implantation of an electrode into the fornix, stimulators were activated, with settings remaining constant for one year. PET was used to measure the functional connectivity of the hippocampal and cortical networks, as well as to correlate changes in cerebral glucose metabolism with patients’ cognitive and neuropsychiatric outcomes at baseline, 1 month and 12 months after DBS. ADAS-cog and QOL-AD assessed cognitive and neuropsychiatric changes.
Major Results: Both the mean and standard deviation of ADAS-cog and QOL-AD scores appeared to worsen over time. PET scans identified a frontal-temporal-parietal-striatal-thalamic network and a frontal-temporal-parietal-occipital-hippocampal network after 1 year of DBS. High baseline metabolism in brain regions commonly affected by AD indicated less global cognitive decline. These brain regions were also correlated with increased metabolism after 1 year of DBS and less decline in ADAS-cog and QOL-AD scores. Low baseline metabolism in brain regions less commonly affected by AD indicated less global cognitive decline. These brain regions were also correlated with decreased metabolism after 1 year of DBS and less decline in ADAS-cog and QOL-AD. Correlations with the change in metabolism after 1 month of DBS were not significant.
Conclusions: Increased cerebral metabolism was identified in cortical-subcortical and corticalhippocampal networks after 1 year of DBS, which correlated with increased cognitive function and quality of life in patients. Activation of the frontal-temporal-parietal-striatalthalamic network suggests memory and other cognitive functions are affected by DBS of the fornix. Improved functional activity in the frontal-temporal-parietal-occipitalhippocampal network may be important for hippocampal input into the default mode network that is often affected in AD patients. Since different baseline levels of glucose metabolism in brain regions commonly or less commonly associated with AD were observed, cerebral glucose metabolism measures could be used to predict DBS response in patients or even as a technique for patient selection.
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Smith, G.S., Laxton, A.W., Tang-Wai, D.F., McAndrews, M.P., Diaconescu, A.O., Workman, C.I., Lozano, A.M. (2012). Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease. Archives of Neurology, 69, 1141-1148. doi:10.1001/archneurol.2012.590
Summary by: Vanessa Ferlaino
18 Summary of:
Neurofeedback and standard pharmacological intervention in ADHD: A randomized controlled trial with six-month follow-up
Authors: Victoria Meisel, Mateu Servera, Gloria Garcia-Banda, Esther Cardo, Inmaculada Moreno Background/Introduction:
This study examined the efficacy of neurofeedback (NF) training in treating Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents by comparing it to the standard pharmacological intervention. Neurofeedback is an operant-conditioning technique that trains participants to regulate their inattention and hyperactivity through feedback of their neurophysiological signals, that are measured using EEG. Many studies have reported that children with ADHD show abnormalities in electrophysiology such as increased frontal theta activity and decreased beta activity, thus, NF primarily focuses on training participants to regulate their theta and beta activity. As existent studies regarding NF and ADHD have shown to be methodologically inadequate, this study was designed to overcome previous limitations by including randomization, teacher and parent reports and follow-up data.
Materials and Methods:
The study began with 63 recruited children that were of ages 7 to 14; as those with comorbid disorders, IQ in ranges below 80, unwillingness to undergo randomization, and taking medication were excluded, the final sample consisted of 23 children. Through random selection, 12 of the children were chosen to participate in 40 sessions of NF treatment, attending two 35-minute sessions per week, while 11 received a dosage of 1mg/ kg methylphenidate (standard ADHD pharmacological treatment) per day. The NF sessions were presented as games such as puzzles or races, and participants were rewarded as they increased their theta activity and decreased beta activity. Behavioural changes were assessed at pre-treatment (PRE), post-treatment (POST), two-month (FU1) follow-up and six month (FU2) follow-up using the following measures: ADHD rating scale, Oppositional defiant disorder rating scale, Likert scale, and Weiss Functional Impairment Rating Scale.
Major Results:
As there were no significant differences in age, sex, IQ and subtype of ADHD, data analysis was focused on comparing the results from the pre-assessment phase to the three other assessments. The group that received the NF training showed significant improvement in ADHD symptoms, functional impairment, academic performance, and inattention according to parental reports; the teachers only reported medium improvements in those categories, that were not considered significant. Hyperactivity and oppositional defiant behaviour, however, showed less significant change as according to the mothers and teachers. The methylphenidate group also showed significant improvements in ADHD symptoms, hyperactivity, and inattention. Teachers also reported significant reduction in oppositional defiant behaviour. The methylphenidate group, however, did not show significant improvement in academic performance as reported by the mothers and teachers. Thus, the most significant difference between the two groups was the change in academic performance. The two and six-month post-treatment assessments showed that the NF group maintained the achieved improvements, however, since not all participants remained free of medication after treatment and because of the small sample size, these results should be interpreted carefully until more advanced studies replicate the results.
Conclusions:
This study shows through practice and through learning how to change our brains, it can be possible to rewire the neural circuits in our brain without the need of pharmacological interventions. Once learned, these changes can be long lasting and provide benefits in the long term. Although, it is not yet understood how neurofeedback produces these long-lasting changes in the brain, and what molecular mechanisms are involved, future research that is able to study the underlying mechanism of neurofeedback might help us gain an even better understanding of the brain functioning.
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Meisel, V., Servera, M., Garcia-Banda, G., Cardo, E., & Moreno, I. (2013). Neurofeedback and standard pharmacological intervention in ADHD: A randomized controlled trial with six-month follow-up. Biological Psychology, (94): 12-21.
Summary by: Floriana Ferri
20 Summary of:
Transient activation of specific neurons in mice by selective expression of the capsaicin receptor
Authors: Güler, A. D., Rainwater, A., Parker, J. G., Jones, G. L., Argilli, E., Arenkiel, B. R., Ehlers, M. D., Bonci, A., & Palmiter, R. D. Background/Introduction:
The ability to remotely induce activity in neurons is essential in elucidating how a neuronal population might interact within complex circuits. Manipulating neural activity in vivo in a precisely controlled manner allows one to directly correlate behavioural responses. Various techniques have been developed to this effect, such as optogenetics and genetically engineered receptors. However, while these techniques have been incredibly successful in controlling neural activity in vivo, they are not without their limitations – the former is both labour-intensive and invasive, and the latter often has either low temporal resolution or lack of cellular specificity. In this paper, Güler et al present a non-invasive model, where neural activity in genetically defined populations can be induced directly, rapidly and reversibly by selective expression of capsaicin receptor TRPV1.
Materials and Methods:
Triple transgenic mice lines DAT-TRPV1 and ePet-TRPV1 were created by crossing Trpv1 knockout mice (B6.129X1-Trpv1tm1Jul/J) to Gt(ROSA)26Sor-stopflox-Trpv1-ires-ECFP, Slc6a3Cre or ePet–Cre mice. To confirm selective expression of TRPV1 and capsaicin-dependent activity in DA neurons, whole-cell patch-clamp recordings were performed on VTA slices. DA neurons were identified by their spontaneous firing rate and following 8 min of stable baseline recordings, capsaicin was applied for 8 min. To measure electrophysiology in freely moving mice, four-tetrode microdrives were implanted and, after two weeks recovery, recordings were taken through Cheetah acquisition software (Neuralynx); baseline recordings identified putative DA neurons, and capsaicin was administered following 10 min of stable baseline recordings. Three tests for characteristic DA activity were performed. First, to monitor locomotor behaviour following capsaicin administration, mice were placed in an arena and video-recorded via Ethovision video analysis software (Noldus Information Technology) to track travelled distances and consecutive beam breaks in activity chambers. Second, food consumption following 4 days habituation, blocked access to food and then drug or vehicle administration was measured with BioDAQ food monitoring system (Research Diets). Third, in a two-bottle capsaicin preference test, mice were presented with two solutions with either almond or vanilla flavouring, where one flavour was paired with capsaicin and the other with vehicle. Mice were first allowed access to only one of the solutions during an 8 day association phase, and then they were given free access to both solutions for 4 days; vehicle and capsaicin solution consumption were monitored.
Major Results:
Güler et al created a triple transgenic mouse line where the capsaicin receptor TRPV1 was expressed under the control of dopamine transporter promoter (DAT-TRPV1). The authors demonstrated that the receptor was selectively expressed in dopaminergic neurons and that DA neural activity was capsaicin-dependent. Peripheral or oral delivery of capsaicin was sufficient to rapidly and reversibly induce the characteristic DA locomotion and behavioural responses in vivo. Further, Güler et al created a second transgenic line using R26-TRPV1 mice, expressed under the control of serotonergic enhancer region gene Pet1. Similarly, TRPV1 was specifically expressed in 5-HT neuronal populations and capsaicin-dependent activity induced rapid and reversible behaviours characteristic of 5-HT neurons. Successful application of the genetic remote control technique to two distinct populations suggests that this model is translatable across neural systems.
Conclusions:
Güler et al have presented a new non-invasive technique by which neural activity can be specifically, reversibly and rapidly induced through selective activation of TRPV1, thereby addressing some of the limitations of recent techniques. Since Güler et al demonstrated that capsaicin could successfully induce transient activity in two neural populations, TRPV1 expression is a technique with the potential for widespread application. Addition of this method to the repertoire of neural effectors may prove instrumental in elucidating complex neural circuits.
21
G端ler, A. D., Rainwater, A., Parker, J. G., Jones, G. L., Argilli, E., Arenkiel, B. R., ... & Palmiter, R. D. (2012). Transient activation of specific neurons in mice by selective expression of the capsaicin receptor. Nature communications, 3, 746.
Summary by: Sonja Ing
22 Summary of:
Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players
Authors: Pashtun Shahim, MD; Yelverton Tegner,MD, PhD; David H. Wilson, PhD; Jeffrey Randall, PhD; Tobias Skillback, MD; David Pazooki, MD, PhD; Birgitta Kallberg, BSc; Kaj Blennow, MD, PhD; Henrik Zetterberg, MD, PhD Background/Introduction:
Current concussion evaluation protocols require physicians to determine a patient’s recovery based on symptoms that only offer subjective information, and may not truly reflect the extent of damage done to the brain. Therefore, a need for objective evaluation of concussion and recovery assessment arises in sports with high rates of concussion such as hockey. T-tau and neurofilament light were previously shown to indicate neuronal damage in cerebrospinal fluid, but the invasive nature of lumbar punctures would be incompatible with sports participation. T-tau, along with neuron-specific enolase (NSE) and S-100 calcium-binding protein B (S-100B), previously shown to increase in Olympic boxers after bouts with high rates of head strikes, were tested for in the blood contents of athletes.
Materials and Methods:
Professional ice hockey players in the Swedish Hockey League were included in the study during the 2012-2013 season. In the preseason before a game, players from two teams had blood samples taken before a friendly game, while one of the two teams also had samples taken after a game without occurrence of head injury. During the season, concussed players had blood samples taken 1, 12, 36, 48 and 144 hours after injury (most concussions show observed recovery after 6 days), then when players were given return to play status. Plasma and serum were separated. Plasma t-tau was measured using a novel immunoassay while S-100B and NSE were measured on a modular E170 instrument. All samples were measured using the same batch of reagents at the same time.
Major Results:
Plasma t-tau levels were shown to increase in hockey players who sustained a concussion; up to 10 times the levels recorded in the preseason baseline sample, with the highest levels being recorded 1 hour after the concussion incident. Serum S-100B levels increased 1 hour post-concussion, but dropped back to baseline levels within 12 hours. Serum NSE did not significantly increase after concussion in the players. Additionally, serum S-100B and NSE, not plasma t-tau, increased after a game in which no head injury occurred. These findings indicate that increases S-100B and NSE are not specific to brain injury, especially in the case of NSE. Effect size was also analyzed in the study. In more severe cases of concussion (those lasting 7 to 10 days, 10 days or more, and those with loss of consciousness), t-tau 1 hour after concussion was higher compared to individuals who returned to play within 6 days; this trend was insignificant, but 1 hour t-tau measurements showed strong correlation with the length of concussive symptoms. Additionally, individuals whose concussive symptoms lasted longer than 6 days had greater concentrations of t-tau at 144 hours post-injury compared to those who returned to play in under 6 days.
Conclusions:
In cases of sports-related concussion, blood t-tau measurements may serve as a practical method of concussion diagnosis as well as determining return to play status in athletes. However, other factors should also be taken into account for concussion evaluation, and research on t-tau outside of neurodegenerative disease is still preliminary, with this particular study also limited by low sample size and a high rate of unpaired measurements. As some mechanisms of concussion are still unknown and varied, subjective evaluation of symptoms is still required, and there may be other potential biomarkers for concussions – the authors mention that neurofilament light, which is CNS-specific like t-tau, may merit future investigation.
23
Shahim, P., Tegner, Y., Wilson, D.H., Randall, J., Skillb채ck, T., Pazooki, D., Kallberg, B., Blennow, K., & Zetterberg, H. (2014). Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurology, 71(6), 684-692. doi: 10.1001/jamaneurol.2014.367
Summary by: Ricky Ng
24 Summary of:
Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits
Authors: Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, and David Sulzer. Background/Introduction: Autism spectrum disorders (ASD) has no known origin and includes deficits in cognitive abilities including communication skills, social interactions, and emotional control. One common characteristic of the disorder is aberrant excessive cortical dendritic spine growth and reduced pruning of postsynaptic glutamatergic synapses. Researchers hypothesize mutations in genes that inhibit the mammalian target of rapamycin (mTOR) kinase to be linked to ASD, as overactive mTOR is thought to lead to excessive synaptic protein synthesis. mTOR also acts downstream to inhibit macroautophagy (autophagy) – a process involved in neuronal pruning. They predict that the over activity of mTOR leads to reduced autophagy contributing to ASD.
Materials and Methods:
Representative Golgi images were used for postmortem human temporal lobe images. Linear regressions, ANOVA and other statistical models were used for comparing pruning over different time spans or between multiple groups. Novel object recognition tests were used for social tests of mice, with more sniffing of a novel object representing more social behaviors, as well as other social tests like three-chamber testing paradigm. Confocal imaging was performed using Dil-labeled neurons that were labeled using a Helios gene gun system. Mouse and human brain tissue were lysed with 1X RIPA buffer supplemented with protease and phosphatase inhibitors and subject to western blot. Mice strains were obtained from other labs and crossed to obtain desired mice ASD phenotypes.
Major Results:
Researchers showed greater dendritic spine density and reduced spine pruning in ASD patients in layer V pyramidal neurons in the superior middle temporal lobe, an area associated with ASD due to its influence on social and communication networks in the brain. By using Tsc2+/+ mice, mice with a functional Tsc2 gene that inhibits mTOR activity, compared to Tsc2+/- mutated mice, ASD social phenotypes were observed as well as greater spine density and reduced spine pruning, suggesting mTOR hyperactivity is related to these ASD characteristics. When Tsc2+/- mice were given rapamycin, a substance blocking mTOR kinase, spine pruning was corrected and spine density was brought to control levels. mTOR hyperactivity was found to be related to reduced autophagy activity, and activity could also be restored to control levels once rapamycin was given. Finally, researchers tested Tsc2+/- mice that also had a loss of autophagy proteins and therefore no autophagy (Atg7CKO) with rapamycin and found no correction of pruning and dendrite density of these Tsc2+/-:Atg7CKO mice or just Ast7CKO mice, like the corrections observed with Tsc2+/- mice.
Conclusions: From these results, researchers concluded that hyperactivity in mTOR is related to reduced downstream autophagy and both are found in mice with social ASD deficit phenotypes. They determined that mTOR-regulated autophagy is required for postnatal developmental spine pruning and that ASD spine density phenotypes can be corrected with activation of autophagy. These results provide great insight into the relation of dendritic spine pruning and autism, and may suggest ways of correcting these structural differences in ASD patients.
25
Guomei, T., et al. (2014). Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Cell Press, 83, 1131-1143
Summary by: Jessica Gosio
26 Summary of:
Locus-specific epigenetic remodelling controls addiction- and depression-related behaviors
Authors: Elizabeth A Heller, Hannah M Cates, Catherine J Pe単a, Haosheng Sun, Ningyi Shao, Jian Feng, Sam A Golden, James P Herman, Jessica J Walsh, Michelle Mazei-Robison, Deveroux Ferguson, Scott Knight, Mark A Gerber, Christian Nievera, Ming-Hu Han, Scott J Russo, Carol S Tamminga, Rachael L Neve, Li Shen, H Steve Zhang, Feng Zhang & Eric J Nestler. Background/Introduction: Previous studies have been unable to show the mechanisms involved with the relationship between chromatin modification and its regulation on drug- or stress-evoked plasticity for behaviour. This study attempts to resolve this issue using the transcription factor FosB residing in the nucleus accumbens, which is a key reward brain area for drug addiction and stress. A specific methylation on histone H3 lysine 9 (H3K9me2 by histone methyltransferase G9a) is a repressive histone modification that is crucial in the regulation of drug and stress behaviour. However, the previous studies were limited to only show widespread effects of this H3K9me2 at multiple loci. This study aims to develop stronger proof of linking epigenetic modifications with one specific, using engineered transcription factors.
Materials and Methods:
Two engineered transcription factors, zinc-finger proteins (ZFPs) or transcription activator-like effectors (TALEs) made in silico to build to specific locus in the genome, allowing for strict regulation of its transcription activity. This allows for the investigation for the gene of interest and a causal observation between turning on a locus and possible plastic changes observed in drug or stress behaviour. ZFPs and TALEs have also been applied in vitro for investigating epigenetic remodeling associated with chromatin-modifying enzyme, as well as the investigation of cocaine-evoke and stressevoked epigenetic changes in vivo of the Fosb locus in the nucleus accumbens. Methods consist of Western blotting, Immunohistochemistry, locomotor sensitization, viral-mediated gene transfer and nucleus accumbens RNA isolation and qRT-PCR. For discovery of the regulation from these transcription factors, cocaine doses and training to cause social avoidance was also conducted.
Major Results:
From the generation of the ZFPs transcription factors targeting the the specific locus of the Fosb gene in vivo, the overall indicates the histone post-translational modification on the Fosb promoter was controlled by ZFPs. Also, they were able to show bi-directional control of the Fosb gene expression, which was found to be evident when acetylation on the Histone 3 Lysine 9 and 14 (H3K9/K14) promoted gene transcription activation, while H3K9me2 repressed gene expression when looking at mRNA levels. Specificity of the locus was also evident, since there was no other location of methylation enrichment in other parts of the nucleus accumbens extract. After establishing the mechanism, regulation of reward behaviour by ZFPs demonstrated that the mice that had the methylation H3K9 had the locomotor sensitization blocked, while the activation epigenetic changes (e.g. acetylation) shown an accentuation of the sensitization effects from their locomotion. On the other hand, mice that have the H3K9 methylation enrichment, analogous to ones in depressed humans, shown to have less social interaction and higher anxiety compared to the control mice that underwent the same subthreshold stimulus. This was shown through less exploration time in the maze and conducting a chronic social defeat procedure.
Conclusions: Two main engineered transcription factors were able to create epigenetic changes on the Fosb promoter site, where Fosb-ZFP35-p65 was found to be associated to create acetylation on the promoter site, thus allowing an increase in transcription and presented possible correlation of this acetylation and cocaine-enhanced behaviour related to this Fosb gene. On the other hand, repressive methylation by the Fosb-ZFP35-G9a was able to block cocaine locomotion in mice, representing a dysregulation in cocaine sensitization. From previous studies, Fosb gene was known for its role in pathophysiology in drug addiction for both rodents and humans. By being able to study this gene and its epigenetic changes of it, possible future treatment may become available once the foundation of epigenetic changes is established for the understanding of its association with depression and addiction.
27
Heller, E.A. et al. (2014). Locus-specific epigenetic remodeling controls addiction- and depressionrelated behaviour. Nat Neurosci, 17(12), 1720-1727. Received from http://www.nature.com/neuro/ journal/v17/n12/abs/nn.3871.html
Summary by: David Giang
28 Summary of:
Sleep deprivation prevents stimulation-induced increase of levels of P-CREB and BDNF: Protection by caffeine
Authors: Ibrahim A. Alhaider, Abdulaziz M. Aleisa, Trinh T. Tran, Karim A. Alkadhi Background/Introduction: Previous evidence has shown that sleep deprivation either before or after learning impairs memory formation through the reduction of hippocampal activity and impaired late long-term potentiation (L-LTP). The expression and activation of cAMP response element binding protein (CREB) as well as other transcription factors are required for protein synthesis to occur during L-LTP. The influx of calcium through the binding of glutamate to the NMDA receptors will allow for the activation of calcium-calmodulindependent protein kinase IV (CaMKIV), that will go on to activate CREB by way of phosphorylation. In sleep-deprived individuals, CREB and brain-derived neurotrophic factor (BDNF) expression levels are reduced in the hippocampus that will therefore have implications to synaptic plasticity involving spatial learning task and induction of LTP. In previous studies caffeine has been shown to have protective properties relating to symptoms that correlate with neurodegenerative diseases. The researchers wanted to investigate the protective properties of caffeine on learning and memory impairment induced in sleep-deprived rats.
Materials and Methods:
The researchers used radial arm water maze (RAWM), which is a spatial test that is a combination of the radial arm task and the Morris water maze, in order to measure longterm memory. Rats that were treated with caffeine were given the same dose that matched the daily human intake; this treatment lasted for 4 weeks. Electrophysiological recordings were obtain by way of population spike (pSpike) at the CA1 area in the hippocampus, multiple high frequency stimulation (MHFS) was done to the Schaffer collaterals were used in order to induce L-LTP. Five hours after L-LTP was induced in the hippocampal region, the right hippocampus was removed to examine the molecular levels of P-CREB and BDNF in the CA1 area of the hippocampus by way of an immunoblot analysis.
Major Results: The number of error committed by the rats that were treated with caffeine before the onset of sleep deprivation in RAWN task was reduced, showing that the caffeine treatments lessen the impairment of long-term spatial memory in rats with sleep deprivation. When L-LTP was induced, it was found that the magnitude of the sleepdeprived rats treated with caffeine was similar to that of the rats that were not sleepdeprived, showing that the caffeine may have some protective effect in sleep-deprived rats. When examining the molecular expression of P-CREB, it was shown that the sleepdeprived rats treated with caffeine had increase levels of P-CREB compared to the just sleep-deprived rats not treated with caffeine, suggesting that a decrease of P-CREB could be an explanation to the reduction of L-LTP in sleep deprivation. The levels of BDNF in the sleep-deprived rats treated with caffeine were similar to the levels seen when no sleep deprivation occurred
Conclusions:
The researchers showed that impaired learning and memory in sleep-deprived animals can be due to the reduced levels of P-CREB and BDNF that are important in L-LTP. They showed that caffeine was able to maintain the levels of P-CREB and BDNF, in sleepdeprived rats, similar to that of rats that were not sleep-deprived. When A1 receptors are activated through adenosine binding, they will block the release of glutamate thereby preventing the induction of L-LTP. Caffeine is thought to block the A1 receptors, explaining the neuroprotective effects as well as suggesting that adenosine have a potential key role in sleep.
29
Ibrahim A. Alhaider, Abdulaziz M. Aleisa, Trinh T. Tran, Karim A. Alkadhi. “Sleep deprivation prevents stimulation-induced increase of levels of P-CREB and BDNF: Protection by caffeine “ Molecular and Cellular Neuroscience 46 (2011) doi:10.1016/j.mcn.2011.02.006 Published online 19 Feburary 2011
Summary by: Akua Obeng-Dei
30 Summary of:
Investigating the long-term effect of subchronic phencyclidinetreatment on novel object recognition and the association between the gut microbiota and behavior in the animal model of schizophrenia
Authors: B. Pyndt Jørgensen, L. Krych, T.B. Pedersen, N. Plath, J.P. Redrobe, A.K. Hansen, D.S. Nielsen, C.S. Pedersen, C. Larsen, D.B. Sørensen Background/Introduction:
Phencyclidine (PCP) is an NMDA receptor antagonist that results in a schizophrenialike phenotype in rodents when subjected to subchronic PCP (subPCP) treatment. subPCP treated rats are thus used as a model for studying schizophrenia, showing cognitive deficits and increased locomotor sensitivity in response to acute PCP (aPCP) treatment – traits characteristic for schizophrenia. Variance has been reported in this model and may be resulting from variations in gut microbiota (GM) due to modulation of the microbiotagut-brain axis (mGBA). Accordingly, GM has been associated with memory performance and locomotor activity. The purpose of this study was to examine the duration of subPCP-induced cognitive impairment and furthermore to study the effect of subPCP on gut microbiota in association with behavior.
Materials and Methods:
Rats were treated with PCP for one week (and control group with saline water) followed by one week of washout. The rats were then tested in novel object recognition test (NOR) to study their spatial memory at 0, 3, or 6 weeks after washout. Fecal samples were obtained after NOR for genetic analysis. Next, the rats (the control group inclusive) were administered aPCP prior to testing in locomotor activity assay (MOTR) to study their locomotor sensitivity. These experiments were repeated with rats that were additionally administered ampicillin in order to monitor any variance caused by differences in GM.
