Synapse 2016 Volume 10

cornell

synapse THE UNDERGRADUATE JOURNAL OF NEUROSCIENCE

Vol 9 | 2015

cornell

synapse

THE UNDERGRADUATE JOURNAL OF NEUROSCIENCE VOLUME 10 2016

EDITORS-IN-CHIEF Joesph An ‘16 Nikil Prasad ‘17

CONTRIBUTING EDITORS/WRITERS Mary Abramczuk Sydney Galindez Ha Eun Lee Clara Liao Derek Nie Antione Saint-Victor Rebecca Whitman

Faculty Advisor: Dr. Carl Hopkins

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TABLE OF CONTENTS NEWS & REVIEWS 3

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Disrupting memories to battle addiction

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Novel immunotherapeutics for Alzheimer’s

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Social deficit treatment for ASD children

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Lewy Body Dementia: a disease forgotten

Lack of sleep can cause neuronal death

SENIOR SPOTLIGHT 11

Joseph An

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Annie Erickson

15

Alex Farhang

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Ian Pengra

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NEWS & REVIEWS

Disrupting memories to battle addiction Using a glycogen phosphorylase inhibitor (DAB) to attenuate drug-seeking behavior in cocaine-addicted rats

By: Clara Liao

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here is a ubiquitous social stigma associated with drug users. Society tends to outcast drug abusers and assumes that their addiction is a result of a moral failing. We are all familiar with this usual film trope: the slacker who chooses to get high instead of getting his life together. But as simple observers of this lifestyle, we can only see the superficial behaviors (and mediocre acting). What we can’t observe on screen is what drives this behavior – what goes on in their brains.

Drugs of abuse characteristically hijack physiological mechanisms that result in the user’s overvaluation of the drug. This leads to cognitive impairments and an essentially uncontrollably heightened desire for the substance. These physical changes in the brain ultimately compel detrimental drug-seeking behaviors (Viens, 2007). Drug addiction is especially difficult to overcome due to a phenomenon known as the incubation of craving. After a period of abstinence from drug use, neural salience of drug-associated cues increases after withdrawal. This can enhance the likelihood of relapse and make addiction very difficult to overcome (Li et al., 2008). It is now thought that among these physiological drug-induced changes is the development of a “drug memory” upon which addiction is contingent.

In an attempt to find a way to abate compulsive drug-seeking behavior, researchers have explored the strategy of blocking memory

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reconsolidation in order to mitigate the drug memory. A recent study by Boury-Jamot et al. focused on impairing the acquisition of the drug memory by hindering a long-term memory formation pathway in the basolateral amygdala (BLA). This pathway starts with astrocytes. Astrocytes are specialized cells that biochemically support neurons, but they have been found to be more than merely a support system; they release glycogen-derived L-Lactate that is transferred to neurons, a metabolite that has been found to be critical in long-term memory

formation. Previous studies have shown that impairing glycogen phosphorylase activity in the BLA leads to a disruption in the lactate transfer and a distrubance in the formation of long-term memory (Suzuki et al., 2008). The Boury-Jamot et al. study took this idea a step further and hypothesized that glycogenolysis inhibition in the BLA would impair the acquisition of cocaine-induced drug memory.

Measuring drug memory in rats is not as difficult task as one might imagine. In fact, there is a standard paradigm called the conditioned place preference (CPP) test used to measure drug addiction. This behavioral model uses an animal’s preference for cocaine infusion as a proxy

Figure 1. Astrocyte-derived lactate is crucial for cocaine-induced CPP. CPP is measured as time spent in cocaine compartment minus time spent in saline compartment. Data analysis shows significant preference for cocaine compartment in Vehicle and DAB + L-Lactate treated animals. No preference is shown for DAB only treated rats.

Adapted from Boury-Jamo et al., 2015.

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NEWS & REVIEWS for addiction. A highly addicted rat will spend significantly more time in a chamber that provides an infusion of cocaine than in a chamber that provides an infusion of saline.