Major Results: It was found that subPCP had a negative impact on memory performance in NOR, and this effect lasted for 3 weeks. After 6 weeks, the effect had subsided and the memory performance was similar to the control group. Consistent with earlier studies, the subPCP increased locomotor activity in response to aPCP, and this increased activity was still evident 6 weeks after washout. GM analysis showed a difference between subPCP treated and control groups when restricted to bacteria present in at least 50% of the samples. A significant correlation between GM profile and memory performance was evident. Interestingly, antibiotic reduction of GM rescued the cognitive deficits in subPCP treated rats and their memory performance were similar to the control group, while the performance of the vehicle treated group was not affected by antibiotics. Ampicillin treatment did not affect locomotor activity.
Conclusions:
- Loss of cognition in subPCP-treated rats was evident for 3 weeks, why it is recommended that the schizophrenic rat model is used up to 3 weeks after subPCP when studying the effects of novel drugs on NOR. - GM profiles correlates to cognition, and antibiotic reduction of GM neutralizes the subPCP induced loss of memory. A difference was observed in the GM of rats subjected to subPCP. Together these data indicate that the changes in GM is caused by the subPCP-treatment, and that the subPCP-induced memory deficits are mediated through changes in GM.
These findings are relevant in regarding to development of new drugs in treating schizophrenia, as it allows researchers to make better use of the schizophrenic rat model as well as taking the variance caused by GM into account.
31
Jørgensen, B. P., Krych L., Pedersen T. B., Plath N., Redrobe J. P., Hansen A. K., … Sørensen D. B. (2015) Investigating the Long-term Effect of Subchronic Phencyclidine-treatment on Novel Object Recognition and the Association between the Gut Microbiota and Behavior in the Animal Model of Schizophrenia. Physiology & Behavior, 141, 32-39.
Summary by: Mie Andersen
32 Summary of:
Schizophrenia Susceptibility pathway Neuregulin 1-ErbB4 Suppresses Src Upregulation of NMDA receptors
Authors: Graham M Pitcher, Lorraine V Kalia, David Ng, Nathalie M Goodfellow, Kathleen T Yee, Evelyn K Lambe & Michael W Salter NMDA glutaminergic receptors associated with synaptic plasticity may also play an important role in the development of Schizophrenia. Previous research suggests that hallucinations and cognitive dysfunction in Schizophrenic patients stem from the reduced activity of these receptors. At a cellular level, NMDA receptors involved in synaptic plasticity depend on Src tyrosine kinase mediated phosphorylation to enhance receptor activity. Schizophrenic patients display reduced levels of phosphorylated NMDA receptors compared to normal individuals. Hyperactive Nrg and Erbb4 genes, potential hallmark genes for schizophrenia, are hypothesized to suppress NMDA receptor activity and block LTP. Nrg produces the ligand NRG1, Erbb4 produces the receptor ErbB4, and the two couple to elicit downstream signaling pathways. This study attempted to link reduced NMDA receptor activity to the presence of these genes. Adult rat and mouse brain slices from the hippocampus and prefrontal cortex were studied. In the hippocampus, Schaffer Collateral fibers were stimulated and whole cell recordings were observed in the CA1 region. In the prefrontal cortex, corticocortical neurons in layers II and III were stimulated, and whole cell recordings were observed in pyramidal neurons of layer V. Antagonists were used to block AMPA and GABAa receptors in order to isolate EPSC recordings only from the NMDA receptors. To determine specific effects of NRG1-ErbB4 ligand-receptor signaling on NMDA receptors, both Src-enhanced NMDA receptors and Src-independent NMDA receptors (controls cells) were compared. To activate Src in the tyrosine kinase-dependent NMDA receptors, phosphopeptide, EPQ(pY)EEIPIA was administered intracellularly. NRG1beta, a soluble form of NRG1, was then added in excess to both receptor samples. Before adding the NRG1beta, cells with NMDA receptors and active Src tyrosine kinase displayed markedly higher levels of EPSPs compared to NMDA receptors without active Src. When NRG1beta was added to these neurons, the activity levels of the Srcindependent neurons remained the same while the Src-dependent cells displayed levels of activity that matched the control cells. NRG1beta did not, however, reduce the activity of Src-dependent NMDA receptors below the level of activity observed in control cells. The presence of the ErbB4 receptors already in the cells was necessary for NRG1 to facilitate its suppressive effect. When investigating knockout mice without the Erbb4 gene, NRG1beta did not have a place to bind, and did not elicit an effect on the Srcdependent NMDA receptors. Similar results were found in neurons of the hippocampus and prefrontal cortex. Elevated activity of Src tyrosine kinase-dependent NMDA receptors appeared to be a critical component in proper cognitive function. This study concluded that excess NRG1 suppresses this process. The proposed mechanism of this suppression included NRG-1/ErbB4 signaling inhibiting the catalytic activity of the Src kinase, thus preventing phosphorylation of the NMDA receptor and reducing downstream pathways including long-term potentiation. This could explain some of the positive symptoms, such as cognitive disarray and hallucinations displayed by Schizophrenic patients, but mapping out the precise molecular pathway requires additional research. Understanding the physiological mechanism for Schizophrenic symptoms can help provide further insight into more effective treatment methods. This study suggests that seeking ways to counteract the suppressed Src-dependent NMDA receptor activity should be the target of future research.
33
Sources for images: http://www.nature.com/nm/journal/v17/n4/images/nm0411-425-F1.jpg
Pitcher G.M, Kalia L.V, Ng D, Goodfellow N.M, Yee K.T, Lambe E.K, Salter M.W. (2011). Schizophrenia susceptibility pathway neuregulin 1-erbb4 suppresses Src upregulation of NMDA receptors. Nature Medicine. 17, 470-478.
Summary by: Madli Vahtra
34 Summary of:
Dopamine D1 and D5 Receptors Modulate Spike TimingDependent Plasticity at Medial Perforant Path to Dentate Granule Cell Synapses
Authors: Kechun Yang and John A. Dani Background/Introduction:
Previous studies have shown a dopaminergic influence on the dentate gyrus facilitating synaptic plasticity in the hippocampus—specifically in spatial learning and memory. However, the actual mechanism of how dopamine regulates spike timing-dependent LTP (tLTP) is unknown. Previous attempts have used whole cell patch-clamp protocols that have disturbed the intracellular environment rendering it difficult to understand downstream mechanisms initiated by dopamine receptors. It is known DA1 and DA5 receptors are found in the hippocampus, which Yung and Dani showed are central to tLTP. Yung and Dani suggest that since tLTP is the synaptic strengthening between pre and postsynaptic neurons dependent on time delay between firing, understanding the role of dopamine—a neurotransmitter important in detecting salient events and reward—and the hippocampus—important for spatial information—are important in linking reward and salience to the external environment, mediated by DA1 and DA5 receptor activation.
Materials and Methods:
Hippocampal slices of genetically variant mice (either DA1, DA5 or Kv4.2 (potassium channel) knockouts) and wild type mice were used. Using perforated patch-clamp techniques, the intracellular composition of cells could be maintained, allowing Yang and Dani to look at cellular mechanisms. It also provided a baseline recording, important in STDP ratio. A bipolar electrode inserted into the perforant pathway caused EPSPs in presynaptic neurons, either before or after postsynaptic action potentials (at 100 Hz) with variable time delays in between. This allowed for calculation of the STDP ratio—the “average peak amplitude of 40 consecutive EPSPs…divided by average peak of 20 consecutive EPSPs during baseline”. The role of DA1 was studied using DA1 receptor inhibitors or agonists, which bathed the granule cells. The STDP ratio was calculated in both scenarios implicating the role of DA1 and DA5 receptors in tLTP.
Major Results: The DA1 receptor inhibitor showed a negative STDP ratio, which was interpreted to be tLTD (timingdependent LTD) whereas DA1 receptor agonist had the opposite effect and led to tLTP. Furthermore, DA1 receptor activation when presynaptic neurons were stimulated 30 ms prior to postsynaptic neurons, the STDP ratio was above baseline, thus indicative of LTP. Yet, DA1 receptor inactivation for the same conditions causes tLTP but to a lesser extent. Furthermore, it is the only condition in which DA1 receptor inactivation can cause tLTP, otherwise tLTD is always observed. Moreover, when DA1 receptors are activated, tLTP can occur over a larger time interval—regardless of which neuron fires first, pre or postsynaptic. The marked difference in DA1 receptor activation vs. inactivation occurs within 10ms of either neuron firing first; inactivation resulting in lowest STDP ratio (greatest extent of tLTD). Furthermore, when the same procedure was conducted on 9 DA1 knockout mice and 9 DA5 knockout mice, seven of the nine in the former experienced tLTD whereas all nine experienced tLTD in the latter. Since DA1 and DA5 receptors cannot be accurately distinguished, it can only be concluded that both these receptors are important in tLTP, and that DA5 is more important. The importance of DA1 and DA5 on downstream effectors was tested using Kv4.2 knockout mice (lack IA potassium channel current) and it was observed that lack of this subunit and DA1 inactivation resulted in tLTP but to a lesser degree than solely DA1 receptor activation. Thus, DA1 probably has some role in turning off IA potassium channels, which facilitates tLTP. They showed the inactivation of the IA potassium channel might be linked to the MAPK-MEK cascade.
Conclusions: One of the major conclusions drawn in this paper is that dopamine is an important facilitator of timing-dependent LTP. The DA1 and DA5 receptors in the granule cells of the hippocampus are receptive and activated by dopamine, a neurotransmitter important in stimulus salience and rewards. The hippocampus gets input from the entorhinal cortex providing spatial information; thus, there can be a link between drug tolerances learned to be associated with the environment. Furthermore, LTP is a mechanism important in learning and memory, thus dopamine facilitates spatial learning and memory in the hippocampus, and increases the time frame for the potentiation to occur. A clinical implication this study has is the role of DA1 and DA5 receptors in memory-related neurodegenerative disorders, such as in Parkinson’s disease. Lastly, this paper provides insight to possible mechanisms of dopamine modulted tLTP in the hippocampus. Previously it was known that it is possible dopamine influences synaptic strength at the hippocampus, but now there is a better understand of the receptors involved and the possible mechanisms (blocking of potassium A-currents).
35
Yang, K., & Dani, J.A. (2014). Dopamine D1 and D5 Receptors Modulate Spike Timing-Dependent Plasticity at Medial Perforant Path to Dentate Granule Cell Synapses. J Neurosci, 34(48), 1588815897. doi:10.1523/JNEUROSCI.2400-14.2014
Summary by: Pranay Siriya
36 Summary of:
Conditioned same-sex partner preference in male rats is facilitated by oxytocin and dopamine: Effect on sexually dimorphic brain nuclei
Authors: Rodrigo Triana-Del Rio, Miriam B. Tecamachaltzi-Silvaran, Victor X. Diaz-Estrada, Deissy Herrera-Covarrubias, Aleph A. Corona-Morales, James G. Pfaus, Genaro A. Coria-Avila Background/Introduction:
This research focused on development of same-sex social and sexual preference in male rats. Researchers hypothesized that male cohabitation with rats injected with oxytocin, quinpirole (D2 agonist) or oxytocin and quinpirole could result in same-sex partner preference and that neither drugs nor cohabitation alone could yield equivalent preference. Particular importance was placed on dopamine receptor and oxytocin activity due to past studied enhancement effects on social attachment. Knowledge of social and sexual preference in relation to reduced sizes in the sexually dimorphic nucleus of the medial preoptic area (SDN-POA) as well as the supraoptic nucleus of the hypothalamus (SON) was also explored.
Materials and Methods:
Male rats were injected with saline, quinpirole, oxytocin, both oxytocin and quinpirole or nothing at all during either cohabitation with another male rat or alone. Injected and non-injected rats experienced three 24-hour trials of cohabitation with an almond-scented male (conditioned stimulus). Social and sexual preference was measured after the last trial, drug-free (to ensure outcomes were based solely on learning). Subjects later chose between their familiar scented male and an unscented, sexually receptive female. Preference was measured in terms of mounts, contacts, genital investigations, intromissions, ejaculations, non-contact erections and female-like solicitations. After the first experiment, subject brains were processed for Nissl dye (stained with cresyl violet) to aid in measuring SDNPOA and SON sizes. Digital photographs enabled software to calculate nuclei areas.
Major Results: Male rats that received quinpirole, oxytocin or no injection without cohabitation showed preference for females (higher visit incidence, more body contact, mounting, non-contact erections and olfactory investigations). Saline injections paired with male cohabitation also resulted in opposite-sex female partner preference. Rats who received quinpirole, oxytocin and quinpirole and oxytocin together, all with cohabitation, displayed same-sex preference for their male partner in terms of increased visit frequency and duration, shorter contact latency, as well as more body contact, olfactory investigations, female-like solicitations, and non-contact erections with the male partners. No significant findings emerged from SDN-POA and SON measurements, as same-sex preference was not seen to correspond with the sizes of these nuclei. Males who received quinpirole and oxytocin together with cohabitation, as well as those who received only oxytocin with and without cohabitation had the smallest SDN-POA areas. Rats who received quinpirole with cohabitation and both quinpirole and oxytocin with cohabitation had the largest SON areas. In essence, the most significant findings suggest that with increased dopamine receptor and oxytocin activity, conditioned same-sex social/sexual partner preference can develop when accompanied by cohabitation, but this did not correlate with decreases in SDN-POA and SON areas.
Conclusions: This research indicates that conditioned same-sex social and sexual partner preference in supposed formerly heterosexual male rats can develop when male cohabitation occurs along with injections of quinpirole, oxytocin, or both, showing that varying neurotransmitter dynamics can have significant consequences on the effects of conditioning. With cohabitation and enhanced oxytocin, quinpirole and both oxytocin and quinpirole, learning was maintained and expressed three days after training, without drugs, showing that stimulus-response training paired with specific heightened neurotransmitter activity can result in enhanced learning. This study also demonstrates the complexity of the interaction between context and neurotransmitters in sexual preference development.
37
Triana-Del Rio, R., Tecamachaltzi-Silvaran, M. B., Diaz-Estrada, V. X., Herrera-Covarrubias, D., Corona-Morales, A. A., Pfaus, J. G., & Coria Avila, G. A. (2015). Conditioned same-sex partner preference in male rats is facilitated by oxytocin and dopamine: Effect on sexually dimorphic brain nuclei, Behavioural Brain Research, 283.
Summary by: Alana Brown
38 Summary of:
Emotional learning selectively and retroactively strengthens memories for related events
Authors: Joesph E Dunsmoor, Vishnu P Murty, Lila Davachi & Elizabeth A. Phelps Background/Introduction:
Previous research suggest that after a memory has been encoded, it can be further strengthened at a future time by a novel event such as an increase in arousal or stress. It has been postulated that unstable memories are tagged for consolidation at a later time by long-term potentiation (LTP) via a synaptic tag and capture mechanism in the hippocampus. However, the specificity in the strengthening of previously encoded memories has not been clearly elucidated. Dunsmoor et al.’s study employs human participants to investigate the possibility of specifically enhancing a previously encoded weak episodic memory by presenting information related in context to the previously encoded memory in an amygdala dependent manner.
Materials and Methods:
In the pre-conditioning phase of the experiment, participants were shown 60 photographs using a stimulus presentation software and asked to classify them into the basic categories of tools or animals. Then participants were put through a fear conditioning trial where an uncomfortable shock is paired with certain photograph presentations (either tools or animals) that the participants were not previously aware of. Following that, in a post-conditioning phase, participants were again shown 60 photographs and asked to classify them similarly to the pre-conditioning phase. In a second part of the experiment, subjects were given a recognition task using the originally presented photographs either immediately after the post-conditioning phase or after a 6 or 24 hr delay.
Major Results: A significant result was found in the 24 hour delay condition. Specifically, memories that were conceptually related to the conditioned stimulus from the pre-conditioning photographs were enhanced but not other memories encoded at the same time. This suggests that in the pre-conditioning phase, weak memories formed of the photographs presented, later, if emotionally relevant information is presented, it will retroactively strengthens memories of previously encoded photographs that are related to the emotional conditioning. This retroactive enhancement of memory did not occur in the 6 hr delay period condition or the immediately after post-conditioning phase, suggesting that this enhancement of previously encoded memories via fear conditioning requires some time for consolidation. Dunsmoor et al. suggests that during the preconditioning task, encoding occurred while leaving a tag in the hippocampus, fear conditioning via the amygdala modulates the tag in the hippocampus and can enhance past memories related in context to the conditioning stimulus.
Conclusions: This study suggests that previously encoded weak memories can be strengthened by a related future experience. The strengthened past memory is conceptually relevant to the future stimulus and other memories coded at the same time are not enhanced. These findings may contribute to the field of neuroscience globally: if emotional events can selectively enhance memories of experiences that we’ve had in the past, this mechanism may be related to intrusive memories and overgeneralizations of fear memories that may in turn lead to stress related neurological disorders. This is a field that requires future empirical research.
39
Joesph E Dunsmoor, Vishnu P Murty, Lila Davachi & Elizabeth A. Phelps. “Emotional learning selectively and retroactively strengthens memories for related events� Nature (2015) doi: 10.1038/ nn.14106 Published online 21 January 2015.
Summary by: Chuqi Sandy Wang
40 Summary of:
Effects of Resveratrol on Memory Performance, Hippocampal Functional Connectivity, and Glucose Metabolism in Healthy Older Adults
Authors: A. Veronica Witte, Lucia Kerti, Daniel S. Margulies, and Agnes Floel Background/Introduction:
Resveratrol is a plant-based polyphenol often used as a calorie restricted mimetic which are thought to slow the process of neurodegeneration. The compound is found in foods such as red grapes therefore found in wine, as well as peanuts and Japanese knotweed. The effects of resveratrol have been tested on many animal models with the following conclusions: helps reduce oxidative damage, reduce proinflammatory molecules, reduce blood pressure (by a means of improved vascularity) and potentially alters gene expression. In mouse with AD, resveratrol has been noted to deter the learning and cognitive deficits that is associated with the disorder. However, aside from short-term studies on inflammation and glucose digestion, the effects of resveratrol supplementation have not been investigated with regards to long term effects on memory and learning.
Materials and Methods:
Initial screening of individuals via telephone interviews. Overweight (but not obese) participants were targeted. Baseline visits consisted of psychological and medical examinations using standardized tests such as the Mini Mental State Examination and Beck’s Depression Inventory. There were 23 subjects in both the control and treatment group that were randomly chosen—the control subjects were matched with treatment subjects according to age, sex, and body mass index. Treatment group was given two 13-week stocks of resveratrol capsules, amounting to 26 weeks of supplementing with resveratrol 4 times a day. Control group was given two 13-weeks supply of indistinguishable placebo capsules. Memory assessments (via the Auditory Learning Verbal Test), neuroimaging (using MRI and diffusion tensor imaging) anthropogenic data and blood content were evaluated before and after the intervention trial.
Major Results: The group with resveratrol supplementation was able to significantly improve their memory retention scores from baseline testing. Increases in functional connectivity within the hippocampus to various brain regions were observed. Improvements in memory retention coincided with increases in functional connectivity in the medial pre frontal cortex which also happened to negatively correlate with decreases in HbA1c. Leptin levels increased for the resveratrol treatment group whilst they decreased for the placebo group.
Conclusions: Resveratrol has the ability to enhance functional connectivity in the hippocampus demonstrating it’s beneficial effects on memory and learning as well as it’s ability to lower glucose markers in the blood. It has been known that elevated glucose levels have harmful effects on the brain thus further research could indicate whether it was the more efficient glucose metabolism that contributed to the cognitive improvements. This study suggest resveratrol as a potential use to alleviate the effects of age-related brain deterioration.
41
Witte, V., Kerti, L., Margulies, D., & Floel, A. (2014). Effects of Resveratrol on Memory Performance, Hippocampal Functional Connectivity, and Glucose Metabolism in Healthy Older Adults. The Journal of Neuroscience, 34(23), 7862-7870.
Summary by: Vanessa Bracaglia
42 Summary of:
Deletion of a-neurexin II results in autism-related behaviours in mice.
Authors: J Dachtler, J Glasper, RN Cohen, JL Ivorra, DJ Swiffen, AJ Jackson, MK Harte, RJ Rodgers and SJ Clapcote Background/Introduction:
Autism is a widely known cognitive disorder that is characterized by the lack of social engagement, communication and language progression, possibly due to various biological causal factors. Recently, it was found that two unrelated autism individuals carried mutations on exon 1 of the NRXN2 gene that synthesizes the synaptic adhesion protein a-neurexin II (Nrxn2a). Neurexins are responsible for connecting neurons, constituting various effects. They can bind molecules for pre-synaptic release or bind neuroligins of the post-synaptic neuron to alter NMDA, AMPA or GABAergic receptors, depicting inhibitory or excitatory properties of the cell. It was hypothesized that Nrxn2a knockout (Nrxn2a KO) mice would result in autismassociated behaviour, suggesting synaptic dysfunction as a possible cause for this disorder. For experimental purposes, only Nrxn2a expression was eliminated by mutation on the first exon of the NRXN2 gene, and the B-neurexin II was still allowed expression.
Materials and Methods:
Three different types of mice strains (Nrxn 1 heterozygous KO, Nrxn2 homozygous KO and Nrxn3 wild-type) were continuously outbred to the C57BL/6NCrl strain to achieve Nrxn2a KO heterozygotes that are wild-type (WT) at Nrxn1 and Nrxn3. This F1 generation was then intercrossed to achieve WT or Nrxn2a KO progeny. Mice were allowed to develop past 8 weeks of age before being used for experimental behavioural testing. Such tests included the open field test, emergence test, social interaction testing and novel conspecific exploration. Quantitative RT- PCR analysis and western blot analysis were done afterwards to quantify noticeable differences from various genes expressed in the frontal cortex and hippocampus that interact with a-neurexin either at the pre-synaptic/ post-synaptic level.
Major Results:
Nrxn2a KO mice were placed in a three-chambered assay to test for sociability, with a choice of interacting with a novel mouse or an empty wire cage. The Nrxn2a KO mice showed much less interest in terms of engagement with the unfamiliar mouse, suggesting social deficits, which is a symptom of autism. Moreover, upon introduction of a novel mouse in addition to the first stranger mouse, the Nrxn2a KO had failed to preference to either. The WT mice realized they have interacted with the old stranger mice and preferred the new one. This suggests that Nrxn2a KO mice may have reduced social memory of what they have observed. To determine anxiety levels in mice, the open field test allowed mice to explore a luminous open arena. Graphs showed that Nrxn2a KO mice displayed more thigmotaxis (contact with the wall) than wild-type mice, and spent elongated periods in the peripheral zone. In the emergence test, Nrxn2A KO mice needed a lengthier amount of time to emerge from the small enclosure to luminous open arena, suggesting higher aversion to a new stimulus. These last two tests measured state anxiety in mice, which is a temporary emotional response as a reflex to a danger signal. The Nrxn2a KO mice viewed the open bright space as more of a threat than the WT companions did, feeling more anxious to approach the different environment. Levels of aversion can be correlated with anxiety, but the causality has not yet been determined. Western blotting showed that Munc18-1, a protein engaging with syntaxin-1 during presynaptic vesicular release, was drastically reduced in the Nrxn2a KO hippocampus. This altered pathway is one of many, and may have led to autisticrelated behaviours.
Conclusions: Only some core symptoms of autism such as decreased sociability with conspecifics and avoidance or latency to explore were shown, while other symptoms were not displayed/tested for. The procedures during this experiment were able to measure social novelty interactions and brief anxiety levels. However other symptoms such as cognitive deficiency, repetitive behaviours or language impairments were not observed/ could not be measured. Such an experiment done with Nrxn2a KO mice gives insight into further exploration for autism, a rather complex genetic neurodevelopmental disorder that may be linked to various genes. Deciphering the biological basis of autism by its genetic and perhaps, non-genetic factors would be of great contribution towards those who have it, especially in school settings.
43
Dachtler, J. et al. (2014). Deletion of a-neurexin II results in autism-related behaviours in mice. Translational Psychiatry, 4(484), 1-8. Retrieved from http://dx. doi:10.1038/tp.2014.123
Summary by: Vivian Liu
44 Summary of:
Alcohol consumption, drinking patterns, and cognitive function in older Eastern European adults
Authors: Pia Horvat, Marcus Richards, Ruzena Kubinova, Andrzej Pajak, Sofia Malyutina, Sergey Shishkin, Hynek Pikhart, Anne Peasey, M.G. Marmot, Archana Singh-Manoux, Martin Bobak Background/Introduction:
Individuals with dementia show decreased cognitive function, and have been observed to show predictors in their cognition prior to actually having dementia. Observational studies have shown that people who drink moderately not only display increased cognitive test scores, but also decrease the risk of having dementia when older. Although some would argue that alcohol decreases overall cognitive function, a decrease is only observed when individuals engage in binge drinking. No studies have been conducted to show if moderate alcohol consumption actually causes increases in cognitive function, and decreases in risk of dementia.
Materials and Methods:
Participants, aged 45 – 69, from multiple countries where randomly chosen to take part in this study after taking part in the Health, Alcohol and Psychosocial Factors in Easter Europe (HAPIEE) study, where they had to self-report their alcohol consumption (amount and frequency), health, and take part in a physical examination (2002-2005). They later had to take cognitive tests. Nurses were trained in administering the test while scores were later assessed by scientists. In alcohol consumption a scale was developed and participants were placed on a discrete spectrum of non-drinkers to problem drinkers. The test scores were compared with drinking habits. The same individuals were later re-examined and tested for the same variables as originally tested (2006-2008). Males and females where studied separately.
Major Results: Males tend to compose a larger proportion of the binge and problem drinking populations. Of the individuals studied 58% remained in the same categorization for alcohol consumption amounts, and 44% were in the same category for alcohol consumption frequency. In men alcohol consumption did not significantly correlate with cognitive scores when confounders were considered, but lower cognitive scores in non-drinkers were observed in comparison to baseline scores (moderate- continuous drinkers). For women non-drinkers had lower cognitive test scores. Moderate drinking scores were better than those who drank less. For changes in alcohol consumption men who stopped drinking scored significantly lower than those who continued.
Conclusions: Quantity and frequency of drinking in men did not show any significant data, but women who were moderate drinkers showed increases in cognition. No significant data was observed to show an overall decrease in heavy drinkers. In the scope of this study better cognition is observed in those who continue to drink in comparison to those who either stop or didn’t drink in the first place.
45
This paper claims that those who drink moderately and continue to drink alcohol steadily have increased cognitive function. Each graph displays a different cognitive test for each of the specified drinking conditions. These results are the standardized cognitive scores found in 6,608 men. Those who quit drinking and those who do not drink at all have the lowest scores. Stable drinkers are the baseline Reversed scores are used for all graphs.
Horvat P., Richards M., Kubinova R., et al. “Alcohol consumption, drinking patterns, and cognitive function in older Eastern European adults� 2014. Neurology, 84, 287-295
Summary by: Bernie Longange
46 Summary of:
The artist emerges: Visual art learning alters neural structure and function
Authors: Schlegel, A., Alexander, P., Fogelson, S. V, Li, X., Lu, Z., Kohler, P. J., Riley, E., Tse, P. U., Meng, M. Background/Introduction:
To disambiguate ambiguous stimuli, the visual modality performs Bayesian inferences from previous subjective incidences, allowing for optical illusions and subjective experiences. However, representational artists must overcome these processes to produce works that are true to the external image, and translate their thematic perspectives to a medium, be it a painting or drawing. Once perceived, an artist has improved skills in honing the dorsal stream more associated with spatial information and motor abilities, enabling for motor actions to capture perceived scenarios in painting/drawing. In this work, the neural correlates to these processes, discounting of Bayesian inferences, original cognition, and higher activation of the dorsal processing stream were examined to investigate processes within cultivating representational drawing/painting skills.
Materials and Methods:
17 undergraduates enrolled in an 11-week introductory course about observational drawing/painting (experimental) and 18 undergraduates in an intensive program requiring problem-solving for fixed solutions, as opposed to open ones required of creativity, (control) were randomly selected. Both groups did not discernibly differ in gender, handedness, age (18-22 years), and vision, but these parameters were not tightly controlled due to the nature of the selection process. To measure progress in artistic abilities, 30-minute Torrence Tests of Creative Thinking Figural Form A (TTCT) were administered before and after the course. Furthermore, 4 monthly fMRI and DTI sessions coupled to 2 behavioral tasks, one of which required perceptual abilities and another artistic creativity, were administered to measure changes in brain activity and changes in abilities between the two groups.
Major Results:
TTCT indicated significant improvement of divergent thought process, system/process modeling, and depiction of intricate, rich, salient imagery within individuals of the experimental group compared to control. Of these, skills associated with modeling themes through different paradigms, such as storytelling, correlated significantly with decreased fractional anisotropy of white matter in prefrontal regions from DTI scans. Interestingly, perceptual acuity neither improved nor diminished in the experimental group. From the monthly DTI and fMRI sessions, the experimental group exhibited improvement in creative cognition and motor skills for gesture drawing. To expound, statistical analyses indicated no correlation between increased creative cognition with increased skill in fine motor movements. Lastly, throughout the duration of the study, the initially absent differences in brain activity related to the monthly artistic tasks indicated increasing neural activity in the right anterior lobe of the cerebellum in the experimental group, whilst overall neural activity levels did not change significantly compared to control. Upon analyses, this differential neural activity in the right cerebellum was positively correlated with increased technical skills in complex, motor control of the upper limbs for drawing/painting.
Conclusions: Neural circuitry involved in executing a creative action has been shown to change with gaining creative skills of representational art. The right anterior cerebellum is correlated to proprioceptive feedback and is found to project to hand and arm areas of the left primary motor cortex and eye and hand movements. Increased activation of this area is intuitive with increased technical skills in fine motor movements associated with observational drawing/painting. However, the decreased activation in white matter of frontal lobes correlated to increased creative skills is not well understood.
47
Schlegel, A., Alexander, P., Fogelson, S. V, Li, X., Lu, Z., Kohler, P. J., … Meng, M. (2015). The artist emerges: Visual art learning alters neural structure and function. NeuroImage, 105, 440–451.
Summary by: Dong-Eun (Raquel) Lee
48 Summary of:
Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains
Authors: Renata Viana Abreu, Eliane Moretto Silva-Oliveria, Marcio Flavio Dutra Moraes, Grace Schenatto Pereira and Tasso Moraes-Santos Background/Introduction:
Despite the fact that the brain intakes approximately a fifth of the body’s total oxygen supply, it receives relatively low levels of endogenous antioxidants as compared to other tissues. These two factors in junction allow for increasing numbers of reactive oxygen species (ROS) to take up residence among neurons. This ultimately leads to the gradual accumulation of oxidative damage with age, making the brain highly susceptible to deterioration of cells and therefore decreases in cognitive performance. Coffee contains numerous substances and many of their biological effects have been examined independently. However, little is known about coffee’s overall effects on the body as interactions between components can cause fundamentally different outcomes. As a result, this study seeks to understand the consequences of chronic coffee and caffeine consumption on the endogenous antioxidant system of the brain and in turn, their effects on cognitive performance. On the basis of previous studies, the authors hypothesized that coffee and caffeine would act as a protective food for the brain and thereby slow cognitive decline.
Materials and Methods:
For the purpose of this study, weaned newborn rats were randomly selected and divided into five groups, each subjected to different diets: a control diet, a 3% brewed coffee diet, a 6% brewed coffee diet, a 0.04% caffeine diet and a 0.08% caffeine diet. When the rats were 90 days of age, they partook in two behavior tasks: open field task (to observe their exploratory behavior) and novel object preference task (to observe their short-term and longterm memory). At 100 days of life, the rats were decapitated and their brains were tested for indicators of oxidative damage.
Major Results: It was found that coffee and caffeine supplemented diets had no effect on how much the rats ate, their overall weight gain and their exploratory behavior (it did not increase nor decrease the number of crossings and rearings in the open field test). Additionally, rats in all conditions displayed habituation (indicating normal non-associative memory processes) as exploration was decreased on the second day of testing. Additionally, neither coffee nor caffeine had an effect during the novel performance task administered 90 minutes after, but coffee/caffeine conditions did have better discrimination during the test given 24 hours after, indicating an enrichment in long-term memory. Analysis of brain matter revealed enhancement changes to the antioxidant system, such as increased concentration of potent endogenous antioxidants (mainly glutathione) and increased activity of antioxidant enzymes (glutathione reductase and superoxide dismutase). These alterations are believed to be the fundamental basis for reductions in cognitive decline as brain matter is protected from oxidation.
Conclusions: The most essential finding to be noted from this study is that moderate doses of chronic coffee or caffeine consumption has beneficial effects in reference to cognitive functioning through the pathways of antioxidants, without causing changes in sensory and motor functioning. This study has major implications for the field of neuroscience as caffeine has been shown to act on the central nervous system by blocking certain types of adenosine receptors to negatively impact the production of free radicals in the brain, ultimately acting as a safeguard. Perhaps these findings will lead to discoveries of other preventative measures for neurodegenerative diseases.
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Renata Viana Abreu, Eliane Moretto Silva-Oliveria, Marcio Flavio Dutra Moraes, Grace Schenatto Pereira and Tasso Moraes-Santos. “Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains� Elsvier (2011) doi:10.1016/j.pbb.2011.06.010 Published online 15 June 2011
Summary by: Vonny Pui Ying Wong
50 Summary of:
LTP requires a reserve pool of glutamate receptors independent of subunit type
Authors: Adam J. Granger, Yun Shi, Wei Lu, Manuel Cerpas, and Roger A. Nicoll Background/Introduction:
Long – term potentiation only occurs when there is an increase in AMPA receptors (AMPAR), which strengthens the synapses between neurons when forming new memories in the hippocampus. In the CA1 pyramidal neurons of the hippocampus, they contain mostly GluA1/A2, but it also contains GluA2/A3 receptors. In a research finding they found that LTP will not be generated if GluA1/A2 receptor are not trafficked to the synapse by the C-tail of GluA1, nor if GluA1 is knocked out. In this article they wanted to see if the C-tail of GluA1 has any effect on LTP formation
Materials and Methods:
In this article several known methods were used to do this experiment. One of them is Electrophysiology, where they did voltage – clamp recording of the CA1 pyramidal neurons in either acute hippocampal slice or organotypic slice culture. The second method that was used is the whole-cell synaptic recording, in this method they were recording the response of the whole cell when they induced LTP at 2 Hz for 90 sec. Lastly, they used the Outside-out patches method, where they measured the current of glutamate receptor or Kainate receptor, when the induced HEPES-aCSF (contains many different molecules such as NaCl)
Major Results: The researchers wanted to see what role the GluA1 C-tail has on the trafficking of AMPAR. They did that by looking first at the surface expression of GluA subtype, what they found was, when the C-tail was truncated up to the amino acid 824 (GluA1∆824) or when removed membrane proximal region (GluA∆MPR), there was still surface expression of AMPAR. However, when truncated all of the C-tail there was less surface expression. Later they looked at the basal synaptic transmission and they found that even though GluA1 C-tail was truncated the AMPAR was able to be transmitted to the synapse. Even though the researchers found that the truncated C-tail has no effect on the AMPAR trafficking, but they still wondered if it has an affect on LTP. What they found was that no matter how much of the C-tail is truncated whether small pierces or the whole C-tail LTP was still expressed, but not to the extent as the control. The researchers then wondered what will happen to LTP if the synapse expressed another family type of glutamate receptor called KAR (GluK1) instead of the AMPAR, and they found that LTP was generated with the GluK1 receptor.
Conclusions: Therefore two major findings were concluded, first of all being that whether the C-tail is present or not in the GluA1subunit had no affect on LTP production. It was also found that even if GluA1 subunit is not present, there are other glutamate receptors such as GluK1 that can undergo normal levels of LTP. So regardless of the glutamate subtype, LTP will be generated as long as there is a large amount of receptors on the membrane surface.
51
Granger.A.J, Shi.Y, Lu.W, Cerpas.M, Nicoll. R.A. (2013). LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature, 493(7433), 495-500
Summary by: Ola Taji
52 Summary of:
Oxytocin improves mentalizing - Pronounced effects for individuals with attenuated ability to empathize.
Authors: Melanie Feeser, Yan Fan, Anne Weigand, Adam Hahn, Matti Gärtner, Heinz Böker, Simone Grimm, Malek Bajbouj Background/Introduction: Individuals with high empathy are better equipped for inferring mental and emotional states of other individuals, also known as “mentalizing”. Empathy and mentalizing activities contribute to an understanding of interpersonal interactions, social norms, different beliefs and different perspectives. Past literature displays that the neuromodulator Oxytocin (OXT) is vital in the modulation of social-cognitive functions, promoting social memory, decreasing fear and anxiety, and stimulating social trust and approach. While empathy and mentalizing activities rely on different neural areas and have different ontogenetic trajectories, both are shown to be privy to OXT stimulation. The neuropeptide has shown to enhance empathic accuracy in those who are less socially proficient, by enhancing attentional selectivity towards relevant social stimuli. It is also able to elevate mentalizing abilities as shown by increased accuracy on the Reading the Mind in the Eye Test (RMET). Hypothesis: OXT-induced results would be more distinct for difficult items compared to easy items in mentalizing and that OXT administration would enhance mentalizing abilities in individuals with low empathy as opposed to high empathy.
Materials and Methods:
71 male subjects were subjected to a double-blind, 2 (difficult vs easy items) x 2 (assigned randomly to either an oxytocin (OXT) or the placebo condition) experimental design. Control variables: to ensure group matching, the Mehrfach Wortschatz Intelligenztest, NEO Five-Factor Inventory were completed. The Multidimensional Mood State Questionnaire was completed before OXT administration and after the task to asses mood, wakefulness and calmness. Participants self-administered a dose of 24 international units (IU) nasally 45 minutes prior to the Reading the Mind in the Eye Test (RMET). This test sequentially presents 36 photographs of complex mental states after a fixation cross (that lasts for 1000 ms). Participants are required to infer internal states in others from a selection of four labels presented as quickly and accurately as possible by selecting a correspondingly labeled key on a standard computer keyboard. Correct answers were computed. Empathy, measured using the Empathy Quotient (EQ) which is a 60-item self-report questionnaire with a 4-point Likert scale, was later administered to estimate empathy’s possible moderating effects of OXT.
Major Results: Results showed that there were higher rates of accuracy associated with the OXT group when compared to the placebo group in difficult items on the RMET. In contrast, there was a lack of difference between these two groups on the easy items of the task. Regression analysis confirmed the hypothesis that empathy moderates the results of mentalizing accuracy; participants characterized to be low in empathy (with an EQ one standard deviation below the mean) showed an increase in accuracy with OXT administration as compared to receiving a placebo. On the other hand, there were no differences among the OXT administration and the placebo administration for individuals with an EQ of one standard deviation above the mean (high empathy participants).
Conclusions:
Empathy has a moderating impact on the processing of relevant social information, and individuals who are less receptive to these cues benefit from oxytocin. As oxytocin receptors are found in the amygdala, striatum, hippocampus, nucleus accumbens and midbrain, the presence of this neuropeptide will enhance activity in these regions, which have been long implicated with social bonding in neuroscience. Specifically to the study, oxytocin can incur a variety of prosocial benefits that include enhancing activation in areas associated with empathy (limbic areas) and mentalizing (by establishing connections between the amyglada and the prefrontal cortex).
53
Feeser, M., Fan, Y., Weigand, A., Hahn, A., Gärtner, M., Böker, H., ... & Bajbouj, M. (2015). Oxytocin improves mentalizing–Pronounced effects for individuals with attenuated ability to empathize. Psychoneuroendocrinology. 53, 223- 232.
Summary by: Ashima Agarwal
54 Summary of:
The Involvement of ERK/CREB/Bcl-2 in depression-like behavior in prenatally stressed offspring rats
Authors: Lixia Guan, Ning Jia, Xiaoyan Zhao, Xiaohua Zhang, Guokui Tang, Li Yang, Hongli Sun, Dan Wang, Qian Su, Qian Song, Dongge Cai, Qing Cai, Hui Li, Zhongliang Zhu Background/Introduction: This article studies the expression levels of CREB/ERK/Bcl-2 in rat brains and their immobility time through a swimming test after experiencing prenatal stress (PS). These levels were measured in the hippocampus, prefrontal cortex and striatum. The prenatal stress that was given was social isolation. The motive of the article is to understand the role of the ERK-CREB pathway and its changes that occur after PS exposure and how that reflects in a swimming test. These proteins were studied due to their important functions. CREB is involved in neuronal plasticity and regulating transcription of genes that are associated with stress response. ERK responds to extracellular stimuli by regulating gene expression, cellular growth, synthesis of new proteins in order to protect cells. Bcl-2 is regulated by CREB and is an anti-apoptotic factor. It is involved in regulating cell death, cell plasticity and growth of new neurons. ERK is activated by NMDA receptor excitation. MK-801 is a drug used in the study as it is been demonstrated to be affiliated with antidepressant properties. It is a non-competitive antagonist of NMDA receptor therefore blocks glutamate from binding to this receptor. Saline was used alongside to MK-801. The results showed PS rats showed an increased immobility time. There was lower expression of ERK2 mRNA, CREB mRNA, Bcl-2 mRNA in the hippocampus, prefrontal cortex of PS rats with saline compared to control and MK-801 (modified the expression). The CREB levels were fixed by MK-801 as the levels of CREB were similar to that of the control even after experiencing stress prenatally. There was no significant difference seen in expression of mRNA expression among the three proteins in the striatum. These changes were all reflected in the increased immobility timing correlated to depressive behaviour.
Method/Experiment:
The method that was utilized consisted of mating sexually active male rats to females over night within a room temperature of 22-26 degrees, humidity 60% and with a 12 hour day/night cycle (control group). Each pregnant rat was than separated into a control group, PS-Saline group, and PS-MK-801 group. The control group was not given any stress, but the other two groups were socially isolated 3 times a day for 45 minutes. The rats were given either saline or MK-801 on days 14-21 of pregnancy. The researchers than did a forced swimming test (FST) on the offspring to see the effects of PS on them. Also, RNA was extracted from the three brain areas (hippocampus, striatum and prefrontal cortex) and went through an RT-PCR to examine the intensity of ERK, CREB, and Bcl-2 mRNA expression in each.
55
Guan L., Jia X., Zhao X., Zhang X., et al. (2013). The involvement of ERK/CREB/Bcl-2 in depressionlike behaviour in prenatally stressed offspring rats. Journal of Brain Research Bulletin, 99, 1-8.
Summary by: Ariba Alam
56 Summary of:
Aerobic exercise is the crititical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice
Authors: Martina L. Mustroph, Shi Chen, Shalin C. Desai, Edward B. Cay, Erin K. DeYoung, and Justin S. Rhodes Background/Introduction: The role of sensory and motor enrichment on adult hippocampal neurogenesis has been the target of many studies. Previous research on mice has shown that environmental enrichment increases the level of BDNF gene expression in the dentate gyrus; the increased neurotrophic levels are correlated to the enhanced adult hippocampal neurogenesis and cognitive benefits seen in these animals. Separation of the sensory and motor component of environmental enrichment by later studies showed that presence of motor stimuli alone is responsible and sufficient for neurogenic and pro-cognitive benefits in mice. With the hypothesis that novel and broad sensory stimuli can increase neurogenesis, this study aims to test the effects of different sensory modalities including tactile, visual, dietary, auditory, and vestibular in an environment enriched group and compare the results to the effects of motor stimuli on adult hippocampal neurogenesis and cognitive abilities in mice.
Materials and Methods:
32 male C57BL/67 mice of 5 weeks age were housed singly in either of the 4 housing conditions: Running wheel present (RUN), Novel toys and diet enrichment present (EE), Running wheel and Enrichment present (RUN+EE), and Standard caging (Control). Mice were videotaped and the time spent on the running wheel versus engaged with sensory stimuli was recorded. Mice were injected with BrdU (bromodeoxyuridine) during the first 10 days of the experiment to label the dividing cells. Spatial learning and memory was tested on a water maze during the last 5 days of the experiment following which the animal was euthanized. Coronal hippocampal slices were collected and immunohistochemistry protocols were followed to co-label new neurons with BrdU and NeuN (neuronal nuclear marker). Cells count and imaging were done using a Leica SP2 laser scanning confocal microscope.
Major Results: From the video recordings, it was shown that mice in the RUN group ran a greater distance than mice in RUN+EE, EE, and Control respectively. Performance on water maze was assessed by measuring the path length to find the hidden platform; at the end of the 5 days learning period animals within all groups showed significant decrease in path length, however, mice in the RUN group the path length decreased by 75% in the second day of trial. There was an increase in the volume of granule layer in RUN and EE group, the effect was additive and the largest granule layer was seen in mice of RUN+EE group. Mice in RUN group had the greatest number of BrdU and NeuN co-labeled cells per granule layer volume which was followed by mice in the RUN+EE, EE, and Control group respectively.
Conclusions:
Through segregating and modulating the novelty and modality of different sensory and motor stimuli, this study aimed to find distinct neurogenic and cognitive benefits that could be implemented in treatments for different neurodegenerative and cognitive deficiency disorders. With no significant difference in the levels of neurogenesis between RUN and RUN+EE and the insignificant increase in neurogenesis in EE group compared to the Control, it was shown that sensory stimulations with toys and treats do not have neurogenic benefits. Moreover, lack of enhanced spatial learning in mice in EE group compared to RUN group showed that sensory enrichments of different modalities do not confer cognitive benefits. It was concluded that exercise can enhance the survival of new neurons in the dentate gyrus of mice which is the main drive for pro-cognition and neurogenic benefits.
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Mustroph, M. L., Chen, S., Desai, S. C., Cay, E. B., DeYoung, E. K., & Rhodes, j. S. (2012, September 06). Aerobic exercise is the crititical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience, 219, 62-71.
Mustroph, M. L., Chen, S., Desai, S. C., Cay, E. B., DeYoung, E. K., & Rhodes, j. S. (2012, September 06). Aerobic exercise is the crititical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience, 219, 62-71.
Summary by: Samin Alikhanzadeh
58 Summary of:
KIBRA Polymorphism Is Associated with Individual Differences in Hippocampal Subregions: Evidence From Anatomical Segmentation Using High-Resoultion MRI
Authors: Palombo, D. J., Amaral, R. S., Olsen, R. K., Müller, D. J., Todd, R. M., Anderson, A. K., & Levine, B. Background/Introduction: The KIBRA gene is found throughout the brain and kidney and exists in higher concentrations in the Cornu Ammonis and Dentate Gyrus of the Hippocampus. The gene has been shown to be associated to episodic memory performance. A single nucleotide polymorphism in this gene from cytosine to thymine has been linked to increased performance on episodic memory tasks, especially those involving consolidation and delayed retention. Since the Hippocampus has a strong role in episodic memory, the study theorizes that people who are carriers of the T-allele will have volumetric differences compared to non-carriers. Along with a larger global volume of the hippocampus, regional volumetric enlargements in the Cornu Ammonis and Dentate Gyrus are expected.
Materials and Methods:
32 participants were recruited from a larger study involving genetics and memory. A saliva genotype was preformed for all participants testing for SNP in genes previously implicated in episodic memory (BDNF, KIBRA, APoE, COMT). These results were then used to match participants for all genes and create 2 groups consisting of 18 T-allele carriers and 14 non-carriers. High resolution T2 weighted images taken perpendicular to the long axis of the hippocampus were analyzed and compared using ROI segmentation of the Cornu Ammonis (CA), Dentate Gyrus(DG)/CA, subiculum, medial temporal lobe (further divided into perirhinal cortex. Entorhinal cortex, parahippocampal cortex) and head of tail of hippocampus by single rater blind to group status.
Major Results: Three-mixed design ANCOVAs were used to test for significant differences in whole hippocampus, segmented hippocampus and segmented MTL cortices of carriers and noncarriers of the t-allele SNP. In line with the prediction of the hypothesis, T-carriers were found to have larger overall hippocampal volume than those of non-carriers. T-carriers were also found to have significantly larger segmented hippocampi than no carriers. Using post-hoc analysis the CA and DG/CA were found to be significantly larger in T-carriers and no significant enlargement was found in the subiculum; in this region non-carriers were found to have relatively larger volumes. There were no significant group interactions and KIBRA was found to have no significant effect on MTL structures. Using pot hoc analysis T-carriers were found to have a small but significant increase in volume in the parahippocampal cortex indicating some effect of KIBRA here.
Conclusions:
The KIBRA T-allele SNP was found to be associated with increased volume of the hippocampus, specifically in the CA and DG. If we can identify KIBRA’s effects on memory we may be able to apply this knowledge to develop clinical treatments to help populations in which these areas and functions are targeted like those with Alzheimer’s Disease.
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References: 1) http://www.integragen.com/32-the-genetics-ofautism.htm 2) http://www.thomaskoenig.ch/Lester/Files/ SPAMs_Hippocampus.jpg 3) http://www.jneurosci.org.myaccess.library
Palombo, D. J., Amaral, R. S., Olsen, R. K., Müller, D. J., Todd, R. M., Anderson, A. K., & Levine, B. (2013). KIBRA polymorphism is associated with individual differences in hippocampal subregions: evidence from anatomical segmentation using high-resolution MRI.The Journal of neuroscience : the official journal of the Society for Neuroscience, 33(32), 13088–93. doi:10.1523/ JNEUROSCI.1406-13.2013
Summary by: Megan Cabral
60 Summary of:
Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors
Authors: Dian-Shi Wang, Agnieszka A. Zurek, Irene Lecker, Jieying Yu, Armen M. Abramian, Sinziana Avramescu, Paul A. Davies, Stephen J. Moss, Wei-Yang Lu, Beverley A. Orser Background/Introduction: Acute systemic inflammation caused by infection, autoimmune diseases, and traumatic brain injury can lead to memory loss. Some neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, are known to occur following inflammation. The release of various cytokines during inflammation, primarily interleukin-1β (IL-1β), is correlated with cognitive deficits. It is impractical to inhibit membrane-bound type 1 IL-1 receptors as that would delay wound healing and interfere with normal memory processes. Therefore, it is necessary to identify a downstream mediator to effectively treat inflammation-induced memory deficits. Current studies show that activation of the α5GABAA receptor blocks memory and that reduction of α5GABAA activity improves certain memory-tasks. It is hypothesized that α5GABAA receptors are also involved in inflammationinduced memory deficits.