The researchers tested the hypothesis by injecting one group of rats with a glycogen phosphorylase inhibitor (DAB) and another group of rats with a vehicle control into the BLA. Both groups then received an injection of cocaine. The rats treated with DAB did not show CPP compared to the control rats. This suggests that the inhibition of glycogenolysis is correlated with a lack of CPP for cocaine administration.

To test if this result was due to correlation or causation, the same experiment was repeated, except now the experimental group received DAB in addition to L-lactate before receiving cocaine. This co-administration restored the CPP in the rats, indicating that L-Lactate mediated memory formation is responsible for the change in cocaine addiction (Figure 1) (Boury-Jamot et al., 2015).

This study provides insight into a potential way to mitigate the longterm effects of cocaine-associated memories that drive drug-seeking behavior. This pathway is a large component of the underlying physiological changes that perpetuate the incubation of craving for cocaine.

References: Boury-Jamot, B., Carrard, A., Martin, J.L., Halfon, O., Magistretti, P.J., Boutrel, B. (2015). Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Molecular Psychiatry, 1-7.

Li, Y., Li, F., Wang, X., Wu, P., Zhao, M., Xu, C., . . . Lu, L. (2008). Central Amygdala Extracellular Signal-Regulated Kinase Signaling Pathway Is Critical to Incubation of Opiate Craving. Journal of Neuroscience, 28(49): 13248-13257.

Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ et al.

(2011).Astrocyte-neuron lactate transport is required for long-term memory formation.Cell; 144: 810–823.

Viens, A. M. (2007). Addiction, responsibility and moral psychology. Am. J. Bioethics, 7: 17-19.

Lack of sleep can cause neuronal death Sleep-deprivation in mice increases oxidative stress and apoptosis in locus coeruleus neurons sleep would undermine your relative academic performance. But By: Ha Eun Lee what about the long-term effects very time exam season rolls this lifestyle may be having on our around many students find brain? When we consider the perthemselves performing the manent impact of sleep deprivation, same routine in order to squeeze would our decision on whether out an extra tenth of a GPA point: or not to sleep tip the other way? an all-nighter. It’s no controversial In a study conducted by Zhang et news that missing out on sleep has al. at the University of Pennsylvania, negative impacts on our health, but researchers have shown that extendthe chance to cram in more infor- ed sleep deprivation may have irremation before tomorrow’s exam is versible impacts on the brain. This often too tempting to ignore. In fact, study contradicts popular belief as with so many of our peers opting well as previous studies that argue to forgo heading to bed, it seems that extended periods of wakefulthat getting an adequate amount of ness only temporarily hinder our

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cognitive performance—the next opportunity to sleep brings about full recovery to the brain (Ingiosi et al., 2013). Zhang et al. found that extended periods of sleep may actually induce apoptosis locus coeruleus (LC) neurons. The LC is found in the pons of the brain stem and is responsible for mediating physiological responses to stress and panic through noradernergic signaling. Because neurons do not divide as readily as peripheral cells do, recovery would be slow or nonexistent, causing permanent damage to normal brain function.

The three-day study involved an experiment in which mice were divided into three groups. The groups were either given normal periods of rest, three additional hours of wakefulness, or eight additional hours of wakefulness. These mice were monitored using electroencephalography (EEG) and electromyography (EMG) to record their wake states.

Furthermore, levels of Sirtuin type 3 (SirT3), which are proteins shown to protect cells from stress-mediated cell death, were measured.

(Sundaresan NR et al., 2008).

Zhang et al. found that extended wakefulness causes metabolic stress to wake-activated cells such as LC neurons (LCns). Increased duration of activation in these cells in order to maintain attention placed LCns under oxidative stress, promoting pro-apoptotic signaling. Interestingly, a short period of sleeplessness was sufficient enough to induce an anti-oxidative response via upregulation of SirT3 translation.

SirT3 upregulation coincided with maintenance of LC homeostasis, suggesting that the presence of this protein helps protect LCns from the damaging effect of metabolic stress.