Materials and Methods:
The experiments were performed on wild-type (WT) and α5GABAA knockout (Gabra5-/-) mice that were 3- to 4-months of age. Experiments began three hours after injection of IL-1β (1 μg kg-1) or bacterial endotoxin lipopolysaccharide (LPS) (125 μg kg-1) to ensure peak plasma levels of cytokines. Pavlovian fear conditioning using a tone (3,600 Hz tone, 20 seconds) with an electric foot shock (2 seconds, 0.5 mA) was used to study memory performance. Hippocampal slices, cell cultures, and neuron-microglia co-cultures were used for whole-cell voltage clamp recordings. LTP was induced via theta burst stimulation (10 stimulus train at 5 Hz, each train had four pulses at 100 Hz). Tonic GABAergic currents were recorded at -60 mV, using 0.5 μM or 5 μM GABA for cultured or sliced neurons respectively. Cell surface biotinylation assay was used to determine expression of α1, α2, or α5 subunits from the GABAA receptor.
Major Results: Inflammation via IL-1β or LPS resulted in impaired contextual fear memory in WT mice, as indicated by lower freezing scores. Gabra5-/- mice were not affected. This suggests that the α5GABAA receptors are necessary for impaired contextual fear memory. It was found that inhibition of α5GABAA receptors using L-655,708 could reverse the effects induced by IL-1β in WT mice. Using hippocampal slices, it was determined that LPSmediated inflammation resulted in a smaller increase in LTP in WT mice. This decrease was not seen in Gabra5-/- mice. The reduction in LTP was eliminated after application of L-655,708. In addition, it was found that mice treated with IL-1β had a 2-fold increase in tonic inhibitory current density in CA1 pyramidal neurons. In cultured neurons, it was determined that the amplitude of the tonic current produced by α5GABAA receptors was dependent on the concentration of the IL-1β treatment. Application of other cytokines, such as TNF-α and IL-6, did not produce a current. Introduction of L-655,708 into the IL-1β-treated WT neuron inhibited the tonic current. WT hippocampal slices treated with IL-1β showed greater expression of α5GABAA receptors. It was determined that inhibition of p38 mitogen-activated protein kinase via SB203,580 blocked the IL-1β-induced tonic current in WT neurons by reducing α5GABAA receptor expression on the membrane surface.
Conclusions:
The results from this experiment show that inflammation can cause memory deficits via an increase in tonic currents produced by α5GABAA receptors. Although no treatments currently exist, the use of α5GABAA receptor inverse agonists, rather than antagonists, for can be used in future experiments to determine possible treatments for inflammationinduced memory loss.
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Wang, D.S., Zurek, A.A., Lecker, I., Yu, J., Abramian, A.M., Avramescu, S., Davies, P.A., Moss, S.J., Lu, W.Y., Orser, B.A. Memory deficits induced by inflammation are regulated by Îą5-subunit-containing GABAA receptors. Cell Reports, 2, 488-496.
Summary by: Sammy Cai
62 Summary of:
Reduced anxiety-like behaviour and central neurochemical change in germ-free mice
Authors: Neufeld, K.M., Kang, N., Bienenstock, J., and Foster, J.A Background/Introduction: Previous studies have shown and established the importance of intestinal microbiota, which is formed in the first few days after birth, on the development and function of gut, immune, and endocrine systems. There has also been observed that bowel diseases tend to be accompanied by anxiety and mood disorders. And, diet, which changes intestinal microbiota, also alters learning and memory. The interaction between microbiota and the brain/behaviour is, however, poorly understood. This study demonstrates the effect of intestinal microbiota on behaviour and the central nervous. Neufeld et al. shows that germ free mice with no intestinal microbiota have lower anxiety and higher exploratory behaviours.
Materials and Methods:
Eight-week-old germ free (GF) and specific pathogen free (SPF) female Swiss Webster mice were used. Fifty-one hours after the mice arrived, their behaviours were tested using elevated plus maze, and their number of arm entries and duration in arms were recorded. Blood and brain samples were also collected from a separate group of mice to test for corticosterone, brain-derived neurotrophic factor (BDNF), 5HT1A serotonin receptor, and N-methyl-D-aspartate (NMDA) subunit levels. A standard radioimmunoassay kit was used to measure the corticosterone levels. And, in situ hybridization was used to identify and measure the mRNA expression levels of BDNF, 5HT1A receptor and NMDA subunit. Then, statistical programs were used to compare and determine the statistical significance of the data.
Major Results: In the elevated plus maze, GF mice spent more time in the open arms, less time in the closed arms, and entered open arms more frequently compared to SPF mice. GF mice’s plasma corticosterone level, however, was higher than SPF mice’s. GF mice also increased in BDNF mRNA expression, specifically in the dentate gyrus of the hippocampus, while the expressions in other regions, CA1 and CA3, did not differ compared to SPF mice. On the other hand, compared to SPF mice, GF mice’s 5HT1A receptor and NMDA mRNA expression decreased in the dentate gyrus and central amygdala, respectively. The expression of 5HT1A mRNA expression did not differ between GF mice and SPF mice in the CA1 region. The NMDA subunit that showed significant decrease was the NR2B subunit.
Conclusions:
The presence or the absence of intestinal microbiota influences the development of behavior and central nervous system in mice. GF mice, which have no microbiota, decreased in anxiety-like behaviour and increased in exploratory behaviour. Alterations in the gene expression in BDNF, 5HT1A, NMDA subunit NR2B are consistent with the behavioural findings and contribute to the exploratory behaviour observed. Previous studies have shown that low BDNF levels increase in anxiety-like behaviours; the decrease in serotonin level from 5HT1A receptor increases exploratory behaviour; and NR2B antagonist blocks amygdala synaptic plasticity and fear learning. Thus, higher BDNF levels and lower 5HT1A and NR2B levels in GF mice are related to reduced anxietylike behaviour observed.
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Neufeld, K.M., Kang, N., Bienenstock, J., and Foster, J.A “Reduced anxiety-like behaviour and central neurochemical change in germ-free mice� Neurogastroenterology & Motility (2011) doi: 10.1111/j.1365-2982.2010.01620.x. Published online 05 November 2010.
Summary by: Chun-Chi Chu
64 Summary of:
The Neural Correlates of Cognitive Control: Successful Remembering and Intentional Forgetting
Authors: Avery A. Rizio and Nancy A. Dennis Background/Introduction: This study explores neural activity for forgetting and remembering. The neural differences between incidental and intentional forgetting are under investigation. The hypothesis is that if incidental and intentional forgetting are separate, there should be different neural activity for both. Incidental forgetting would be related to encoding activity. Therefore certain parts of the brain related to the ability and inability to encode information(prefrontal cortex and the medial temporal lobe) should be associated with incidental forgetting. Alternatively, intentional forgetting should be associated with activity in areas of the brain involved in control and inhibition(prefrontal cortex and parietal lobe)
Materials and Methods:
A directed forgetting paradigm was used to induce forgetting and remembering. In the first phase, participants were presented with words and were directed to remember or forget them. Different cognitive processes were executed for the direction to remember or forget. The second stage involved a task that served as a distraction. In the third stage(retrieval stage), participants were shown the words again( including new words) and participants were asked if they did or did not recognize them. Words that were directed to be forgotten and were indeed forgotten during the retrieval stage were represented as intentionally forgotten. Words that were directed to be remembered but were in turn forgotten during the retrieval stage were represented as incidentally forgotten. An MRI and psychophyioslogical interaction analysis were used to detect brain areas that were active during stages.
Major Results: Intentional forgetting in participants is associated with right parietal cortex activity. On the other hand, incidental forgetting is connected to a greater extent with activity in the left inferior frontal gyrus, left superior frontal gyrus, early visual cortex, and left superior parietal lobe. In addition, intentional forgetting was associated with prefrontal cortex activity inhibiting medial temporal lobe activity. The medial temporal lobe is involved with encoding, and there is an inhibition of its activity during intentional forgetting. In contrast, there is no sign of inhibition for incidental forgetting. Therefore there is a difference in incidental forgetting and intentional forgetting like hypothesized. Also, it has been hypothesized that the right parietal cortex is associated with controlled processes including intentional motivations like intentional forgetting and it has been shown that intentional forgetting has activity in the right parietal cortex.
Conclusions:
This study has shown that memory suppression is controlled by separate processes depending on which type of memory loss. Specifically, there is a difference between incidental and intentional forgetting as shown by the different brain region activity. This is relevant to neuroscience because it provided additional information regarding the cognitive control of memory and neural activity associated with it.
65
Dennis, N. A., Rizio, A. A. (2013). The Neural Correlates of Cognitive Control: Successful Remembering and Intentional Forgetting. Journal of Cognitive Neuroscience, 25(2), pp. 297-312.
Summary by: Chantel George
66 Summary of:
Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress
Authors: Amanda J. Myers, Leanne Williams, Justine M. Gatt, Erica Z. McAuley-Clark, Carol DobsonStone, Peter R. Schofield, Charles B. Nemeroff Background/Introduction: The neuropeptide Oxytocin (OXT) is a mammalian hormone that is synthesized both in the paraventricular and supraoptic nuclei of the hypothalamus but also in other brain regions. It targets oxytocin receptors (OXTR) that are located similarly. Once produced, the hormone is transported to the posterior pituitary and consecutively released into the blood circulation. OXT is commonly associated with maternal behaviour as well as lactation and parturition, however, the findings of several studies suggest that the hormone may also be involved in altered mood, anxiety and depression phenotypes. Moreover, alterations in OXT levels were also shown to correlate with early life stress (ELS). Combining these two aspects, this study investigated whether ELS could influence the susceptibility of certain OXTR haplotypes to develop depression.
Materials and Methods:
Out of the initial amount of 1226 participants, 653 were qualified to take part in the study. Criteria for inclusion were availability of Depression Anxiety Stress Scale (DASS) and Early Life Stress Questionnaire (ELSQ) scores. DNA had to be available previously and its genotyping must have been successful. The genotyping revealed 7 SNPs that had the desired quality characteristics. In order to detect further genetic variance on the OXTR gene, MaCH-Admix was run. Of the found SNPs, 51 were analyzed. To investigate the downstream effects of all those OXTR SNPs, brain tissue was gained from brain tissue storing institutions. Only brains of individuals that were classified as cognitively normal at the time of death were included. For analysis purpose, four different tests where then conducted to investigate the following 1. The differences in DASS scores between individuals with and without ELS 2. Covariates contributing to the relationship between DASS and ELS 3. The effects of SNPs on symptoms and the influence of ELS on symptom-genotype interaction by using certain models 4. Whether SNPs had downstream effects especially on OXTR expression levels by performing the analysis in human brain
Major Results: For test 1, significant differences between DASS scores of people experiencing no traumatic events in their early life and people that were exposed to at least one event classified as ELS could be shown. The results were consistent for all parameters in the DASS score (depression, anxiety, stress). Test 2 did not reveal significant covariates in demographic variables. Also, those variables did not contribute to the relationship between DASS and ELS. Moving forward to test 3, stress and depression symptoms were significantly affected by the SNP genotype in contrast to anxiety, where this was not the case. Furthermore, in the context of ELS, the researchers were able to find SNPs significant for each symptom. One of the found SNPs was rs139832701, which is located very close to OXTR. It not only showed significant results in the ELS including model of DASS depression and stress, but also had main effects on depression and stress scores. However, for DASS anxiety, these correlations could not be detected. In test 4, the previously associated SNPs did not show any significant effects on OXTR levels in the human brains, concluding that their mechanism of action does not include a change in OXTR levels. In contrast, another SNP (rs3831817) was shown to significantly affect OXTR levels.
Conclusions:
It was found that certain variants on the OXTR gene as well as early life stress seem to have an influence on depression, anxiety and stress in later life. The strongest signs of association were made with the rs139832701 SNP. However, it could not be shown in which downstream mechanism rs139832701 acts upon OXTR, which could be the subject of a consecutive study.
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Sources http://www.phantasiereisen.de/stressmanagement-mit-zehn-punkte-skala.html http://www.phantasiereisen.de/stressmanagement-mit-zehn-punkte-skala.html http://ghr.nlm.nih.gov/chromosome/X http://de.fotolia.com/id/9423787http://www.rdnattural.es/plantas-y-nutrientes-para-el-organismo/diccionario-medico/gen/
Amanda J. Myers, Leanne Williams, Justine M. Gatt, Erica Z. McAuley-Clark, Carol Dobson-Stone, Peter R. Schofield, Charles B. Nemeroff “Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress” Elsevier – Journal of Psychiatric Research
Summary by: Patrick Hornlimann
68 Summary of:
Exposure to kynurenic acid during adolescence increases signtracking and impairs long-term potentiation in adulthood
Authors: Nicole E. DeAngeli, Travis P. Todd, Stephen E. Chang, Hermes H. Yeh, Pamela W. Yeh, David J. Bucci Background/Introduction: This experiment was conducted to determine the long-term effects of high exposure to kynurenic acid (KYNA) during youth on adult long-term potentiation (LTP) and sensitivity to cues related to reward. KYNA has been shown in past studies to be an antagonist to NMDA and alpha7 nicotinic acetylcholine receptors that play a key role in LTP and therefore may impair cognitive functions. KYNA also impacts reward behaviours by modulating dopamine release into the nucleus accumbens. Past experiments have shown that the increases in KYNA in experimental models mimicked the KYNA increases found in schizophrenic individuals. Therefore this experiment postulated that increased levels of KYNA in adolescents would increase reward-seeking behaviours and would decrease the ability for learning and memory at the adult stage.
Materials and Methods:
The experiment was conducted on 16 male rats and began on post-natal day (PND) 27. The animals were injected with L-KYN, a KYNA precursor, from days 27-29, and then allowed to rest for 3 days; this interval was repeated until 15 injections had been administered. The injections were administered in this method so that the animal would not have metabolic adaptation. The control group followed the same process, but were injected with a vehicle. To assess changes in reward seeking behaviours on PND 100 the animals were placed in a cage where they were active for 60-minute sessions per day for 7 days. During the sessions they were exposed to 25 conditioned stimuli (CS+) responses –pressing lever lead to food, and 25 stimuli free (CS-) responses – no outcome for pressing the lever. In the second experiment, to assess changes in LTP, on PND 70 the brains of the animals were removed and electrophysiological recordings were taken. Excitatory post-synaptic field potentials (fEPSP) were monitored for 10 minutes before stimulation of the Schaffer collateral and then every minute for 42 minutes post LTP induction. Recordings were made by the use of an electrode in the CA1.
Major Results: From the reward seeking experiment it was determined that the control group and the experimental group had no differences when pressing the lever in the CS- condition, however, there was a significant difference in lever pressing between groups in the CS+ condition. The experiment also showed that while the experimental group initially had a greater response to the stimulus, over the course of the experiment the two groups developed a similar response rate. The overall result showed that the groups acted similarly in both the CS- condition and the late CS+ condition and acted differently in the early CS+ condition. The final result of the first experiment showed that the L-KYN group had a greater response to the food cup in the CS- than the CS+ condition but the control group showed no difference. The LTP experiment showed that the control group had a significant increase of field excitatory post-synaptic potential (fEPSP) from baseline, showing that LTP has occurred. Conversely, the L-KYA treated group had no statistically significant increase.
Conclusions:
This study showed that when L-KYA was present in higher levels early in life there was an increase in sensitivity to rewards due to the increase in dopamine levels at the nucleus accumbens. This increase in sensitivity to reward can play a role in the development of addiction later in life. It was also demonstrated that early high levels of L-KYA will result in diminished ability for LTP and deficits in social behaviour, both of which are hippocampal related. This is relevant to understand and to treat the cognitive symptoms of schizophrenia. Individuals with schizophrenia tend to have high levels of KYNA when young and will exhibit behavioural changes when they are adults. This may be linked to the effect of KYNA on the hippocampus and further examination can lead to potential therapies.
69
Images from:http://images.clipartof.com/small/1212555-Cartoon-Of-An-Outlined-Chinese-Zodiac-Rat-RoyaltyFree-Vector-Clipart.jpg, http://i46.photobucket.com/albums/f119/ttorek/syringe.jpg, http://www.nature.com/ ncomms/2013/130827/ncomms3258/images/ncomms3258-f4.jpg, http://www.indmedica.com/journals/images/curr_neuro/01_02_14_fig01.jpg and http://journal.frontiersin.org/ Journal/10.3389/fnbeh.2014.00451/abstract
Bucci, D. J., Chang, S. E., DeAngeli, N. E., Todd, T. P., Yeh, H. H., & Yeh, P. W. (2015). Exposure to kynurenic acid during adolescence increases sign-tracking and impairs long-term potentiation in adulthood. Frontiers in Behavioral Neuroscience, 8, 1-9. doi: 10.3389/fnbeh.2014.00451
Summary by: Shikha Kuthiala
70 Summary of:
A Potential Spatial Working Memory Training Task to Improve Both Episodic Memory and Fluid Intelligence
Authors: Rudebeck, S., Bor, D., Ormond, A., O’Reilly, J., Lee, A., & Chao, L. Background/Introduction: Previous studies suggest that training working memory activates the medial temporal lobe, which can contribute to better episodic memory by stimulating interacting brain areas. Most studies do not examine the small effects of training on episodic memory processes, such as familiarity in the perirhinal cortex and recollection in the hippocampus. Rudebeck et al. follow up on their recent finding that a high demand of executive function to process complex spatial information increases prefrontal cortex activity too. Development of a new spatial task targeting both episodic memory processes necessitates participants to adjust their viewpoint accordingly. Thus, multiple training tasks are not required to improve cognition, as their spatial working memory task led to stronger long-term memory and fluid intelligence for abstract reasoning.
Materials and Methods:
Participants are split into a control group and a training group, which follows a daily behavioural procedure for 20 minutes over 20 weekdays. The training task requires monitoring a 3D room with 8 picture frames of real world scenes that are presented in 12 blocks sequentially. The program contains unfamiliar indoor and outdoor scenes without color, people, objects or words, to avoid verbal encoding. Subjects identify repetition of a picture frame location with one response, and a scene image with another. Participants are assessed similarly pre and post training with the BOMAT to measure problem solving skills and two computer-based recognition tasks. Participants complete a matrix of patterns in order to fill an empty field during the BOMAT. The object and scene recognition memory tasks present a distinct set of 120 items during the encoding phase, in which the participant either states if each scene is indoor or outdoor, or if an everyday object would fit in a shoebox. Filler tasks take 20 minutes before moving onto the test phase, in which 120 new items are randomly added to distract the participant, who provides a recognition judgment on a 6-point confidence scale.
Major Results: No significant differences in pre-training scores account for the improvements in the training group, which is split at the median into a high gain and low gain group for recollection and familiarity. Both groups achieve greater scores with time, but there are significant differences between them, as well as the high gain compared to the control, and the low gain versus the control. The training group performs significantly better on the BOMAT, in comparison with the control group. However, low pre-training scores lead to higher BOMAT scores, irrespective of training task gain. In addition, the gain scores positively correlate with the recognition tasks for both episodic memory processes. There is a significant difference between the high gain group compared with the control, or compared with the low gain group. Even if the object and scene tasks are considered separately, there is still no significant difference between the scores for the low gain and control groups. Therefore, training score improvement links with increased recognition seen through familiarity scores, whereas poor recollection pre-training predicted a marked improvement only in recollection scores, regardless of training scores.
Conclusions:
For optimal encoding and retrieval of episodic memory, the ability to maintain information in working memory is crucial. Also, neural mechanisms overlap as medial temporal lobe lesions affect working memory if/when the stimuli are difficult to verbalize or relational processing is complicated. Moreover, BOMAT improvements are due to the task-induced activation of a common network from the lateral prefrontal cortex to the parietal cortex, leading to better episodic memory. Hence, the more working memory is improved, the larger transfer affects episodic memory, and so the prefrontal cortex and medial temporal lobe structures are involved in non-specific gains. As a result, depending on the cognitive skills required, appropriate training tasks must be created based on existing ability and training task gains pursued. Furthermore, the hippocampus is important for both recollection and familiarity as well as object and scene recognition, implying that further research would allow generalization to all forms of episodic memory in various populations by using different kinds of stimuli and targeting certain neural processes.
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Benit, N., & Soellner, R. (2014). Misst gut, ist gut? Vergleich eines abstrakten und eines berufsbezogenen Matrizentests. Journal of Business and Media Psychology, (1). Retrieved from http://journal-bmp.de/2012/05/1068/ http://cdn.iphonephotographyschool.com/wp-content/uploads/Black-White-iPhone-Photos-21.jpg https://ellenandjim.files.wordpress.com/2012/03/1963houseforjacksonsnovel.jpg
Rudebeck, S., Bor, D., Ormond, A., O’Reilly, J., Lee, A., & Chao, L. “A Potential Spatial Working Memory Training Task to Improve Both Episodic Memory and Fluid Intelligence” (2012). PLoS ONE, E50431-E50431. Retrieved February 6, 2015, from http://journals.plos.org/plosone/ article?id=10.1371/journal.pone.0050431
Summary by: Shonali Rajesh Lakhani
72 Summary of:
Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression
Authors: Woosuk Chung, Su Yeon Choi, Eunee Lee, Haram Park, Jaeseung Kang, Hanwool Park, Yeonsoo Choi, Dongsoo Lee, Sae-Geun Park, Ryunhee Kim, Yi Sul Cho, Jeonghoon Choi, Myoung-Hwan Kim, Jong Won Lee, Seungjoon Lee, Issac Rhim, Min Whan Jung, Daesoo Kim, Yong Chul Bae & Eunjoon Kim Background/Introduction: Social deficits are observed in many neuropsychiatric disorders such as autism spectrum disorder, schizophrenia, and attention deficit hyperactivity disorder. IRSp53 is an excitatory synaptic signalling scaffold protein that has been implicated with the control of the actin cytoskeleton. Its deficiency has been shown to reduce AMPA/NMDA ratios. IRSp53 knockout mice demonstrate augmented NMDAR function, augmented long-term potentiation dependent on NMDA receptors, and diminished hippocampusdependent memory and learning. Certain drugs can be used to normalize NMDA function. MPEP is a metabotropic glutamate receptor 5 (mGluR) antagonist and memantine is a NMDA receptor antagonist that is used to treat Alzheimer’s disease.
Materials and Methods:
Behavioural experiments such as the three chambered test or counting the number of ultrasonic vocalizations was done to quantify social activity were done with in both wild type and IRSp53 knockout male mice. In vivo experiments involved injections of the drugs and saline followed by electrophysiological recording. LTD experiments were done with sagital and coronal slices acquired with a vibratome from 21-28 day old mice. The slices were placed in artificial cerebrospinal fluid that was infused with the drugs memantine or MPEP. Layer II/III pyrimidal neurons from the prelimbic medial prefrontal cortex were recorded for excitatory post synaptic currents (EPSC). Whole-cell patch clamp recordings and field potential recordings were used.
Major Results: IRSp53 knockout mice displayed many social deficits. Compared to wild-type mice, they spent less time with the stranger mice in the three chambered setup, sniffing, and following stranger mice. The IRSp53 knockout mice also exhibited fewer ultrasonic vocalizations, more time spent on emitting the first vocalization, greater locomotion in an open field and home cage, and more movement in a 48 hour period. Injecting the mice with memantine or MPEP rescued social interaction in the IRSp53 knockout mice. IRSp53 knockout mice had impaired LTD of NMDA receptor EPSCs but normal LTD of AMPA receptor EPSCs and mGluR-dependent LTD in the medial prefrontal cortex. Furthermore, the neurons had a lower apical dendrite complexity, less miniature EPSC amplitude and frequency, and excitatory synapses. Memantine increased firing rates in the medial prefrontal cortex slices for both the wild type and IRSp53 knockout mice but induced a even greater increase in IRSp53 knockout mice.
Conclusions:
This paper demonstrated that a deficiency in a single protein, IRSp53, could cause social deficits and unravelled part of the mechanism by which it might do so, which is the hyperactivity of NMDA receptors. It also demonstrated two drugs that can rescue the social deficit. Describing biological mechanisms for disorders and diseases furthers the study of neuroscience by adding to the collection of knowledge which may help to find better and more effective treatments in the future.
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Woosuk Chung, Su Yeon Choi, Eunee Lee, Haram Park, Jaeseung Kang, Hanwool Park, Yeonsoo Choi, Dongsoo Lee, Sae-Geun Park, Ryunhee Kim, Yi Sul Cho, Jeonghoon Choi, Myoung-Hwan Kim, Jong Won Lee, Seungjoon Lee, Issac Rhim, Min Whan Jung, Daesoo Kim, Yong Chul Bae & Eunjoon Kim “Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression” Nature Neuroscience (2015). doi:10.1038/nn.3927 Published online 26 January 2015
Summary by: Victor Lee
74 Summary of:
Effects of defeat stress on behavioural flexibility in males and females: modulation by the mu-opioid receptor
Authors: Sarah A. Laredo, Michael Q. Steinman, Cindee F. Robles, Benjamin J. Ragen and Brain C. Trainor Background/Introduction: Behavioural flexibility is a method to adjust and respond to changing environments. Stress can negatively affect behavioural flexibility. This is demonstrated in studies with anxiety and depression patients performing worse on behavioural flexibility tasks when compared to controls. Animal models have also shown that defeat stress such as aggression from peers can reduce behavioural flexibility. Mu-opioid receptors (MORs) in the orbitofrontal cortex (OFC) are known to mediate behavioural flexibility. Noteworthy is that sex differences exist in the cortical areas controlling behavioural flexibility indicating that stress may sexes differently. This study looks at how stress affects MOR control impacting behavioural flexibility between the sexes. While stress in males has shown to enhance behavioural flexibility with MOR activation, females’ response to stress has not. Thus, the authors hypothesize that defeat social stress will down-regulate MOR function and decrease behavioural flexibility in males while stressed females will have a null response.
Materials and Methods:
Male and female California mice were subjected to 3 days of either a social defeat condition where they were caged with an aggressive mouse or in a control condition in an empty cage. Four weeks after conditioning, the mice were tested on a Barnes maze and taught to find the same exit hole for 5 days then in a reversal period the mice must adapt to find a new exit hole. After the trails, some rats were sacrificed for MOR autoradiography to analyse MOR binding in OFC. The Barnes maze test was also conducted with MOR antagonists, (ß-FNA) and MOR agonist, morphine injections once before acquisition period and once before reversal period.
Major Results: Number of errors and travel distance were measured from the Barnes maze test. The reversal period had a new exit hole testing the mice for behavioural flexibility. Stressed males made more errors in finding the new exit hole compared to control males and stressed females. Stressed males also entered the former target hole more frequently than stressed females indicating inflexibility. In the MOR autoradiography, stressed males had a reduction in MOR binding to OFC compared to control while there were no differences in stressed and control female mice. Antagonising MOR with ß-FNA increased the number of errors stressed males made compared to saline-injected males or females. In contrast, females receiving ß-FNA made significantly fewer errors than saline-injected females. MOR agonist, morphine increased stressed male performance in the reversal period and travelled less distance to find the exit hole. These results indicate that upregulating MOR for greater activation can improve behavioural flexibility in stressed males resulting in less erroneous steps and faster learning curves while females have differing responses.
Conclusions:
Behavioural flexibility in males but not females is impaired when exposed to social stress. The process is mediated by MOR binding with inhibitions leading to poorer performance in reversal trials for stressed males than females whereas MOR agonists have a reverse effect on males. These results suggest that future neuroscience research needs to consider the differences between the sexes and study certain processes independently. Understanding the effect of MOR with stress on behavioural flexibility and sex differences can result in more targeted and effective psychiatric treatments for males versus females.
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Laredo, S.A., Steinman, M.Q., Robles, C.F., Ragen, B.J., & Trainor, B.C. (2015). Effects of defeat stress on behavioural flexibility in males and females: modulation by the mu-opioid receptor. European Journal of Neuroscience, 1-8. doi:10.1111/ejn.12824
Summary by: Ella Lew
76 Summary of:
Hippocampal Memory Traces Are Differentially Modulated by Experience, Time, and Adult Neurogenesis
Authors: Denny, C., (2014). Kheirbek, M., Alba, E., Tanaka, K., Brachman, R., Laughman, K., Tomm, N., Turi, G., Losonczy, A., Hen, R. Background/Introduction:
Memory traces are theorized to be ensembles of cells activated during retrieval of a memory. This study aims to visualize the memory traces of fearful episodic memories in the dental gyrus (DG) and CA3 regions of the hippocampus (HPC), regions currently theorized to be important in episodic and contextual memories. Expression pattern of the Arc gene in DG and CA3 are closely associated with synaptic plasticity and HPC dependent memory, and its presence is useful as a marker for such processes. Cells that expressed Arc both during encoding of fearful memory and during later re-exposure to the same context were hypothesized to form the memory trace. The effects of optogenetic inhibition of encoding cells, and X-ray ablation of adult-born neurons from subgranular region of DG on memory trace were also tested.
Materials and Methods:
In the ArcCreERT2 x R26R-stop-floxed-EYFP line, when Arc is expressed, so is EYFP and the cells will fluoresce red temporarily (Arc+). Addition of tamoxifen (TAM) activates cre-lox mediated deletion of a regulatory element causing the cells to permanently fluoresce green (EYFP+). Mice were injected with TAM then subjected to context dependent fear conditioning (CFC) in the form of foot shock in Context A. Mice were later returned to either unchanged Context A or novel Context B, their stress behavior recorded and hippocampal slice used for immunohistochemistry analysis. Yellow fluorescence indicates Arc expression during both encoding and retrieval (EYFP+/Arc+). C-fos was used as a marker for CA3 instead of Arc, because Arc expression was mostly dendritic. For optoinhibition test fibre optics were installed above DG and CA3 on ArcCreERT2xArch-GFP line of mice to allow toggle on and off of photostimulation.
Major Results: Mice were returned either 5 days (recent) or 30 days (remote) to Context A or B. In recent re-exposure, mice froze more in context A. EYFP+ and Arc+ levels were similar, but significantly higher EYFP+/Arc+ (c-fos+) for Context A in both DG and CA3, suggesting better retrieval of encoded memory in Context A. In remote re-exposure, high degrees of freezing were observed in both Context A and B, and number of all labeled cells were similar, which may indicate memory generalization. CA3 levels of EYFP+/c-fos+ was significantly lower in remote compared to recent. The same was not observed for DG. For the optoinhibition test mice were placed into Context A 2 weeks later, the first 3 minutes with light ON and following 3 minutes with lights OFF. 2 days later the same mice were placed in Context B with same light epochs. Less freezing was observed during lights on in both Context A and B in ArcCreERT2- mice than ArcCreERT2+, but freezing levels became similar when lights were turned back on. This suggests that neurons marked during encoding are necessary for memory retrieval. X-ray ablated mice and control were subjected to either 1 or 3 foot shocks and returned to Context A 6 weeks later. In 1 shock CFC, x-ray mice showed less context elicited freezing than control. Interestingly, only the numbers of EYFP+/c-fos+ were significantly different in x-ray mice and not EYFP+/Arc+, showing that the memory trace was affected in CA3 rather than DG, the site of neurogenesis. In 3 shocks CFC, no significant difference in freezing or number of all labeled cells was observed, suggesting that intense conditioning could rescue the effect of neurogenesis deficit.
Conclusions:
The authors propose cells in DG and CA3 re-activated during memory retrieval were component of memory trace for the CFC. They were surprised that many cells activated during encoding were not the same as those activated during retrieval, and that may due to retrieval cells correspond to multiple related memories. Decrease in CA3 reactivation in remote re-exposure may suggest that the component of memory trace has moved away to other parts of the brain. Decreased reactivation in CA3 rather than DG in response to adultborn neuron ablation was surprising, but the same result has been observed in other studies. The newly recruited neurons may function in transmission of information from DG to CA3.
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Denny, C., (2014). Kheirbek, M., Alba, E., Tanaka, K., Brachman, R., Laughman, K., Tomm, N., Turi, G., Losonczy, A., Hen, R. Hippocampal Memory Traces Are Differentially Modulated by Experience, Time, and Adult Neurogenesis. Neuron, 83(1), 189-201.
Summary by: Yi Xuan Li
78 Summary of:
VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation
Authors: Taryn E Greider, Melissa A Herman, Candice Contet, Laura A Tan, Hector Vargas-Perez, Ami Cohen, Michal Chwalek, Geith Maal-Bared, John Freilling, Joel E Schlosburg, Laura Clarke, Elena Crawford, Pascale Koebel, Vez Repunte-Canonigo, Pietro P Sanna, Andrew R Tapper, Marisa Roberto, Brigitte L Kieffer, Paul E Sawchenko, George F Koob, Derek van der Kooy, Olivier George. Background/Introduction: It is hypothesized that neuroadaptations, in which dopamine (DA) activity in the ventral tegmental area (VTA) is decreased and corticotropin-releasing factor (CRF) activation is increased, is responsible for drug addiction. Although past studies on nicotine addiction and abstinence in nondependent animals suggested that forebrain-originated axons release CRF into the VTA, the precise mechanism on how DA interacts with CRF in the VTA is unknown. In this paper, the authors showed that chronic nicotine results in DA neurons to express CRF and recruit local CRF neurons to the VTA, mediating withdrawal aversion in rodents.
Materials and Methods:
The authors used Crh mRNA in situ hybridization to identify CRF neurons in the pVTA. To examine chronic nicotine effects on CRF neuron recruitment to the pVTA, they used CRF immunohistochemistry. Downregulation of Crh mRNA in drug naïve, nicotinedependent and nicotine-withdrawn mice allowed them to examine CRF’s GABAgeric effects on DA neurons, aversive behaviours and escalating nicotine-intakes. They measured spontaneous inhibitory postsynaptic currents (sIPSCs), used place conditioning and self-administration of nicotine respectively. CRF1 receptors in pVTA were then blocked with MPZP antagonists to test if they were involved in withdrawal aversion.
Major Results: Compared to the saline-control condition, CRF peptide density was decreased in mice under both nicotine-dependent and withdrawal conditions, indicating there is local release of pVTA CRF in chronic nicotinic exposure. Downregulation of Crh mRNA in pVTA of nicotine dependence mice showed increased sIPSC frequencies compared to control nicotinic-dependent mice without Crh downregulated. This indicates that Crh downregulation can reverse the GABAergic regulation of DA neurons due to long-term nicotine exposure. Nicotine-withdrawn mice did not respond aversively to withdrawal, and self-administration of nicotine-intake was reduced significantly in rats that had longer access to nicotine in mice with downregulated Crh compared to controls. By blocking CRF1 receptors, withdrawal aversion was not observed in mice treated with MPZP under nicotine-withdrawn conditions. This indicates that CRF1 receptor activation in nicotine-withdrawal is required for producing the aversive withdrawal behaviour and blocking these receptors would prevent this response.
Conclusions:
In conclusion, the authors showed how CRF neurons expressed in VTA DA neurons could be one interacting pathway responsible for nicotine addiction through withdrawal averse and inducing drug intake responses. This paper provides greater understandings to the mechanisms of drug addiction and further work is needed to elucidate whether this pathway also occur in humans, which may aid in therapeutic approaches for drug addiction in humans.
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Picture idea from: Fields, H.L., Margolis, E.B. (2015). Understanding opioid reward. Trends in Neurosciences, doi:10.1016/j.tins.2015.01.002
Grieder, T.E., Herman, M.A., Contet, C., Tan, L.A., Vargas-Perez, H., Cohen, A.,‌George, O. (2014). VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nature Neuroscience, 17(12), 1751-1758.
Summary by: Rose Ly
80 Summary of:
Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease
Authors: Mark Murphy, Yvette M. Wilson, Ernesto Vargas, Kathryn M. Munro, Belinda Smith, Amy Huang, Qiao-Xin Li, Junhua Xiao, Colin L. Masters, Christopher A. Reid, Graham L. Barrett Background/Introduction: The common signs of the Alzheimer’s disease are the amyloid plaques formation and the degeneration of the cholinergic neurons in brain. Previous studies have shown that the binding of amyloid-beta protein to the p75 neurotrophin receptors could promote cell death and neurodegeneration. The p75 has a negative effect on the synaptic transmission and the release of neurotransmitter. Previous studies suggested that p75 plays a role in the neurodegeneration in AD patients. Murphy et al. bred mutant AD transgenic mice Tg2576 (contain the human APP gene) with reduce level of p75 to perform in multiple cognitive tasks. They were able to show that the down-regulation of the p75 can ameliorate the memory deficit in the AD transgenic mice.
Materials and Methods:
The AD transgenic mice Tg2576 were crossed with p75-/- mice to produce the Tg2576/ p75+/- mice with lower p75 expression. Four types of mice with different genotypes were used in the experiment: wild type p75, mutant p75, Tg2576, and Tg2576/p75+/. Mice were between 4 to 8 months old in the tests, except for the Barnes maze test which used 2 age groups (4-8 months and 12-14 months). PCR was used to determine the genotypes of the mice. Western blot analysis was used to show the different level of p75 expression across genotypes. Several memory experiments were performed: fear conditioning testing for fear memory; Y maze testing for short term memory; and Barnes maze testing for spatial memory. Field excitatory postsynaptic potentials (fEPSC) and the LTP level (using tetanic stimulation) of the hippocampal CA1 neurons from the mice brain slices were measured. The amyloid-beta levels were determined using the enzyme-linked immunosorbent assay.
Major Results: Reducing the level of p75 receptors in the Tg2576 mice showed significant improvement in performance in all of the cognitive tests. The Tg2576 mice exhibited less shock response in the fear conditioning test compare to the other three groups. The Tg2576/ p75+/- mice preferred to use more spatial search strategy in the Barnes Maze and have longer memory retention about the familiar arms in the Y maze. The synaptic transmission of the hippocampal CA1 neurons was enhanced after the reduction of p75. The LTP of the Tg2576/p75+/- and wild type exhibited similar magnitudes whereas the Tg2576 had a reduction in LTP. There was an increase in human Ab expression in the Tg2576 mice with reduction of p75.
Conclusions:
The down-regulation of p75 rescued the memory deficit, synaptic transmission, neuronal death in the AD transgenic mice Tg2576. The reduction of p75 in Tg2576 not only attenuated the symptoms, the performances of the Tg2576/p75+/- were somewhat comparable to the wild type mice. If future research seek out techniques/medications that could target the p75 in human AD patients, they might be feasible to rescue some of the deficits of the disease.
81
Mark Murphy, Yvette M. Wilson, Ernesto Vargas, Kathryn M. Munro, Belinda Smith, Amy Huang, Qiao-Xin Li, Junhua Xiao, Colin L. Masters, Christopher A. Reid, Graham L. Barrett “Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease” Neurobiology of Aging (2014) 1-13 DOI: http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.014 Published online 25 September 2014
Summary by: Tong Mai
82 Summary of:
Correlation of Brain Biomarker Neuron Specific Enolase (NSE) with Degree of Disability and Neurological Worsening in Cerebrovascular Stroke
Authors: Anuradha Bharosay, Vivek Vikram Bharosay, Meena Varma, Kiran Saxena, Ajoy Sodani, Ravi Saxena Background/Introduction: Ischemic stroke is one of the world’s leading causes of death. In countries where MRI or CT scans are not widely available, being able to find biomarkers in the blood to diagnose stroke would be very beneficial. This study aims to find a biomarker that can be found within 72 hours of the stroke occurrence. Neuron specific enolase (NSE) is an enzyme released from the neurons upon apoptosis and crosses the blood brain barrier. This can be measured in the bloodstream. Also, the severity of stroke, degree of disability, and neurological worsening can be determined by using the National Institute of Health Stroke Scale (NIHSS). Hypothesis: Higher levels of NSE will correspond to higher degree of disability and neurological worsening in cerebrovascular stroke patients.
Materials and Methods:
Normal levels of cerebrospinal fluid NSE are 17.3 ng/ml and this was used to distinguish between control group and the study group. Adults who were over 21 years of age and had a stroke less than 72 hours ago were chosen for the study group. For the control group, adults who had no clinical signs and symptoms of cerebrovascular disease were chosen. Blood samples were drawn and immunoassay was done using monoclonal antibody against gamma, gamma-NSE isoform. NIHSS was used to assess the severity of stroke and neurological worsening was assessed with the same scale by adding at least two points extra to the NIHSS score if conditions worsened between admission day and day five.
Major Results: In the study group, approximately 47% of the adults had NSE levels >25ng/ml and about 9% had >35ng/ml. The study group generally had higher NSE levels, as mean for study group was 22.68 ng/ml and for control group was 7.48 ng/ml. In the control group, all adults had NSE levels below 25ng/ml. As the NSE levels in the blood increased, the severity of stroke also increases, providing a high positive correlation of 92%. Similarly, there was also a positive correlation between the NIH scores, plus addition of two points, and the worsening of disability in stroke patients. NSE found in the blood is a result of apoptosis of endothelial cells, after which the NSE found in the cytosol is able to spill out and cause the blood brain barrier (BBB) and into the bloodstream. Adults who had higher levels of NSE also were the ones who tended to have worse neurological outcome.
Conclusions:
Biomarkers such as NSE allow to gain more understanding of the neural and vascular pathways of brain related injuries. As there was a high positive correlation between NSE levels and neurological worsening, biomarker NSE can be used to determine future consequences after the onset of stroke. This is why it is so important to find a biomarker relating to stroke to have rapid treatment within the onset of stroke, instead of waiting for CT or MRI scan, the diagnosis and treatment can be made within 48 hours.
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http://www.futuremedicineonline.com/detail_news.php?id=143 http://www.nlm.nih.gov/medlineplus/ency/imagepages/9076.htm https://lookfordiagnosis.com/mesh_info.php?term=immunoassay&lang=1 http://sigmadiagnosticsinc.com/neuron-specific-enolase-nse-elisa/
Bharosay, A., Bharosay, V., Varma, M., Saxena, K., Sodani, A., & Saxena, R. (2011). Correlation of Brain Biomarker Neuron Specific Enolase (NSE) with Degree of Disability and Neurological Worsening in Cerebrovascular Stroke. Indian Journal of Clinical Biochemistry, 27(2), 186-190. Retrieved February 1, 2014.
Summary by: Fazila Malek
84 Summary of:
Neuroprotective effects of collagen matrix in rats after traumatic brain injury
Authors: Samuel S. Shin, Ramesh Grandhi, Jeremy Henchir, Hong Q. Yan, Stephen F. Badylak & C. Edward Dixon Background/Introduction: Traumatic brain injury (TBI) is a problem that plagues all human populations, yet very little treatment options are available. TBI is often characterized by neuronal loss, inflammation, and neurological deficits both acutely and long-term. Here, the authors’ implant bovine collagen matrices into controlled cortical impact (CCI) injured rats in order to test their efficacy in preventing the symptoms associated with TBI. Collagen has intrinsic abilities to aid in neuronal survival, and cellular migration, making it a good candidate for the graft. No exogenous growth factors are used to promote regeneration in this study.
Materials and Methods:
Four groups of rats were used; TBI rats+collagen matrix graft (IC), sham rats+collagen matrix graft (SC), TBI rats+no graft (IN), sham rats+no graft (SN). TBI was induced under anaesthesia using craniectomy CCI procedure (for IC and IN), CCI exposes brain tissue by disrupting the meninges; thus facilitating collagen matrix graft implantation(for IC). Crossing a balance beam was used as a test of motor abilities of rats on d1-5, this was normalized by recording latency versus a pre-treatment cross-time in the same animal. A hidden platform Morris water maze (MWM) was used for training of spatial learning. Removal of the platform and time spent in the correct quadrant post-training was used to measure spatial memory. After sacrifice, brain tissue was fixed, sliced and measured for volume and cell counts were made of specific CA1 and CA3 hippocampal sections. GFAP staining was used to visualize astrocytes at injury & graft site. Trichrome staining was used to visualize brain slices and detect remaining collagen from graft at the injury site.
Major Results: IC and IN rats exhibited statistically equally depressed performance on both beam balance and beam walking tests versus SC an SN rats, demonstrating no difference in motor ability. IC rats outperformed IN rats in the MWM latency spatial memory task, meaning they learned to find the submerged platform faster, IC rats also demonstrated a more uniform, progressive form of learning from trial to trial. IC and IN rats exhibited equal reduction in time spent in the correct quadrant of the MWM after removal of the platform versus SC and SN rats. Collagen matrix graft implantation resulted in decreased lesion volume accompanied by lesser-reduced CA1 and CA3 neurons in hippocampal slices in IC rats versus IN rats. GFAP staining of astrocytes in the CCI region is equal in IC and IN, meaning there is no excess glial scar associated with the collagen matrix graft versus IN. Finally, tricolour staining of brain slices reveals no matrix-collagen remains bordering the CCI site.
Conclusions:
The use of a collagen matrix graft following CCI induced TBI in rats led to decreased injury size, increased neuronal survival, and equivalent astroglial scarring versus nontreated TBI rats. Collagen matrix grafting also allowed ameliorated spatial learning versus non-treated TBI rats. Since no bovine collagen remained exposed at the injury site following sacrifice of the rats, the authors propose its benefits remain as a transient scaffolding to facilitate repair post-injury. More tests to elucidate the mechanisms the graft uses to ameliorate prognosis following rat TBI are required for more definitive conclusions.
Image sources (top left to bottom right): http://www.nap.edu/openbook.php?record_id=13121&page=33 http://www.hindawi.com/journals/bmri/2014/672409/fig1/ clipart entitled paper
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Shin, S.C., Grandhi, R., Henchir, J., Yan, H.Q., Badylak, S.F. & Dixon, C.E. (2015). Neuroprotective effects of collagen matrix in rats after traumatic brain injury. Restorative Neurology and Neuroscience. [Epub ahead of print] doi: 10.3233/RNN-140430
Summary by: Catherine Matolcsy
86 Summary of:
Differentially Methylated Plasticity Genes in the Amygdala of Young Primates are Linked to Anxious Temperament, an at Risk Phenoytpe for Anxiety and Depressive Disorders.
Authors: Ried S. Alisch, Pankaj Chopra, Andrew S. Fox, Kailei Chen, Andrew T. J. White, Patrick H. Roseboom, Sunduz Keles, and Ned H, Kalin. Background/Introduction: Rhesus monkeys are an ideal animal model for human childhood anxious temperament (a risk factor for future anxiety and depression) due to their brain and social structure. Young rhesus monkeys also show anxious temperament (AT) symptoms very similar to those seen in humans. PET scans suggest that there is higher brain activity in the amygdala and anterior hippocampus in individuals with AT, but that these two areas are not affected by genetic and environmental factors in the same way. This study hypothesizes that high AT individuals will have different expression and methylation of genes that may lead to anxiety.
Materials and Methods:
Whole brains of young AT rhesus monkeys had sections of their amygdala biopsied, and these sections were homogenized before RNA and DNA extraction. Reduced representation bisulphite sequencing gave information on dinucleotide methylation. Sequences were mapped to a human genome reference and filtered. Methylation was log transformed and correlated as a percentage with AT severity (graphed as a continuous variable). Fixed effect regression models were used to find 1) the level of methylation which could most predict gene expression and 2) the gene expression that correlated best with AT. All methylation data was assigned to a gene element, such as upstream, exon, gene body etc.
Major Results: Regions within the gene body and farther away from the transcription start site tended to be more methylated. CpG islands were much less methylated than the areas around them, which is consistent with other studies. 3’USR and intergenic regions were most statistically overmethylated or unmethylated. This suggests that AT associated DNA methylation is not random. 5489 CpG sites were found to be correlated with AT, some negatively and some positively. Most of these areas are under 10% methylated, but those genes that were over 60% methylated were more likely to be related to AT. Chromosome 1 has more AT related methylation, and chromose 19 has less, than would be expected by chance. The AT associated genes were found to be related to such functions as neuron generation and synaptic transmission, and many of them have been implicated in psychiatric disorders before. Statistically differential gene transcription was found in the same monkeys, in 22 genes that were also found have AT associated methylation changes. These genes include two glutamate receptors which have been shown to have roles in fear and anxiety behaviour, and genes with roles in brain plasticity
Conclusions:
Important genes which were found to have differential methylation and reduced gene expression predicting AT phenotype include BCL11A and JAG1. BCL11A is a downstream glutamate receptor effector involved in neurite branching, and JAG1 is a NOTCH receptor with a role in spatial memory formation and plasticity. Although both of these genes show the most methylation inside CpG islands, overmethylation of CpGs outside of CpG islands probably contribute to the majority of AT changes. The observed methylation changes most likely impact factor binding sites or noncoding RNA regulatory sites.
87
Alisch R. S. et al. (2014). Differentially Methylated Plasticity Genes in the Amygdala of Young Primates are Linked to Anxious Temperament, an at Risk Phenotype for Anxiety and Depressive Disorders. The Journal of Neuroscience, 34(47), 15548-15556.