In contrast, mice repeatedly

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NEWS & REVIEWS placed under extended periods of wakefulness had decreased levels of brain levels of SirT3 protein relative to groups placed under shorter periods of wakefulness (Fig. 1). This decrease in SirT3 protein levels correlated to increased oxida- Figure 1. Red staining indicates noradernergic neurons. Green stain indicates tive damage, breakdown of presence of catalase which protects against reactive oxygen species (oxidative stress). metabolic homeostasis, and Short periods of wakefulness upregulated catalase expression in LCns, while mice the permanent loss of LCns. placed under extended periods of wakefulness experienced a decrease in catalase While the extent of LCns expression, suggesting a decreased capacity to combat oxidative stress. Adapted from loss due to sleep deprivation Zhang et al., 2014. seen in the study does not References: Age-Related Hearing Loss under Caloric clearly reveal whether it has signifi- Ingiosi, A. M., Opp, M. R., & Krueger, J. Restriction. Cell, 143(5), 802-812. cant impact on the brain functional- M. (2013). Sleep and immune function: Sundaresan NR, Samant SA, Pillai Glial contributions and consequences of ity, repeatedly being sleep deprived, aging. Current Opinion in Neurobiology, VB, Rajamohan SB, Gupta MP (Aua lifestyle common in workers with 23(5), 806-811. gust 2008).”SIRT3 is a stress responsive deacetylase in cardiomyocytes that pronight-shift occupations, may be suf- Rey, N. L., Jardanhazi-Kurutz, D., Terwel, ficient to exacerbate neurodegener- D., Kummer, M. P., Jourdan, F., Didier, A., tects cells from stress-mediated cell death by deacetylation of Ku-70”. Mol. Cell. Biol. ative processes (Zhang et al., 2014). & Heneka, M. T. (2012). Locus coeruleus 28 (20): 6384–401. degeneration exacerbates olfactory deficits For example, loss of LCns has been in APP/PS1 transgenic mice. Neurobiology Zhang, J., Zhu, Y., Zhan, G., Fenik, P., linked to neurodegenerative dis- of Aging, 33(2).

Panossian, L., Wang, M. M., . . . Veasey, S. (2014). Extended Wakefulness: Comproeases such as Alzheimer’s disease Someya, S., Yu, W., Hallows, W. C., Xu, J., mised Metabolics in and Degeneration and Parkinson’s disease (Rey et al. Vann, J. M., Leeuwenburgh, C., . . . Prolla, of Locus Coeruleus Neurons. Journal of 2012) while reduced SirT3 produc- T. A. (2010). Sirt3 Mediates Reduction of Neuroscience, 34(12), 4418-4431.

Oxidative Damage and Prevention of tion has been linked to age-related hearing loss (Someya et al., 2010). Novel immunotherapeutics for Alzheimer’s These findings suggest that while Antibody-mediated passive immunotherapy to target and destroy sleep deprivation may not have an cytotoxic amyloid-ß plaques mulation of neuofibrillary tangles immediately noticeable impact, reBy: Derek Nie composed of misfolded tau proteins peated “offenses” may have signifine of the world’s most are observed. Ultimately these metcant long-term effects on the brain, widespread neurologi- abolic dysfunctions result in cortiincreasing the likelihood of neurocal disorder and the most cal neuronal death and clinical dedegenerative diseases and deteriorating the brain’s ability to effective- common form of dementia, Alz- mentia (Jack and Holtzman, 2013).

No effective treatments to “cure, ly maintain attentiveness. However, heimer’s disease currently affects this study also suggests that SirT3 over 5 million people in the United prevent, or slow the progression” of protein may help prevent these ef- States alone (Ulrich et al., 2015). AD have been developed. The most Overt pathology in most Alz- recent and prominent efforts aim fects of sleep deprivation, but further studies would be required to come heimer’s disease (AD) patients be- to target Aß production through to a clear conclusion. Until preven- comes observable during old age. use of small molecule inhibitors, tative measures are found, sacrific- One or two decades before adverse or immunotherapy approaches to ing a few hours of sleep for a better cognitive effects become observ- reduce the impact of amyloid or grade in a class may have graver con- able, amyloid-ß (Aß) plaques—ag- tau pathology (Ulrich et al., 2015).

These therapeutic efforts all face sequences than you think they do. gregated clumps of protein from nerve cell membranes—accumulate a central challenge: getting past the in the brain. Subsequently, accu- blood-brain barrier (BBB), a spe-

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NEWS & REVIEWS cialized network of cells that modulate trafficking to and from the central nervous network (CNS) through the brain vasculature (Ulrich et al., 2015). For some neurodegenerative diseases, it is predicted that the BBB breaks down during disease progression, allowing for potential toxins, pathogens, and activated immune cells to enter the brain (Zlokovic, 2011). Research into AD models, however, reveal data indicating that the BBB is undisrupted by AD, so creating BBB bypassing therapies are necessary in order to effectively treat the disease (Bien-Ly et al., 2015).

One potential solution is to engineer smarter therapeutic antibodies.

Some researchers propose using an endogenous transcytosis mechanism, such as the transferrin receptor (TfR), to increase the rate at which therapeutic antibodies can penetrate the BBB and reach the brain (Yu et al., 2014). These bispecific antibodies would utilize the transferrin (TfR) system—which is responsible for iron uptake — to cross the BBB and target ß-secretase (BACE1) for immune cell-mediated destruction. BACE1 is an enzyme required to produce ß-amyloid plaques and is therefore a likely target for immunotherapy (Dennis and Watts, 2012). Anti-TfR/BACE1 antibodies were previously demonstrated to

be effective in reducing ß-amyloid plaque load in mouse brains, and the antibodies have also performed favorably in recent primate studies.

The search to optimally develop potential therapeutic antibodies to be able to traverse the BBB is ongoing. In addition, Bien-Ly et al. have raised the possibility that carriers of the APOe4 allele exhibit changed IgG antibody (Ab) permeability (Bien-Ly et al., 2015). This allele is the “strongest known genetic risk factor” for late-onset AD. This genetic marker is also linked to cerebral amyloid angiopathy (CAA), a commonly co-occurring vascular disease that involves fibrillary Aß deposits in the vessel walls of cerebral arteries and capillaries, leading to reduced blood flow and hemorrhaging (Ulrich et al., 2015). A finding that carriers of the APOe4 allele exhibit did indeed change IgG antibody permeability would be significant—this would mean that peripheral antibodies may normally be playing a significant role in amyloid-beta peptide clearance, and their hampered ability to cross the BBB may contribute to pathology.

Promising future studies include those that aim to investigate possible links between IgG Ab and the BBB. One idea would be applying highly quantitative methods to investigate if more severe CAA

Social deficit treatment for ASD children

Use of oxytocin-containing nasal spray to alleviate social cognitive deficits in children with autism spectrum disorder (ASD) treated or even cured at the pop of By: Sydney Galindez a pill. Today, scientists are making magine waking up and find- continual strides in order to change ing yourself in a world where this dream into impactful reality.

A prevalent disorder that has spiked suffering from neurodevelopmental disease is just an uncom- interest for pushing therapeutic fortable memory of the past. A limits is autism spectrum disorder world where such afflictions can be (ASD) (Churchland and Winkiel-

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affects how IgG Ab passively diffuses into the brain (Ulrich et al., 2015). Conversely, Bien-Ly et al. suggest testing whether sustained dosing using IgG Ab can alter the permeability of the BBB over time.

In the larger field, antibody therapy has also been hailed as a “magic bullet” that has galvanized continued research for passive immunotherapy. Given these conditions, it is likely that future scientists will continue to investigate ways to alter BBB permeability in order to maximize the efficacy of antibody therapies and improve the quality of life for AD patients.

References: Bien-Ly N., Boswell C.A., Jeet S., Beach T.G., Hoyte K., Luk W., Shihadeh V., Ulufatu S., Foreman O., Lu Y., DeVoss J., van der Brug M., Watts R.J. (2015). Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies. Neuron.

88, 289-297.

Jack C.R., Holtzman D.M. (2013). Biomarker Modeling of Alzheimer’s Disease.

Neuron. 80,1347-1358.

Ulrich J.D., Huynh, T.P., Holtzman D.M. (2015). Re-evaluation of the Blood-Brain Barrier in the Presence of Alzheimer’s Disease Pathology.