Summary by: Lucy McPhee
88 Summary of:
Musical Experience and the Aging Auditory System: Implications for Cognitive Abilities and Hearing Speech in Noise
Authors: Alexandra Parbery-Clark, Dana L. Strait, Samira Anderson, Emily Hittner, Nina Kraus Background/Introduction: The purpose of this study was to investigate if adults from ages 45-65 that have had previous musical experience can comprehend speech in background noise more effectively than adults who have had no musical experience. This does not only mean understanding speech at the basic level, but also determining if underlying cognitive abilities have not been compromised. There are a complexity of reasons as to why hearing becomes difficult, some include hearing loss due to age, as well as attention and memory are factors in this issue. There have been studies suggesting that hearing becomes integrated with attention, which is the ability to focus on a specific sound, and other cognitive functions. Therefore, better memory calls for an increase in understanding speech and targeted sounds. One of the tests used in this study is known as Backward Masking, which is a way to measure one’s perception of sound as it is being played with another sound at the same time in order to make it difficult to understand. There have already been studies showing that having previous musical experience does in fact have a positive effect on perception of speech to the point where areas of the brain that process auditory sounds have been improved compared to non-musicians (tested on only younger populations), consequently, this study focused on an the older musical and non-musical population.
Materials and Methods:
Out of 37 participants, 18 were considered musicians, which indicated that they played instruments for over 30 years. The rest that were not musicians either had absolutely no previous musical training or had 3 or less years of experience. Prior to beginning the tests, all participants were asked to rate their musical skills, how many hours they participated in physical activity, all were tested for normal cognition and hearing, and were also tested for IQ levels. This was a way of controlling confounding variables within the study in order to be able to manipulate only the variable of musical experience while all others remain constant. The study also took into account that physical activity could be a possible factor that can affect cognition and even hearing, therefore, the participants were categorized based on the amount of hours each spent on physical activity. Results showed no significant differences between the categories. Then, the participants partook in a series of tests to assess understanding speech in background noise, any auditory and visual memory improvements, and included the backward masking test for cognitive hearing ability. After all tests were completed, the researchers used statistical analyses to find any relationships in the data.
Major Results:
Throughout all the tests, excluding the visual component of memory, the results for musically experienced participants showed a significant improvement to non-musicians. That being said, the musicians were able to understand speech and had lower scores, suggesting better results than non-musicians as the tests progressively became more challenging. Being able to understand speech in background noise correlated with memory relating to the auditory path, such that a positive relationship demonstrated improved results for both variables. In addition to having lower scores, musicians demonstrated lower signal-to-noise-ratio (SNR), meaning the ability to perceive a target signal playing simultaneously with background noise at different volumes. A lower result indicates that the participant was able to distinguish both sounds even though they were relatively the same volume. Correlations among the tests that measured for the same variable of speech perception were calculated and found that no significant relationship could be determined even though participants had similar results for each test. Other statistical analyses that were calculated also suggest no significant relationships between number of musical training years and its effect on cognition.
Conclusions:
Activities such as playing an instrument can have some serious implications on enhancing the brain as we age. It can improve our memory, speech perception and cognitive performance. It is important to begin developing these skills at an earlier age as it is easier to take up new interests and learn quickly and practice should be continued even until adulthood in order to attain the aforementioned result. These results can be implemented in the present population such that, as life expectancy increases, there will be an increase of older adults who will have difficulty hearing, thus having musical experience may provide some reinforcement to overcome daily auditory obstacles.
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Parbery-Clark A, Strait DL, Anderson S, Hittner E, Kraus N (2011) Musical Experience and the Aging Auditory System: Implications for Cognitive Abilities and Hearing Speech in Noise. PLoS ONE 6(5): e18082. doi:10.1371/journal.pone.0018082
Summary by: Arinda Muntean
90 Summary of:
Fast BDNF serum level increase and diurnal BDNF oscillations are associated with therapeutic response after partial sleep deprivation
Authors: Maria Giese, Johannes Beck, Serge Brand, Flavio Muheim, Ulrich Hemmeter, Martin Hatzinger, Edith Holsboer-Trachsler, Anne Eckert Background/Introduction:
Brain-derived neurotrophic factors (BDNFs) affect neuroplasticity, and serum BDNF levels exhibit circadian patterns in which mornings have the highest and midnights the lowest levels of BDNFs. Because patients with major depressive disorder (MDD) have decreased hippocampal BDNF levels, BDNF has been proposed as a potential target for antidepressant treatments and as a biomarker for therapy efficacy because of BDNF’s ability to readily cross the blood-brain barrier. In this study, researchers studied the effectiveness of increased BDNF levels after partial sleep deprivation (PSD) therapy as a potential antidepressant treatment. They further tested whether pre-existing BDNF circadian patterns are an early predictor of antidepressant therapy responsiveness. They hypothesized that if patients had stable BDNF diurnal patterns and higher levels of BDNF before PSD treatment, then PSD treatment will garner better antidepressive results than those patients who began treatment with lower baseline BDNF levels.
Materials and Methods:
28 major depression patients (15 female, 13 male) around the ages of 19-65 were studied. All participants were evaluated using the Hamilton Depression Rating Scale (HDRS) before partial sleep deprivation (PSD) treatment, in which they were woken up at 1:30 AM. Participants were randomly assigned either modafinil (drug to reduce daytime sleepiness) or placebo after PSD. Blood was drawn from each patient at seven different time points: Day 1 (Before PSD for baseline BDNF assessment) • 8am • 2pm • 8pm Day 2 (After PSD) • 1.30 am (right after being awoken) • 8am • 2pm • 8pm ELISA kits were used to assess serum BDNF levels, and two weeks after PSD treatment, all patient were evaluated again using the HDRS scale. All statistical analysis was done using Two-way ANOVA.
Major Results:
All participants’ BDNF oscillation patterns on day 1 before PSD treatment showed highest BDNF levels in the morning (8am) and lowest at midnight (day 2—1:30AM), as was expected. After PSD (day 2), mean BDNF levels increased 10.4% (8am), 16.2% (2pm), and 20.7% (8pm) when compared to pre-treatment levels, showing that PSD results in rapid BDNF level increases. However, modafinil and placebo treatments showed no significant differences in HDRS ratings or BDNF levels, showing that managing sleep patterns after PSD treatment has no significant effect on treatment efficacy. Two weeks after PSD, however, participants took the HDRS questionnaire and those who scored lower on it, and therefore had better antidepressant results from the PSD, were classified as “longterm responders” (n=10), whereas those who did not show lasting treatment effects and scored higher HDRS scores were classified as “non-responders” (n=18). Long-term responders not only had higher post-PSD (Day 2) BDNF levels than their counterparts, but also had higher serum BDNF levels pre-PSD treatment (Day 1).
Conclusions:
Partial sleep deprivation (PSD) is effective in inducing rapid increase in BDNF levels and garnering relief from depressive episodes, yet both of these outcomes are short-lived. More importantly, however, patient predisposition to stable BDNF circadian rhythms and higher BDNF levels prior to therapy are good predictors of antidepressant treatment efficacy and response in a patient. In short, BDNF’s role in neurogenesis and long-term potentiation are critical to mood disorders like depression and targeted studies into BDNF activity can prove worthwhile in Neuroscience and Psychiatry.
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Maria Giese, Johannes Beck, Serge Brand, Flavio Muheim, Ulrich Hemmeter, Martin Hatzinger, Edith Holsboer-Trachsler, Anne Eckert “Fast BDNF serum level increase and diurnal BDNF oscillations are associated with therapeutic response after partial sleep deprivation� Journal of Psychiatric Research, 59(2014) 1-7.
Summary by: Yuki Nishimura
92 Summary of:
Changes in White Matter Integrity before Conversion from Cognitive Impairment to Alzheimer’s disease
Authors: Defrancesco, M., Egger, K., Marksteiner, J., Esterhammer, R., Hinterhuber, H., Deisenhammer, E. A., & Schocke, M. Background/Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes the loss of memory and cognitive decline over time. Since it is a progressive disease, individuals whom display a “mild cognitive impairment (MCI)” may have a higher probability of developing AD, but not always since it is an onset for other neurodegenerative diseases as well. Those individuals with MCI that develops AD are called converters, and those that do not develop AD are called non-converters. Previous studies have identified that patients that exhibit pre-clinical AD has atrophy of gray matter (GM) in many cortical and subcortical structures as well as a loss of white matter (WM) integrity in the brain.
Materials and Methods:
Data from fifty five German speaking patients older than 62 years of age were collected; 13 MCI converters, 14 MCI non-converters, and 28 healthy individuals. All subjects were given a clinical interview and neuropsychological assessment which include, the MMSE and CERAD battery to test for cognitive functions. Diffusion weighted imaging and T1weighted structural MRI scans were obtained for each subject and were compared using voxel-based morphometry (VBM) analysis and apparent diffusion coefficient (ADC) maps constructed which reflected the mean diffusivity values (MD). VBM is a technique that allows for difference in brain volume to be compared. MD values reflected on the ADC maps, are a measure of diffusivity of water protons in the brain structure.
Major Results: Based on the multiple regression analysis in MCI converters through T1 MRI scans, it was seen that they scored lower on the MMSE and verbal memory test, this had a positive correlation with increased GM atrophy in the left putamen and the left inferior frontal gyrus which are structures that are involved in speech functions. Using VBM analysis of the T1 MRI scans to compare MCI converters and non-converters, results showed that there is more GM atrophy in converters in the left parietal, left putamen, left insula, right parahippocampal gyrus, left and right frontal lobe, as well as a very consistent decrease in GM density in the left temporal lobe. However, no significant difference was seen in the brain volume of MCI non-converters and healthy individuals. From ADC maps, when comparing MCI converters and healthy individuals, there shows a widespread increase of MD values are seen in GM of the left limbic lobe, right middle temporal lobe, and the basal ganglia. Increased MD values of white matter is in the parietal, frontal, and temporal lobe. An increase of MD value is due to neuronal loss in those areas resulting in a disruption of the brain structure, thus having a larger extracellular space to allow for more diffusion of water protons. Once again, the difference in non-converters and healthy individuals is not significant.
Conclusions:
From this correlation study, changes in MD values can be detected throughout the brain for GM and WM atrophy and lesions. Also, the difference between MCI converters and MCI non-converters can be distinguished since data shows that there is not much difference between non-converters and healthy individuals. Changes in MD values detect areas of neurodegeneration and neuronal loss. This suggests that MD can be a potential biomarker to more accurately identify the early onset of AD from MCI conversion, to allow an earlier treatment of the disease.
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Defrancesco, M., Egger, K., Marksteiner, J., Esterhammer, R., Hinterhuber, H., Deisenhammer, E. A., & Schocke, M. (2014). Changes in White Matter Integrity before Conversion from Mild Cognitive Impairment to Alzheimer’s Disease. PLoS ONE, 9(8), e106062.
Summary by: Miranda Nong
94 Summary of:
Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons
Authors: Jing Zhang, Yan Zhu, Guanxia Zhan, Polina Fenik, Lori Panossian, Maxime M. Wang, Shayla Reid, David Lai, James G, Davis, Joseph Baur, & Sigrid Veasey Background/Introduction: Previous studies have shown that extended wakefulness can reduce antioxidant activity and ATP production in the brain, but few studies have shown the metabolic responses to sleep deprivation in wake-active neurons. Zhang et al. showed that the neurons in the locus ceruleus (wake active) fail to maintain SirT3 pathways in extended sleep loss, resulting in neuronal degeneration. The SirT3 pathway is an essential metabolic homeostatic pathway for short-term wakefulness, located in the mitochondrial membrane. It is a NAD+ dependent enzyme that coordinates ATP production and antioxidant production. Low levels of NAD+ and increased oxidative stress (high concentrations of superoxide) can impair SirT3.
Materials and Methods:
SirT3wt (wild type) and SirT3-/- (loss of SirT3 function) mice were introduced to 3 treatment groups: rest, short-term wakefulness (3 hours in light), and long term wakefulness (8 hours in light). All mice underwent surgery to implant EEG and EMG recording wires to observe sleep homeostasis given different genotypes, SirT3wt and SirT3-/-. To visualize the locus ceruleus neurons, they were tagged with anti-tyrosine hydroxylate (red fluorescence) to view under confocal microscopes. To observe the level of SirT3 activity, dihydroethidine (green fluorescence), a superoxide indicator was used. Dihydroethidine freely passes the blood brain barrier and converts to fluorescent dihydroethidine in the presence of superoxide in neurons.
Major Results: mRNA and protein concentrations increased for short term wakefulness than rest and extended wakefulness. This allowed for the maintenance of redox homeostasis in the locus ceruleus neurons. When wake duration was observed given superoxide availability, extended wakefulness showed the highest superoxide level whereas rest and short term wakefulness declined. In addition, SirT3 acetylation in the mitochondria had a significant increase for extended wakefulness when compared to rest and short term wakefulness. SirT3 acetylation in the cytosol had no significant differences within the 3 groups. This suggests that the SirT3 pathway is more responsive to extended wakefulness in the mitochondria. When the dendrites of locus ceruleus neurons were observed, SirT3wt in extended wakefulness showed a reduction of dendritic segments when compared to rest. The neuron cell estimate shows a reduction in neurons by 25%. In SirT3-/-, the difference in neuron cell estimate was not significant. When the dendritic segments were observed, there was no loss but changed in morphology, increase beading and vacuolization.
Conclusions:
Short term wakefulness was found to upregulate SirT3 levels in the mitochondria and increase antioxidant enzyme production, ultimately promoting metabolic homeostasis. In the case of extended wakefulness, SirT3 activity dropped. This was supported by the increase in mitochondrial acetylation of proteins as well as an increase in superoxide production. The next step in research could be on overexpression of SirT3 in neurons. If this could protect cells, it could lead to a promising therapeutic method for sleep deprived individuals.
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Zhang J., Zhu Y., Zhan G., Fenik P., Panossian L., Wang M.M., …Veasey S. (2014). Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons. Journal of Neuroscience, 34(12), 4418-31. doi: 10.1523/JNEUROSCI.5025-12.2014.
Summary by: Hyun Park
96 Summary of:
Traces of Experience in the Lateral Entorhinal Cortex
Authors: Albert Tsao, May-Britt Moser, and Edvard I. Moser Background/Introduction: The entorhinal cortex is a structure that shares reciprocal connections with the hippocampus and neocortical structures and so it can be viewed as a hub for cortical information processing and long-term memory formation. The lateral part of the entorhinal cortex (LEC) is believed to play a role in encoding information about objects within the environment. The goal of the Tsao et al.’s study was to explore whether neurons in the LEC respond simply to physical features of an object within a spatial location or whether the LEC encodes a higher order representation of an object, such as a previous experience with it.
Materials and Methods:
To address this question, the authors implanted rats with tetrodes for single unit recording and trained the animals to run in the enclosed environment, a 1x1 m box with black walls, containing both proximal and distal cues. After habituation, the animals were given three consecutive 10 min trials: “object-free” trial (to determine baseline activity), “object” trial with an object placed at a specific location, followed by the “object-free trial” again. The initial task was then modified such that the object trials included novel objects in a different location, a familiar object in the novel environment (the same box but with brown walls and different spatial cues), a familiar object in a familiar environment but different locations, and also an object was substituted with the rewarding microstimulation of the medial forebrain bundle (MFB) when a rat entered a specific location. While the rats were performing the task, single call activity was recorded from the LEC.
Major Results:
Activity of the single units was quantified as the mean frequency of cell firing. The firing rate of a neuron when a rat was in the location of the object was compared to firing rate outside of the object area. The researchers identified one group of cells that increased the firing rate when the animal entered the location of the object during the “object” trials and a second group of neurons that responded to the location of the object on the following “object-free” trials, i.e., the cells were representing a trace of the familiar object. When tested with the novel object, the activity of the new “object” and the “object-trace” cells could be identified. When the authors moved the familiar object to different locations within the box, the activity of the “trace” cell increased at every location where the familiar object was encountered during the previous trial. However, when a familiar object was placed in the novel environment, the “trace” cell activity did not follow it, suggesting that the trace cells code for experience in a unique environment. Finally, when the rats were tested with the MFB microstimulation delivered at a specific location instead of an object, one set of the LEC neurons responded to the experience of stimulation itself and a distinct set of “trace” cells increased the firing rate when the animal entered the location where during the previous trial, but not the current trial, the stimulation was delivered. Tsao et al. demonstrated that the differential neuronal activity was not due to animal’s movement behaviour.
Conclusions:
In conclusion, the authors emphasize that the LEC “object-trace” cells represent a unique group of neurons, activity of which is distinct from the place cells or “misplace” cells found in the hippocampus, or any pair-association cells in the temporal lobe. It is still not clear whether the LEC processes the information about the location of an object present in the past, or this information is being coded for in the hippocampus and then sent back to the LEC. Finally, Tsao et al. compare their findings of the “trace” cells with the report about similar cells coding for past experience in the anterior cingulate (ACC). It is possible that the LEC serves as an interface between the hippocampus and the ACC in the distributed network of the long-term memory formation.
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Tsao, A., Moser, M. B., & Moser, E. I. (2013). Traces of experience in the lateral entorhinal cortex. Current Biology, 23(5), 399-405.
Summary by: Maryna Pilkiw
98 Summary of:
The effects of social defeat on behavior and dopaminergic markers in mice
Authors: H.-M. Jin, S. Shrestha Muna, T.R. Bagalkot, Y. Cui, B.K. Yadav, Y.C. Chung Background/Introduction:
The impacts of motivation and reward on an organism’s body are regulated mainly through the neurotransmitter dopamine. DARPP is a phosphoprotein that has been proven to play an important role in normal functioning of dopaminoceptive neurons by acting as a mediator between dopamine and several other neurotransmitters and the dopaminoceptive neurons. The experiment conducted in the discussed article tests the effects that social defeat has on mice behaviour and their dopamine levels. Social defeat is the phenomenon where an organism is defeated by others of its kind in a confrontation. This defeat results in the activation of the stress axis leading to a stress response in the body. Since dopamine is the neurotransmitter than is know to be associated with reward and motivation it would most likely be impacted as result of social defeat.
Hypothesis
Mice subjected to the social defeat procedure will show a decrease performance levels in locomotion light preference, novel object recognition, social integration, Morris water maze and forced swimming test for the defeated mice as compared to the control mice.
Materials and Methods:
The experiment used mice aged between seven and 14 weeks and weighing 22–25g and 40–44 g. The researchers executed a social defeat procedure that inflicted social defeat stress on selected mice and lasted 10 days. This form of stress is directed at making the organism feel beneath its social compatriots and feeling defeated. They also kept a set of control mice that weren’t subjected to any artificially induced stress as a control condition. A locomotion test, light/dark preference test, novel object recognition test, social integration test, Morris water maze test and the forced swimming test were conducted on both the control and the mice subject to the social defeat procedure. Finally, western blotting procedure was used on mice brains after conducting the experiment to test dopamine levels in the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HIP) of both the defeated and control mice.
Major Results:
A significant reduction was observed in the total movement of defeated mice as compared to the control mice. Defeated mice were also found to prefer spending much longer time in dark and congested areas as compared to the control mice. Additionally, Defeated mice performed worse on novel recognition test as compared to control mice. Similarly, in the social interaction test defeated mice spent a decreased amount of time, social sniffing as compared to the control mice. As for the difference in dopamine 1 and 2 receptor, no significant differences were seen between the control and defeated mice. The phosphor- Thr34 and Thr75 DARPP beta-actin levels showed a significant difference between the defeated and control mice, as the defeated mice were observed to have much higher levels of DARPP in their prefrontal cortex (PFC) and amygdala (AMY) as compared to the control.
Conclusions:
Social defeat can result in an organism activating symptoms that involve defense mechanisms that one would usually see when an organism is under stress. The experiment conducted in the article discussed above showed that a defeated organism shows symptoms similar to a depressed or anxious organism with signs of cognitive impairment. These symptoms can be attributed to the changes in dopamine levels in the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HIP) of defeated mice as compared to control mice, which were tested, and shown to be different from each other.
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Diagrams taken form: Jin, H. M., Muna, S. S., Bagalkot, T. R., Cui, Y., Yadav, B. K., & Chung, Y. C. (2015). The Effects of Social Defeat on Behavior and Dopaminergic Markers in Mice. Neuroscience. 228, 167-177
Jin, H. M., Muna, S. S., Bagalkot, T. R., Cui, Y., Yadav, B. K., & Chung, Y. C. (2015). The Effects of Social Defeat on Behavior and Dopaminergic Markers in Mice. Neuroscience. 228, 167-177
Summary by: Joravir Singh Riar
100 Summary of:
Exercise and time-dependant benefits to learning and memory
Authors: N.C. Berchtold, N. Castello and C.W. Cotman Background/Introduction: Much research has been done to investigate the role of exercise on cognitive functions, often describing facilitation in rodent memory acquisition on cognitive tasks like the radial-arm water maze (RWM). During these trials, it has been demonstrated that BDNF is a molecular mechanism that is up-regulated in response to exercise. Furthermore, blocking BDNF’s binding to TrkB by antibodies has been shown to attenuate the acquisition of spatial learning tasks. This paper hereby investigates the influence of exercise on acquisition in RWM, the effects of introducing a delay period after exercise on cognitive performance, and the persistence of exercise-induced BDNF protein levels after exercise has ended.
Materials and Methods:
Two groups were created to distinguish between sedentary and exercising mice. The latter had access to running wheels for 3 weeks. At this point wheels were removed and cognitive training began. One exercising group (EX) started the training immediately whilst other groups had a one-week delay (EX/delay 1) or two-week delay (EX/delay 2) before proceeding. The training was a RWM task that took place for four days. Spatial cues on walls were provided in order for mice to recognize the correct arm that leads to the escape platform. If the mouse did not find the platform within one minute, it was guided there. After training, mice brains were extracted to determine average BDNF protein levels. Furthermore, average errors and latency to the escape platform by all mice were determined. A probe trial was done on 4th day of training to assess strength of memory of escape route.
Major Results: The fastest acquisition of the cognitive task in RWM was by EX1 mice, followed closely by EX2 mice. All exercising mice had fewer errors in the RWM than sedentary mice, and also showed better retention of memory during the probe trial. Interestingly, EX mice performed better than EX1 and EX2 in the probe trial, perhaps due to the recency of training, as this group experienced no waiting period. Average BDNF protein levels across all exercising mice were observed to increase for 3-4 weeks after exercise before declining to baseline. BDNF protein levels were highest in the EX group, followed by EX-delay groups and Sedentary groups respectively. Performance scores showed a steep increase in response to small BDNF increments but reached a plateau with more BDNF levels, suggesting a saturation limit to the effect of BDNF on cognitive performance.
Conclusions:
Authors Berchtold et. al have been instrumental in providing further evidence for the facilitative effect of exercise on memory acquisition and retention. This relates greatly to the field of neuroscience as it serves to expand our currently limited understanding of the important effects of exercise on cognitive functions. In addition, this article provides new findings by investigating the effect of exercise delay periods on cognitive performance: enabling future research inquiries in this area by neuroscientists. The authors of this paper also demonstrate another new finding: the temporal dependence effect of exercise on molecular mechanisms of the synapse like BDNF, which is relevant to neuroscience by providing another potential area to investigate in future research.
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Berchtold, N.C. Castello, N. and Cotman C.W. (2010). Exercise and time-dependant benefits to learning and memory. Neuroscience 167 (2010) 588–597.
Summary by:Ashkan Salehi
102 Summary of:
Cognitive impairment following high fat diet consumption is associated with brain inflammation
Authors: Pistell, P. J., Morrison, C. D., Gupta, S., Knight, A. G., Keller, J. N., Ingram, D. K., & Bruce-Keller, A. J. Background/Introduction: Obesity has been linked to chronic inflammation and irregular cytokine production. Clinical research has also shown that obese patients, on average, have deficits in learning and memory when compared to non-obese individuals. However, the mechanism by which obesity affects the brain is unclear. Studies have indicated that brain inflammation is detrimental to cognitive function. Pro-inflammatory cytokines have been found to impair memory. This study examined the relationship between obesity and impaired cognitive ability, and proposed a role for inflammation as the link between the two.
Materials and Methods:
Twelve-month-old C57Bl/6 male mice were used. For 21 weeks, a cohort of mice was administered a Western Diet (WD) consisting of 41% fat, while at the same time a control diet (cWD) was administered to a separate cohort of mice. A third cohort was placed on a high fat lard diet (HL) consisting of 60% fat for 16 weeks, while simultaneously another group was given a control diet (cHL). Mice were then tested for cognitive ability using a stone T-maze. Mice were required to correctly navigate 13 consecutive left and right turns. The number of errors each mouse committed was used as a measure of cognitive ability. Brain tissue slices were then taken from the cerebral cortices of the mice and tested for IL-6, TNF-alpha, MCP-1, and BDNF with an ELISA. As well, western blots for GFAP and Iba-1 were used to measure astrocyte and microglia reactivity, respectively.
Major Results: There was no significant difference found in the number of errors in the Stone T-maze between the WD and cWD groups; therefore the WD diet did not cause a reduction in cognitive ability. Interestingly there also was not a significant difference in the levels of inflammatory cytokines or BDNF growth factor between mice given the WD diet and those given the control cWD diet. Astrocytes were more reactive in WD mice, which was seen by an increase in GFAP expression in the tissue. There were no significant differences in the Iba-1 microglia marker between the two cohorts. Between HL and cHL mice, a significant difference was found in cognitive ability, illustrated by the larger number of errors committed by HL mice. As well, HL mice were found to have higher levels of inflammatory cytokines in brain tissue, and lower levels of BDNF. Astrocytes and microglia were significantly more reactive in HL mice compared to cHL mice.
Conclusions:
Mice given the WD diet were not characterized with either brain inflammation or cognitive impairment. By increasing the fat content to an HL diet, mice were then found to have both brain inflammation and reduced cognitive ability. When taken together this data suggests that obesity may be associated with a reduction in cognitive function, through the inflammation of the brain.
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References For Pictures: http://media.peaceasw.com/2014/02/black-mouse.jpg http://marginalrevolution.com/wp-content/uploads/2013/08/fat-mouse.png http://what.h8r.net/fatmouse/fatmouse.jpg http://blogs-images.forbes.com/joshwolfe/files/2014/06/brain_on_fire.jpg http://cdn.shopify.com/s/files/1/0080/8372/products/tattly_christoph_niemann_low_battery_web_design_01_grande. jpg?v=1336586731
Pistell, P. J., Morrison, C. D., Gupta, S., Knight, A. G., Keller, J. N., Ingram, D. K., & Bruce-Keller, A. J. “Cognitive impairment following high fat diet consumption is associated with brain inflammation “ Journal of Neuroimmunology
Summary by:Husain Shakil
104 Summary of:
Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons during Sleep Deprivation Prevents Memory Deficits Caused by Sleep Loss
Authors: Robbert Havekes, Vibeke M. Bruinenberg, Jennifer C. Tudor, Sarah L. Ferri, Arnd Baumann, Peter Meerlo, and Ted Abel Background/Introduction: The article begins by introducing the reader to the negative effects of sleep deprivation on hippocampal-dependent forms of memory. Multiple behavioural experiments are cited, each observing the negative effect of sleep deprivation on spatial memory in animal models. This is followed by a summary of the known molecular mechanisms behind this phenomenon. Work done by Vecsey et al. (2009) demonstrated that the cAMP degrading enzyme PDE4 phosphodiesterase increased in activity during periods of sleep deprivation. This group also observed that injections of a PDE4 inhibitor (Rolipram) into the hippocampus made memories resistant to sleep deprivation. From these findings, the authors hypothesized that decreases in hippocampal cAMP signalling that occur during sleep deprivation underlie associated memory deficits. To test their hypothesis, the authors aimed to transiently increase cAMP levels in mice during periods of sleep deprivation and observe the effects on spatial memory.
Materials and Methods:
In order to increase cAMP levels solely in the hippocampus, the authors created a viral vector containing the octopamine receptor gene DmOctβ1R. The octopamine receptor is a GPCR natively found in Drosophila. Binding of the octopamine ligand to the receptor results in adenylyl cyclase activation, leading to increased intracellular cAMP levels. The addition of this receptor allowed the authors to increase hippocampal cAMP levels by systemically injecting mice with octopamine. The viral vector also contained a CAMKIIa promoter to ensure the octopamine receptor would only be expressed in excitatory hippocampal neurons, as CAMKIIa is only expressed in such cells. Control mice were given a vector with the DmOctβ1R gene swapped for a GFP gene. Spatial memory was tested in an object-place recognition paradigm. The mice were placed in a chamber with 3 objects and were allowed to explore for 6 minutes. The mice were removed from the chamber and put back in their cages. Some mice were kept awake for 5 hours by experimenters disturbing their cage, while others were allowed to sleep. The mice were placed in the same chamber, with one of the objects in a different location. Task performance was measured based on the preference for the displaced object.
Major Results: The viral delivery of the DmOctβ1R was successful, as expression of the receptor was detected in hippocampal excitatory neurons in the CA1, CA2, CA3, dentate gyrus, and granule cell layer areas. Moreover, IP injections of octopamine resulted in significant cAMP increases in the aforementioned areas. Other brain areas like the prefrontal cortex did not show the same increase, strongly suggesting that the receptor was only present in the hippocampus. The brains of some mice were harvested upon IP injection of octopamine to yield these results. cAMP levels during the trials themselves were not measured. The time mice spent exploring during their 6 minute training trial was not affected by DmOctβ1R presence. Sleep-deprived mice expressing DmOctβ1R performed almost identically to all non-sleep deprived groups. Furthermore, sleep-deprived mice expressing DmOctβ1R significantly outperformed control sleep deprived mice in terms of preference for the displaced object.
Conclusions:
The authors demonstrated that transiently increasing cAMP levels in excitatory hippocampal neurons via octopamine injections protected spatial memories from the negative effects of sleep deprivation. Cognitive deficits associated with sleep deprivation may be mediated by changes in cAMP signalling. Understanding the role cAMP plays in humans and elucidating its downstream effectors could yield insight into the molecular mechanisms of memory consolidation. The clinical applications for sleep-deprived university students are obviously of immense interest as well.
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Havekes, R., Bruinenberg, V., Tudor, J., Ferri, S., Baumann, A., Meerlo, P., & Abel, T. (2014). Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons during Sleep Deprivation Prevents Memory Deficits Caused by Sleep Loss. The Journal of Neuroscience, 34(47), 15715-15721.
Summary by:Arman Shekari
106 Summary of:
Alzheimer Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior
Authors: Alison Burgess, Sonam Dubey, Sharon Yeung, Olivia Hough, Naomi Eterman, Isabelle Aubert, Kullervo Hynynen Background/Introduction: Magnetic resonance (MR) imaging-guided focused ultrasound has been discovered as a technique for locally opening the blood-brain barrier non-invasively to improve the delivery of drugs to the brain. When this method was applied in one hemisphere of the TgCRND8 mouse model of Alzheimer’s disease (AD), plaque load significantly declined even without the delivery of therapeutic agents. The study looked at whether MR imaging-guided focused ultrasound treatments targeting the hippocampus could lead to improvements in behaviour and a reduction in pathological abnormalities associated with AD.
Materials and Methods:
The TgCRND8 mouse model of AD was used in this experiment. The focused ultrasound beam was targeted onto the bilateral dorsal hippocampus for sonication. The sevenmonth-old mice were treated with MR imaging-guided focused ultrasound to open the blood-brain barrier once per week for three weeks. Next, Y-maze analysis was performed. The mice were kept in two of the arms of the maze for 10 minutes, and then were put in the maze again with access to all three arms. The time the mice spent exploring the novel arm was used to test the improvement in spatial memory post-treatment. Immunohistochemical analysis and plaque analysis were also performed.
Major Results: MR imaging-guided focused ultrasound showed that levels of BBB opening were the same in both the TgCRND8 mice and the non-TgCRND8 mice. Without treatment, Tg mice spent 61% less time than the non-Tg mice in the novel arm of the Y-maze. After MR imaging-guided focused ultrasound, Tg mice spent about 99% more time in the novel arm of the Y-maze. The TgCRND8 mice spent 48 seconds in the novel arm after treatment, while without treatment, they spent only about 24 seconds exploring the novel arm. The mice behaviour in the Y-maze was reflected by the significant reduction in the number and size of amyloid plaques in the ultrasound-treated mice. There was a plaque size reduction in the treated TgCRND8 mice by about 20%, and a 19% decrease in plaque load in the hippocampus. In addition, there was an increase in the number of newborn neurons in the hippocampus in the treated mice group, and a 227% increase in dendrite length in both treated non-Tg and TgCRND8 mice.
Conclusions:
The results in the Y-maze suggest that after treatment, the mice had an increase in spatial memory and cognition, which are commonly diminished as AD progresses. This shows that MR imaging-guided focused ultrasound may ameliorate memory deficits in AD, decrease amyloid plaques in the AD brain, and increase the number of neurons and synapses in the hippocampus.
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Source: Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., Hynynen, K. (1994). Alzheimer Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior. Radiology, 273 (3), 736-745.
Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., Hynynen, K. (1994). Alzheimer Disease in a Mouse Model: MR Imaging–guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior. Radiology, 273 (3), 736-745. Summary by:Jaclin Simonetta
108 Summary of:
Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression
Authors: Kessels HW, Nabavi S, Malinow R. Background/Introduction: Alzheimer’s disease (AD) is characterized by an increase in extracellular plaques containing β-amyloid (Aβ) peptide and intracellular tau tangles. In AD models, Aβ has been shown to cause synaptic depression, loss of spines and reduced synaptic plasticity. This article seeks to elucidate the mechanism behind Aβ’s contribution to synaptic deficits in AD. Previous studies have shown that blocking NMDA receptors (NMDARs) can lessen the effects of Aβ on synapses. Composed of two glycine binding GluN1 and two glutamate binding GluN2 subunits, NMDARs are ionotropic receptors that are controlled by a voltage-dependent Mg2+ block. The GluN2 subunit can occur in two isoforms- GluN2A and GluN2B in hippocampal neurons. Upon glutamate binding, its primary function allows Ca2+ ion flow through the receptor however a previous study has proposed a secondary function where there is receptor endocytosis and an NMDAR subunit switch. Based on this background information, the authors of this study focus on the function of NMDARs in the hippocampus in the presence of Aβ oligomers.
Materials and Methods:
Using the Sindbis virus, the authors infected CA1 neurons in hippocampal rat slices with constructs of AP-CT100 (product of β-secretase cleavage of APP, precursor of Aβ) and AP-CT84 (product of α-secretase cleavage of APP). The slices were incubated for 20-30h to allow for expression of the virus. During the incubation period, the authors performed experiments with a variety of drugs including Aβ inhibitors, NMDA antagonists specific for the GluN2 subunit or GluN2B isoform, and ion-channel blockers. Then, neighbouring control and CA1 pyramidal neurons were stimulated with two separate electrodes and the AMPAR-mediated excitatory postsynaptic current (EPSC) and the NMDAR-mediated currents were measured. The EPSC amplitudes were created from an average of 50 sweeps.
Major Results: First, the authors confirmed that there is synaptic AMPAR depression in the increased presence of Aβ produced by APP-CT100 expressing neurons and not with expression of APPCT84 or with expression of APP-CT100 and inhibitors of Aβ production such as a γ-secretase inhibitor or scyllo-inositol. In the next series of experiments, the authors confirmed that the Aβ-driven synaptic depression needs GluN2B activation. During APP-CT100 expression, the slices were incubated with d-APV or R-CPP (NMDAR antagonists), Ro or ifenprodil (antagonists that lock GluN2B in a closed conformation), and PEAQX (competitive GluN2 antagonist). Now that the authors established that Aβ works on the GluN2B subunit of the NMDAR, they wanted to further investigate the NMDAR’s function. During APP-CT100 expression, slices were incubated with MK-801 or ketamine (ion-channel blockers) and CK-7 (blocks NMDAR at glycine binding site). From this set of experiments, the authors were able to conclude that the Aβ driven synaptic depression is not due to ion flux through the NMDAR but rather suggests that there is a change in the GluN2B conformation. Finally, the authors compared NMDAR transmission in infected versus non-infected cells before and after the addition of Ro to find that the ratio of GluN2A:GluN2B increased, suggesting switching of the subunits.
Conclusions:
The authors were able to show that Aβ incudes AMPAR synaptic depression by activating the GluN2B subunit of the NMDAR and not through ion flux of the NMDAR. They also showed that the Aβ oligomers were able to increase the GluN2A:GluN2B ratio by removing the GluN2B NMDARs from synapses. This study provides a preliminary mechanism for Aβ function on synapses. If components of this pathway are identified upon further investigation, they may serve as potential drug targets in AD patients to reduce synaptic depression and thereby learning and memory problems in this population.
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Kessels HW, Nabavi S, Malinow R. (2013). Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression. PNAS, 110(10):4033–4038. doi:10.1073/pnas.1219605110
Summary by: Olivia Singh
110 Summary of:
Default Mode Network Mechanisms of Transcranial Magnetic Stimulation in Depression
Authors: Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. L., Gordon, R., Leuchter, B., Voss, H. U., Casey, B. J., Etkin, A., & Dubin, M. J. Background/Introduction: Depression has been one of the most common psychiatric conditions affect individuals worldwide. However, many of the current antidepressant medications have been shown to be limited in efficacy in terms of treatment and remission prevention. Transcranial magnetic stimulation (TMS) appears to be a safer and more tolerable treatment alternative that is effective in depressed individuals, including those resistant or averse to medication. This study investigates the effects of TMS as a treatment of depression and the mechanisms in which it modulates resting state functional networks in the human brain.
Materials and Methods:
17 depressed individuals and 35 healthy controls were given resting state fMRI scans to establish their resting state functional networks in the brain. Healthy controls were scanned once; whereas depressed individuals were scanned pre- and post-treatment. The treatment consisted of 25 sessions of 10Hz excitatory TMS delivered at the left dorsolateral prefrontal cortex (DLPFC) over 5 weeks. Functional connectivity maps of the Central Executive Network (CEN) and Default Mode Network (DMN) were generated to compare the difference in brain activity between depressed and healthy individuals as well as the difference in brain activity in depressed individuals pre- and post-treatment. The symptom of depressed individuals was assessed using the Hamilton Rating Scale for Depression (HAM-D) pre- and post-treatment.
Major Results: Comparison between pre-treatment depressed and healthy individuals shows hypoconnectivity between the DLPFC and CEN and, contrastly, hyperconnectivity between the subgenual anterior cingulate cortex (sgACC) and DMN in the depressed brain. 25 sessions of TMS treatment at left DLPFC over a 5 weeks period result in mostly normalized connectivity between the DLPFC and DMN but no difference in connectivity between the sgACC and CEN, which remains abnormally elevated. Overall, the symptoms of depressed individuals improved as assessed using the HAM-D by over 9 points.
Conclusions:
Results suggest that TMS treatment modulates functional connectivity in the brain, and provides treatment effect in reducing depressive symptoms. This study has clinical importance in the understanding of depression and further development of more effective treatments.
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Liston, C., Chen, A. C., Zebley, B. D., Drysdale, A. T., Gordon, R., Leuchter, B., ‌ & Dubin, M. J. (2014). Default mode network network mechanisms of transcranial magnetic stimulation in depression. Biological psychiatry, 76(7), 517-526
Summary by: Eugene Tang
112 Summary of:
Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease.
Authors: S. Kriks, J.W. Shim, J. Piao, Y.M. Ganat, D.R. Wakeman, Z. Xie, L. Carrillo-Reid, G. Auyeung, C. Antonacci, A. Buch, et al. Background/Introduction: Kriks, et al. investigated the significance of human pluripotent stem cells (PSCs) in regenerative cell therapy by examining its performance in animal models of Parkinson’s disease.
Materials and Methods:
In this study, a floor-plate protocol (in comparison to the rosette method) was used to derive dopaminergic (DA) neurons from human PSCs cells. The expression of floorplate precursors was especially important to stem cell specialization/differentiation. It is known that CHIR activates canonical Wnt signalling and induces the expression of LMX1A (roof plate marker), which promotes the specialization of PSCs into DA neurons in vivo. Specific precursors such as LMX1A and FOXA2 were expressed after eleven days of exposure to Wnt signalling and sonic hedgehog (SHH) factors. After differentiation these specialized midbrain DA neurons were then obtained and engrafted into three host animal populations, each of which was a model for Parkinson’s. The researchers also looked at ongoing concerns associated with engraftment. One major problem associated with stem cell engraftment would be overgrowth or non-neuronal differentiation in host organisms.
Major Results: The first group of animals used was composed of a control group with non-lesioned mature mice. The stem cell derived DA neurons showed high survival rate even six weeks after engraftment, no overgrowth was observed in the control population. The second group of rodents used was composed of 6-hydroxy-dopamine (6-OHDA) lesioned parkinsonian rats. The development of PSC-derived DA neurons showed high survival rates even after four months. Further analysis illustrated a rescue of amphetamineinduced rotation behaviour, which is usually impaired in rats that are affected by Parkinson’s. In addition, these rats also showed improvements in tests that required movement and motor functions (i.e. stepping test and the cylinder test). Lastly, the final group of animals used was adult MPTP lesioned rhesus monkeys. The stem cells were injected along with the DA precursors in the caudate and putamen (basal ganglia region) within both sides of the brain. In addition, one side of the brain was also injected with green fluorescent protein (GFP) to track the development of the DA neurons. After one month, the results illustrated high DA neuron survival rates and no overgrowth.
Conclusions:
In conclusion, all three animal models showed high efficacy of engrafted PSCderived DA neurons. Thus with future research, we can explore many other biomedical applications of human pluripotent stem cell therapies for treating other neurodegenerative disorders (such as dementia) in addition to Parkinson’s disease.
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S. Kriks, J.W. Shim, J. Piao, Y.M. Ganat, D.R. Wakeman, Z. Xie, L. Carrillo-Reid, G. Auyeung, C. Antonacci, A. Buch, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 480 (2011), pp. 547–551. Retrieved from: http://www.nature.com/nature/journal/v480/n7378/ full/nature10648.html
Summary by: Jiawei Zhang
Huntington’s disease (HD) is a neurodegenerative disease that severely affects motor, cognitive and psychological functions. HD patients are observed with striatum atrophy from the loss of medium-sized spiny neuron. Despite mechanisms regarding how the huntingtin gene causes the degeneration of striatal neurons is unclear, many researchers began to focus on the effects of increased BDNF levels in the striatum and its effect on HD patients. It has been shown the there is a reduction in striatal BDNF protein levels in patients. BDNF deficiency in the striatum causes neuronal alterations such as neuronal loss and dendritic abnormalities that affects HD pathogenesis. Xie et al., tested the effects of increased BDNF expression in the forebrain on a double transgenic mice (of BDNF overexpression gene and YAC gene to induce HD) to observe striatal changes which may influence HD. They used various methods such as Rotarod, Beam walk, footprint, and muscle strength test to examine phenotypic characteristic changes between HD mice (YAC128 mice), BDNF transgenic mice (BTg mice), widetype between YAC128 and BTg, and double transgenic mice (YAC;BTg mice). Xie et al., also performed in situ hybridization, immunoblotting, immunohistochemistry to compare molecular changes within the brain between the four mice strains. They ran a Western Blot to verify that BDNF protein level has increased in the striatum. Xie et al., observed that BDNF overexpression in the forebrain of the YAC128 mice increased BDNF in the striatum. Moreover, BDNF was able to activate TrkB receptor which signals various pathways that mediates neuronal differentiation, neuronal survival, synaptic plasticity and soma size in both YAC128 and BTg mice. BDNF overexpression was able to improve motor related performance of YAC; BTg mice. BDNF overexpression can reverse cognitive deficiencies in YAC128 mice, as seen through improvements in procedural learning of swim tests. As well, BDNF was able to prevent and normalize striatal atrophy (and therefore, brain weight overall) and loss in striatal neurons. In general, amplifying BDNF protein expression increased receptor levels related to neurotransmitters important for striatal function such as dopamine receptor D2. Most importantly, it reversed striatal medium-sized spiny neuronal spine and dendritic morphology that were previously altered in the YAC128 mice. BDNF overexpression was able to prevent and normalize many functions that are affected by HD, such as motor and cognitive deficiencies. On a molecular level, it was also able to reverse atrophy in the striatum and neuronal loss and alterations. Furthermore, it was shown BDNF overexpression can also stimulate signaling pathways that promotes neuronal differentiation and survival in a YAC128 mice. These evidence suggests BDNF overexpression in the striatum is a potential therapeutic treatment for HD. The study did observing activities of seizure in some BTg and YAC; BTg mice and advises to not overstimulate BDNF in epileptic regions in brain regions such as hippocampal and entorhinal cortex.
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Summary by: Yidong Zhan
116 Summary of:
Pharmacological Rescue of Mitochondrial Deficits in iPSCDerived Neural Cells from Patients with Familial Parkinson’s Disease
J, Marder K, Andrabi S, Perez-Torres E, Klein C, McLean JR, Clark L, Isacson O, Sundberg M, Feng J, Trojanowski JQ, Guardia-Laguarta C, Authors: Graziotto Dawson VL, Opala G, Chen L, Moskowitz C, Krainc D, Volpicelli-Daley L, Dawson TM, Scarffe LA, Xie Z, Surmeier DJ, Jiang H, Romero N, Wszolek ZK,
Przedborski S, Cooper O, Huang Z, Mazzulli J, Osborn T, Bogetofte H, Lee VM-Y, Carrillo-Reid L, Ross OA, Uitti RJ, Seo H, Lawson T, Deleidi M, Hargus G
Background/Introduction:
Parkinson’s disease is the result of ongoing degeneration of dopamine-generating neurons and synapses of the nigrostriatal pathway which can be induced by both environmental and genetic factors. This paper looks at the mutations in genes that impact the activity of kinases LRRK2 (leucine-rich repeat kinase 2) and PINK1 (PTEN-induced putative kinase 1) that seem to increase the risk of developing Parkinson’s disease. By using iPSCs (induced pluripotent stem cells) derived from fibroblasts of familial Parkinson’s disease patients as well as healthy patients and patients with the mutations who have not yet shown signs of PD, to form neural cells, researchers from several labs were able to combine assay results to compare the cell phenotypes from each. This paper pays attention to deficits in mitochondrial function in particular.
Materials and Methods:
First, the researchers generated iPSCs from fibroblasts of patients with familial PD, patients carrying the mutations but pre-symptomatic and from healthy subjects used as a control. Next, they observed levels of vulnerability of the derived neural cells to chemical stressors that affect specifically the function of mitochondria or the degradation of proteins using an LDH (lactate dehydrogenase) assay (measuring its release), and used immunocytochemistry to quantify levels of dopamine neurons. They then focused further on the PINK1 mutation by measuring mROS levels in response to cellular stressors (and later GSH levels) by fluorescently labeling the cells with an indicator of mROS and recording the amount of fluorescent cellular events that occurred. Next, oligomycin, followed by FCCP and finally rotenone, all compounds which inhibit proteins or complexes that deal with oxygen consumption, were administered and the oxygen consumption rate was measured using an XF24-3 Extracellular Flux Analyzer during injection of the compounds. To measure rates of mitochondrial mobility, live-cell imaging was used on all three classes of subjects. In the final step the researchers used antioxidants Coenzyme Q10, rapamycin or GW5074 to see if they could pharmacologically rescue the increased vulnerability of PD neural cells to chemical stressors, again measuring the amount of LDH released.
Major Results:
1) Patients with familial PD and pre-symptomatic patients who carry the mutations as well, both show higher vulnerability when exposed to low concentrations of chemical stressors such as valinomycin, which causes the depolarization of mitochondria with an influx of K+ ions. However they do not show vulnerability to CCCP, a chemical stressor that does the same function, except using protons. This may show that the mutations in the derived neural cells cause the inability to respond to mitochondria that has been damaged by K+ ions. 2) Those carrying the PINK1 mutation again demonstrated the inability to handle oxidative stress as seen by a significant increase of mROS (mitochondrial reactive oxygen species), a major cause of cellular stress, and a decrease in GSH, an antioxidant that should be present to prevent damage done by high levels of mROS. 3) The basal oxygen consumption rate of patients with PD with the PINK1 mutation was higher than those who did not carry the mutation, and injection of oligomycin, an inhibitor of ATP-synthase, did not reduce this suggesting that the electron transport chain is impaired in this situation. However in the LKKR2 mutated neural cells, the OCR is less than that of healthy subjects which suggests that the electron transport chain is fine, but that increased kinase activity reduces the OCR. 4) The LKKR2 mutations show more mitochondrial mobility as well as in a more bidirectional manner, and shorter mitochondrial length than in healthy individuals and the PINK1 mutation. This mutation is then further implicated in mitochondrial impairment. 5) Pharmalogical rescue only occurred by coenzyme Q10 rescuing the PINK1 vulnerability to low concentrations of concanamycin A and valinomycin.
Conclusions:
The continuous degeneration of dopamine-generating neurons in the nigrostriatal pathway is the key feature of Parkinson’s disease. The iPSCs generated in this study were efficient in responding to low concentrations of cellular stressors that can be thought to mimic the gradual amassing of dysfunctional mitochondria (as you would see in aging PD patients) and so they provide an opportunity to delve into how these significant mutations affect the degenerative aspects of this disease. Individual treatment is possible by using iPSCs, and can be done by using cellular reprogramming technology as seen from the data collected of which mutations respond to which antioxidants for pharmacological rescuing. In short, these neural cells derived from iPSCs allow for major advances in understanding the foundation of PD and possible treatments.
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Graziotto J, Marder K, Andrabi S, Perez-Torres E, Klein C, McLean JR, Clark L, Isacson O, Sundberg M, Feng J, Trojanowski JQ, Guardia-Laguarta C, Dawson VL, Opala G, Chen L, Moskowitz C, Krainc D, Volpicelli-Daley L, Dawson TM, Scarffe LA, Xie Z, Surmeier DJ, Jiang H, Romero N, Wszolek ZK, Przedborski S, Cooper O, Huang Z, Mazzulli J, Osborn T, Bogetofte H, Lee VM-Y, Carrillo-Reid L, Ross OA, Uitti RJ, Seo H, Lawson T, Deleidi M, Hargus G “Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease” Sci Transl Med (2012) doi: 10.1126/scitranslmed.3003985 Published online 04 July 2012.
Summary by: Nimara Dias-Karunaratne
118 Summary of:
Social Interaction Rescues Memory Deficit in an Animal Model of Alzheimer’s Disease by Increasing BDNF- Dependent Hippocampal Neurogenesis
Authors: Ya-Hsin Hsiao, Hui-Chi Hung, Shun-Hua Chen, and Po-Wu Gean Background/Introduction:
Strong social connections have been found to decrease the risk of cognitive decline and Alzheimer’s but the underlying mechanisms are unknown. BDNF has been found to play an important role in the differentiation and survival of certain neurons involved in LTP, learning and memory. Previous research has revealed that increased BDNF will enhance neurogenesis. Hsiao et al. provided first evidence that when APP/PS1 mutant mice with impaired contextual fear memory are cohoused with wild type mice, there will be increased levels of BdnfmRNA and protein production which will result in increased neurogenesis and ultimately rescue memory in mutant mice.
Materials and Methods:
Male APP/PSI mutant mice were obtained from the Jackson Labertory. At 6 months old an APP/PS1 randomly housed with WT mice for 3 months. 2 APP/PS1 mice where cohoused to serve as control. Sociability of APP/PS1 and WT mice was measured by measuring total duration of contact for 10 minutes. Fear conditioning, morris water maze and object-place recognition was used to test for memory. BdnfmRNA and protein were measured by dissection of hippocampal tissue from the mutant mice. BrdU and NeuN were injected into mice to detect neurogenesis. Methylazoxymethanol acetate, diphtheria toxin and a retrovirus vector encoding DT receptor was injected into post-cohousing mutant mice to block/ablate cell proliferation and test the relationship between neurogenesis and memory improvement. Loss of function by shRNA transfection and overexpression of BDNF was conducted to test for the role of BDNF in rescuing memory. Statistical analysis was conducted to determine significance of the data.
Major Results: After cohousing with WT mice, APP/PS1 mice showcased reversal of contextual memory impairments and performed better in the memory tests. Social interaction with wild type mice increased BDNF mRNA and protein in the hippocampus. Elevated BrdU+/NeuN+ cells in the dentate gyrus after cohousing indicates increased neurogenesis in mutant mice. Chemically blocking cell proliferation using methylazoxymethanol acetate abolished the positive effects of social interaction in APP/PS1 mutants. Ablation of specific mitotic neurons using diphtheria toxin and a retrovirus vector encoding DT receptor also had the same effect. Lastly it was also shown that overexpression of BDNF mimicked memory improving effect while genetic knockdown blocked memory improvement. Which indicates that the rescue of contextual memory by social interaction is mediated by BDNF hippocampal neurogenesis.
Conclusions:
It was found that social interactions in effect reversed memory deficits in APP/PS1 mice. The results provided evidence social housing improves memory and cognition in the mouse model of Alzheimer’s disease via BNDF expression and associated neurogenesis in the hippocampus. The proposed mechanism provided a basis in the prevention, treatment and management of cognitive decline such as Alzheimer’s disease associated dementia .
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Citation: Hsiao YH, Hung HC, Chen SH, Gean PW. (2014) Social Interaction Rescues Memory Deficit in an Animal Model of Alzheimer’s Disease by Increasing BDNF- Dependent Hippocampal Neurogenesis. The Journal of Neuroscience, 34(49), 16207-16219
Hsiao YH, Hung HC, Chen SH, Gean PW. (2014) Social Interaction Rescues Memory Deficit in an Animal Model of Alzheimer’s Disease by Increasing BDNF- Dependent Hippocampal Neurogenesis. The Journal of Neuroscience, 34(49), 16207-16219 Summary by: ZiTeng Li
120 Summary of:
Intra-amygdala microinjection of TNF-α impairs the auditory fear conditioning of rats via glutamate toxicity
Authors: He Jing, Yongxin Hao, Qiang Bi, Jiaozhen Zhang, Pingting Yang Background/Introduction: The production of pro-inflammatory cytokines during systemic infection is known to contribute to cognitive impairment via various mechanisms. This study examines, in particular, the cytokine TNF-α and its effects on cognitive functions by directly injecting TNF-α into the brain. Past research have shown that TNF-α can interfere with proper learning and memory functions. In addition, high levels of TNF-α have also been found in patients with Alzheimer’s disease, a neurodegenerative disorder. Thus, the study further investigates excitotoxicity as a possible mechanism for TNF-α-induced cognitive impairment since TNF-α is known to enhance glutaminergic transmission in vitro.
Materials and Methods:
Cannula implantation surgery was performed on rats to facilitate Intra-amygdala microinjection of TNF-α. Auditory fear conditioning was employed to assess rodent learning and memory function by scoring the freezing responses exhibited in rats. The rats were allowed to habituate to the conditioning chamber on Day 0. On Day 1, the rats were injected with TNF-α (experimental) or ACSF (control). The conditioning session began on Day 2, where the rats first habituated to a tone (CS) and is later subjected to a footshock (US) paired with a tone. The rats then underwent 15 extinction sessions. Foot shock sensitivity was also tested. In order to determine whether the glutaminergic pathway is involved in TNF-α induced cognitive impairment, 1) HPLC was used to measure glutamate (experimental) and GABA (control) levels in the amygdala and 2) Rats were administrated PBS+TNF-α, MK-801 (an NMDAR antagonist), or MK-801+TNF-α before they were subjected to fear conditioning in a second experiment.
Major Results: Rodents treated with TNF-α displayed a lower percentage increase in freezing behaviour during conditioning compared to the rapid increase in rats treated with the vehicle (ACSF). During the extinction phase, the percentage of freezing behaviour in the vehicle group decreased significantly while freezing percentage decreased much less in the TNF-α groups. There were no differences in foot shock sensitivity between the two groups; therefore, the possibility that TNF-α affected fear conditioning is eliminated. TNF-α-treated rats were also found to have higher levels of glutamate in the amygdala than vehicle-treated rats, however, GABA levels remained unchanged. Results of the 2nd fear conditioning experiment showed that rats in the MK-801 groups displayed proper acquisition and extinction of the freezing response whereas it is impaired in TNF-α+PBStreated rats. Moreover, the application of MK-801 with TNF-α is seen to be able to rescue proper fear learning.
Conclusions:
Glutamate levels can be increased in vivo by TNF-α; thus, TNF-α can cause learning and memory deficits via neurotoxicity induced by excessive stimulation of NMDAR by glutamate. Pharmacological blockade of glutaminergic pathway using an NMDAR antagonist such as MK-801 can prevent cognitive dysfunction. The study is relevant to neuroscience because it furthers our understanding of how the immune response and consequent cytokines affect the brain and cognitive function.
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Picture Sources: http://imgs.tuts.dragoart.com/how-to-draw-yuki-sohma-as-rat_1_000000002561_5.png http://images.clipartpanda.com/consternation-clipart-hypodermic-needle.gif http://comparative-cognition-and-behavior -reviews.org/wp/wp-content/uploads/2013/10/kesner_figure1.png http://www.nature.com/nm/journal/v16/n4/images/nm0410-369-F1.jpg
He Jing, Yongxin Hao, Qiang Bi, Jiaozhen Zhang, Pingting Yang “Intra-amygdala microinjection of TNF-α impairs the auditory fear conditioning of rats via glutamate toxicity” Neuroscience Research. (2014). http://dx.doi.org/10.1016/j.neures.2014.10.015 Summary by: Man Lai Ho
122 Summary of:
An fMRI study on the influence of sommeliers’ expertise on the integration of flavor
Authors: Pazart L, Comte A, Magnin E, Millot J-L and Moulin T Background/Introduction: Flavour integration is a complex neurological process. It involves emotions, gustatory and olfactory sensing, and semantic, episodic and flavour memory. Flavour integration is important to study because of its effects on eating behaviour. In this study the authors examine the differences in brain activation during wine sampling between experts and novices via fMRI. By blinding the participants to the types of wine, the authors can show the importance of memory and sensing capabilities in flavour integration. Temporally, the authors hypothesize that wine experts (the better flavour integrators) will be able to integrate flavours before swallowing, contrary to the previous study on this topic.
Materials and Methods:
Ten wine experts were matched with a wine novice of similar age, sex and locality. All 20 subjects did a water pre-test to practice drinking in the controlled way: 7 seconds of swishing the liquid, 13 seconds of after-taste. For the actual task, wine and water were randomized and each was tried twice in a row then rinsed with water. No visual information was possible, as the wine/water was delivered in a custom contraption, and the participants were asked to close their eyes. During the task the participants were measured with an fMRI machine. The water rinse was used as a control.
Major Results: The results highlight the differences between experts and controls during the wine testing trials. The authors analyzed both taste and after-taste activation by all subjects, by group: experts vs contols, and by contrast: expert-controls and controls-experts. For all subjects there was activation in the insula and frontal lobe during taste and aftertaste, and in the pallidum, left parahippocampal gyrus and left thalamus during taste. Analyzing by group revealed significant differences in activation between experts and controls. During taste, experts showed activation in more brain areas, particularly the brainstem, subcortical areas, the amygdala/hippocampus complex, and temporal and occipital lobes. Controls showed greater activation in the parietal lobes. During aftertaste, experts showed much less activation overall. They showed more activation in the right temporal lobe and the left hippocampus than controls, but the controls showed more activation in the caudate nucleus, anterior insula, and frontal, parietal, and temporal lobes.
Conclusions:
The main conclusions to be drawn from the study are that expertise promotes faster and more efficient flavour processing. Further, the brain areas involved appear to be memory-related, implying a deeper understanding of the flavour (associated origins, familiar characteristics). Expertise implies faster processing at the appropriate levels of the brain to integrate flavour from various modalities.
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Images from Pazart et. al. (2014)
Pazart L, Comte A, Magnin E, Millot J-L and Moulin T (2014) An fMRI study on the influence of sommeliers’ expertise on the integration of flavor. Front. Behav. Neurosci. 8:358.
Summary by: Sylvia Jennings
124 Summary of:
BDNF mediates improvements in executive function following a 1-year exercise intervention
Authors: Leckie, R. L., Oberlin, L. E., Voss, M. W., Prakash, R. S., Szabo-Reed, A., ChaddockHeyman, L., ‌Erickson, K. I. Background/Introduction: Ample research in the field of cognitive and behavioral neuroscience has demonstrated a link between age-related neurodegeneration and progressive loss of executive function. Age-related neurodegeneration is the process by which the elderly brain, heaped with knowledge of ones past, undergoes neuronal dwindling and synaptic pruning due to programmed cell death (apoptosis) of brain cells. As neurons are lost, executive function - a higher cognitive ability involved in managing working memory, reasoning, rationalizing and planning forthcoming behaviors - becomes impaired. To decrease the rate of neurodegeneration - particularly in the prefrontal cortex where executive function is regulated - researchers have begun to investigate weather an elevation in brain derived neurotrophic factor (BDNF) can improve neurite outgrowth and cell survival well into old age. A depletion of this growth factor in the prefrontal cortex has been tied to increased neurodegeneration, as demonstrated by reduced grey and white matter volumes and thus compromised executive control. Researchers have considered natural elevation in BDNF serum levels via aerobic exercise. In the following study, Leckie et al. (2014) sought to demonstrate that a 1-year daily exercise intervention, specially that of the aerobic kind, increases BDNF serum levels and improves performance on a test of executive function in elderly subjects.
Materials and Methods:
A sample of 92 elderly adults (mean age = 67) had blood drawn prior to a 1-year exercise intervention. The sample was clotted, incubated and centrifuged to later quantify serum BDNF using an immunoabsorbant assay. Participant’s aerobic fitness levels were assessed prior to appointing them to an exercise condition for a 1-year intervention. The VO2max of all participants - the maximum volume of oxygen used by the subject was measured while completing a cardio fitness test. Following the fitness assessment, subjects were assigned to one of two conditions: 47 participants were assigned to an experimental condition, a 1-year aerobic exercise intervention and 45 were assigned to a control condition, a 1-year stretching and toning exercise intervention. Participants in the aerobic exercise condition were required to walk for 10 minutes daily, thereafter increasing this duration by 5 minutes until a 40 minute maximum exercise period was reached. Participants in the stretching-toning condition completed 4 muscle toning exercises, yoga and one exercise of their choosing, daily. BDNF serum levels were measured at the end of both 1-year exercise intentions. Improvements in executive function following the intervention were assessed via a task-switch paradigm. Numbers were displayed in a square box, where background colour indicated whether subjects were to make even/odd or lower/higher judgments about the number presented. When the background was blue, subjects were asked to determine weather the number was higher (by pressing an X key) or lower (by pressing a Z key) than 5. When the background was pink however, they were asked to make odd (by pressing the N key) or even (by pressing the M key) judgments. A Block consisted of the number presentation for 1500 ms., a fixation period of 3 ms. after which another number was presented. The task was divided into two conditions. In the single task condition, participants made high/low judgments in Block 1 and even/odd judgments during Block 2 for 60 trials. The second mixed condition was subdivided into two trials. During a repeat trial, subjects made one type of judgment (higher/lower or even/odd judgments), similar to the single task condition. In the switch trial, blocks included both higher/lower and odd/even judgments. Accuracy - as a measure of executive function -during the task-switch paradigm was measured based on the difference in percent correct judgments for the mixed condition and the single task condition.
Task-Switch Paradigm Elucidated Condition 1: Single Task Condition - 2 blocks, 60 trials each. Block 1 – Higher/lower than 5 judgment (1500 ms.) - fixation (3 ms.) - Higher/lower than 5 judgment (1500 ms.) Block 2 – Even/odd judgment (1500 ms.) - fixation (3 ms.) – Even/odd judgment (1500 ms.) Condition 2: Mixed Condition – 1 block, 120 trials Repeat Trial (1 Block) - Higher/lower than 5 judgment (1500ms) - fixation (3 ms.) Higher/lower than 5 judgment (1500 ms.) OR Even/odd judgment (1500 ms.) - fixation (3 ms.) – Even/odd judgment (1500 ms.) Switch Trial (1 Block) - Higher/lower than 5 judgment (1500 ms.) - fixation (3 ms.) Even/odd judgment (1500 ms.) (can be reversed)
Major Results: Subjects in the aerobic exercise condition and the stretching and toning condition did not display differences in the pre-intervention serum BDNF levels and VO2max. Post-serum BDNF levels were elevated for participants in the aerobic exercise condition, specifically for subjects > 65 years of age. Thus, age had a moderating effect on aerobic exercise and BDNF serum levels. Global accuracy (mixed trial accuracy - single trial accuracy) was greater for subjects >71 years of age in comparison to younger subjects. Thus, increased BDNF levels due to daily aerobic exercise mediate improvement in executive function. Participants >65 in the stretching and toning condition did not display higher BDNF levels, but rather marked decreases in the post-serum levels of this neurotrophic factor, evidence of age-related neurodegeneration. Subjects in this flexibility exercise conditioning performed poorly on the task-switch paradigm, particular for the mixed condition when they were required to make both higher/lower and even/ odd judgments. Thus, decreased BDNF levels in these subjects led to increased apoptosis of neurons in regions involved in executive function, as demonstrated by the decreased accuracy in judgments. It is worthy to note that local accuracy, switch trial accuracy repeat trial accuracy, was similar for subjects in the aerobic exercise condition and the stretching and toning condition.
Conclusions:
The age of elderly subjects moderates changes in BDNF serum levels as demonstrated by significantly higher amounts of neurotrophic factor in adults >65. Subjects in the 1-year aerobic condition, >71 years of age showed better task-switch performance, with higher accuracy in mixed trials that demand executive function and control. Thus, an increase in serum BDNF levels due to aerobic exercise mediates the effect of this physical activity on task-switch performance. Stretching and toning does not elevate BDNF levels and thus task-switch performance, as mediated by this factor, declines. Thus, elderly individuals should be encouraged to partake in daily aerobic exercise, rather than flexibility exercise to prevent the waning of executive function. A limitation of this study however is the lack of neuroimaging. A similar study should perform fMRI simultaneously as participants complete the task-switch paradigm to look at activity in the prefrontal cortex. The subject’s white matter should also be assessed using tractography to look for neuronal dwindling in regions associated with executive function. Furthermore, subjects prior to intervention should have completed the task-switch paradigm for comparative purposes. Thus, Leckie et al. (2014) found elevated BDNF levels as mitigating factor for neurodegeneration in regions involved in executive control by mediating the effects of aerobic exercise on task-switch performance. Furthermore, age moderated the effect of exercise intervention on BDNF serum levels, with adults >65 showing higher levels of growth factor.
Leckie, R. L., Oberlin, L. E., Voss, M. W., Parkas, R. S., Szabo-Reed, A., Chaddock-Heyman, L., ‌ Erickson, K. I. (2014). BDNF mediates improvements in executive function following a 1-year exercise intervention. Front. Hum. Neurosci, (8) 985, 1-10.
Summary by: Melissa Colaluca
128 Summary of:
Fear of the unexpected: Hippocampus mediates novelty-induced return of extinguished fear in rats
Authors: Stephen Maren Background/Introduction: Many psychological problems such as post-traumatic stress disorder rely on treatments that attempt to weaken or erase learned fears and memories of traumatic experiences through cognitive therapy or administration of drugs. Drugs are often ineffective because their effect on the pathways of the brain involved in fear learning and extinction are still yet to be fully understood. However, it is well known that the hippocampus is involved in detecting associative novelty – a phenomenon where a new stimulus is presented in a familiar context, or a familiar stimulus presented in a new/unfamiliar context. The purpose of the experiment was to understand the role of the hippocampus in the renewal of extinguished memories, and how it affected this process through associative novelty. Normally, when a stimulus or context is familiar to an organism, it will reactivate memories that were learned or conditioned at an earlier point in time. It was hypothesized that blocking the hippocampal pathway that detects associative novelty with the GABAA agonist muscimol would result in the inability to renew previously extinguished fears in rats.
Materials and Methods:
Rats were trained in three conditions – fear conditioning, extinction, and renewal. In the first experiment, the rats were first fear conditioned with a foot shock (US) and tone (CS). 24 hours later their fear was extinguished by presenting the tone without any foot shock. Another 24 hours later, the rats were injected with either the GABAA agonist muscimol (to inactivate the hippocampus) or saline (control), and given a retrieval test (to see if the fear would return) in either the same or different context from where the extinction occurred. In the second experiment, the conditions were identical with the exception that the retrieval test was done in the same context as that of the extinction (no variation in context) but the tone that was presented during this test was either novel or familiar to the rats.
Major Results: In experiment one (where the context was manipulated), saline-injected rats showed higher levels of freezing in the novel context compared to the context where the extinction occurred during the retrieval test. In contrast, the muscimol-injected rats did not show any changes in freezing behaviour between the two contexts. In experiment two (where the conditioned stimulus was manipulated), saline-injected rats showed higher levels of freezing when the new conditioned stimulus was presented compared to the familiar one. The muscimol-injected rats showed similar behaviour but to a much lesser degree
Conclusions:
Although the hippocampus detects novel contexts or stimuli and organisms normally respond strongly to novelty, when the hippocampus is inactivated by the GABAA agonist, muscimol, rats no longer show an increased response to novelty. There is therefore a strong correlation between the hippocampus’ detection of associative novelty and the renewal of extinguished fear responses, because when the hippocampus is inactivated the fear response declines or disappears entirely. One important point to be noted is that in experiment two, there was only a small difference between the saline and muscimol injected rats, most probably because the hippocampus is important in spatial memories and probably detects novelty in context better than in stimuli.
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Maren, Stephen “Fear of the unexpected: Hippocampus mediates novelty-induced return of extinguished fear in rats “ Neurobiology of Learning and Memory (2014) doi:10.1016/j. nlm.2013.06.004 Published online 17 June 2013
Summary by: Divya Mamootil
130 Summary of:
A neuroprotective role for microRNA miR-1000 mediated by limiting glutamate excitotoxicity
Authors: Pushpa Verma, George J Augustine, Mohamed-Raafet Ammar, Ayumu Tashiro & Stephen M Cohen Background/Introduction: Recent studies have shown miRNAs as important players in controlling many cellular and molecular functions. In recent studies, the roles of miRNA in regulating synaptic plasticity, regulating responsiveness in synaptic transmission and neurodegeneration have been established and have been shown to act on neurons either in post-synaptic or pre-synaptic manner via retrograde fashion or through affecting vesicle density. However, the role of miRNA in pre-synaptic terminals affecting neurotransmitter release has not been well established. Verma et al., show the regulation of vesicular glutamate transporter (VGlut) by miRNA-1000 in Drosophila and its contribution to early-onset neurodegeneration and glutamate mediated excitotoxicity. Moreover, the current study draws a potential link in VGlut deregulation by miRNA-1000 to neurodegenerative disorders like Parkinson’s and Alzheimer’s.
Materials and Methods:
Different combinations of miR-1000 mutant alleles were used in the current study. A knockout allele, KO1, of the miR-1000 was made using targeted homologous recombination. A second independent knockout allele, KO2 of the miR-1000 was made using a vector that exchanges GFP, Gal 4 reporters or 202 bp spanning miRNA hairpin of rescue allele, for the miR-1000 locus by recombinase-mediated cassette exchange (RMCE). The rescue allele expression produced roughly half the expression of normal miR-1000 and was used to test the recovery of mutant phenotype. The mean fold change in VGlut mRNA was determined by quantitative PCR with mRNAs extracted from animal heads. UAS-RNAi transgene (VGlut-RNAi) was used to reduce vesicular glutamate transporter mRNA (VGlut). The performance in climbing assay was calculated by measuring the percentage of flies under each miR-1000 mutants that were able to climb >5 cm in a 30-cm column and was used as a model for determining neurodegeneration and movement disorder in Drosophila. The effects of glutamate receptor expression in miR-1000 mutants were determined by mutating NMDA receptor gene Nmdar1. The effects of suppression of apoptosis in neurons were studied by expressing Drosophila inhibitor of apoptosis protein (DIAP1).
Major Results:
The current study found deregulation in the presynaptic vesicular glutamate transporter, its contribution to excess glutamate release and glutamate excitotoxicity and neurodegeneration using three different combinations of miR-1000 mutant alleles. The level of vesicular glutamate transporter mRNA was found to be 4 fold in (KO1/KO2) miR-1000 mutant flies compared to control, rescued and (KO2/+) mutants, confirming deregulation in vesicular glutamate transporter in miR-1000 mutants. Similarly, the median amplitude and frequency of miniature excitatory junction potentials (mEJPs) were found to be significantly higher in (KO1/KO1) mutants compared to control and rescued flies. The contribution of VGlut deregulation to excess glutamate release and increased mEJPs was confirmed by expressing VGlut-RNAi in miRNA-1000 expressing cells. It was found that KO2/KO2-GAL4 fly mutants had their median mEJP frequency and amplitude significantly higher than VGlut-RNAi, KO2/KO2-GAL4 expressing mutants, ratifying the presence of excess glutamate in the synapse. Lastly, it was found that Nmdar1 mutated flies in miR-1000 mutants- Nmdar1, KO2/KO1 and Nmdar1, KO2/+, had improved survival and performance in climbing assay and reduced apoptotic death compared to KO2/KO1 mutant flies. miR-1000 mutants expressing DIAP1 in metabotropic glutamate receptor expressing cells- KO1/KO2; mGluRA-GAL4>UAS-DIAP1 showed increased performance in climbing essay compared to miR-1000 mutants not expressing DIAP1KO1/KO2; mGluRA-GAL4, confirming neurodegeneration in miR-1000 mutants.
Conclusions:
The current study established the regulation of glutamate release by miRNA-1000 in presynaptic terminals by regulating VGlut. It was demonstrated that deregulation in VGlut in defined miR-1000 knockout mutants leads to glutamate excitotoxicity, increased cell death and early-onset neurodegeneration. The current study also has found preservation of similar VGlut regulation in mammals. It’s been found that in a group of Alzheimer’s patients miR-137 (regulates VGlut in humans) levels were minimal. Thus, the current study draws the possibility of using miRNA mediated VGlut regulation as plausible targets for treating neurodegenerative disorders such as Parkinson’s and Alzheimer’s in humans.
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Figure URLs: 1) http://www.nature.com/nrd/journal/v4/n2/fig_tab/nrd1630_F1.html 2) http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3935.html
Pushpa Verma, George J Augustine, Mohamed-Raafet Ammar, Ayumu Tashiro & Stephen M Cohen, “A neuroprotective role for microRNA miR-1000 mediated by limiting glutamate excitotoxicity.” Nature Neuroscience (2015) doi: 10.1038nn.3935 Published online 02 February 2015
Summary by: Padmanabhan Ramanujam