Neuron. 88, 237-239.

Zlokovic B. (2011). Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 12, 723-738.

man, 2012). Oxytocin, a peptide hormone famously known to play a significant role in social bonding and behavior, has also shown promise to serve as a therapeutic to improve social interaction deficits found in autistic children (Heinrichs and Domes, 2008). In a twoyear study at Brain and Mind Center (BMC) of the University of Sydney, researchers explored the possible

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NEWS & REVIEWS applications for oxytocin as an early ASD intervention treatment. The effectiveness and feasibility of an intranasal administration of oxytocin were measured, and the results— one of the first studies of its kind— showed that oxytocin could in fact be clinically effective in autistic children by improving social cognition and behavior (Yatawara et al. 2015).

The study occurred in a series of four phases: screening phase, pre-test assessments, and two experimental phases with follow-up post-test assessments. 39 children between the ages of 3 and 8 were passed through a series of assessments and screened for ASD diagnosis in concordance with the DSM-IVTR (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision). In phase one of the experiments, participants were blindly and randomly assigned to two groups: one that received an oxytocin-based nasal spray and another that was given a placebo nasal spray. All nasal spray administration occurred over the course of five weeks and was completed according to a fixed schedule. In phase two, there was a crossover in which the group that received oxytocin in the

first phase was given the placebo spray and the group that received placebo in the first phase was given oxytocin. This was done in order to reduce confounding covariates. The qualified candidates then completed a series of post-test social interaction and behavior assessments following the experimental phase of the study (Yatawara et al. 2015).

After assessments were made, two primary outcome measures were analyzed: caregiver-rated social responsiveness and changes in caregiver-rated severity of repetitive behavior, along with a series of secondary outcome measures. Caregiver-rated social responsiveness was measured using a fourpoint Likert scale (SRS-P) to assess a child’s social deficits including social awareness, anxiety, communication, and information processing. Changes in caregiver-rated severity of repetitive behavior was measured using the Repetitive Behavior Scale-Revised (RBS-R-P), a scale in which higher scores indicated increased severity of repetitive behavior associated with ASD. Any unfavorable events not included in the assessments were also noted (Yatawara et al., 2015).

Lewy Body Dementia: a disease forgotten The second-most deadly form of dementia is often misdiagnosed as more widely publicized neurodegenerative disorders By: Rebecca Whitman cal Parkinsonian disorder”, however, ewy Body Dementia (LBD) was most recently brought into the is a neurological disorder media spotlight in 2015, as LBD was rarely discussed and relative- found to be a mitigating factor in the ly unknown to the general public death of star actor/comedian Robin unlike disorders such as Alzhei- Williams. Although, LBD is second mer’s and Parkinson’s. This “atypi- to Alzheimer’s disease in being the

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The findings showed significant improvement in participants’ SRS-P scores during the oxytocin-administering phase as well as in experimenter-rated impressions when compared to their initial assessments and the placebo group, respectively (Yatawara et al., 2015).

The intranasal-administered oxytocin also seemed to be tolerated by participants, with minimal adverse effects observed. The effectiveness of the oxytocin nasal spray in mitigating social deficits and its tolerability suggest that this form of intervention could potentially serve as a model for future treatment methods for autism. While further research is still needed to confirm these findings, scientists are continuing to help ASD children find the treatment support they need.

References: Churchland, P. S., & Winkielman, P. (2012). Modulating social behavior with oxytocin: How does it work? What does it mean? Hormones and Behavior, 392-399.

Heinrichs, M., & Domes, G. (2008). Neuropeptides and social behaviour: Effects of oxytocin and vasopressin in humans.

Progress in Brain Research, 170, 337-350.

Yatawara, C. J., Einfeld, S. L., Davenport, T. A., & Guastella, A. J. (2015). The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: A randomized clinical crossover trial. Molecular Psychiatry.

most common cause of dementia in aging populations, it is often misdiagnosed because symptoms closely resemble those of major neurodegenerative diseases like Parkinson’s disease (McKeith et al., 2004).

Lewy bodies are inclusion bodies: nuclear or cytoplasmic collections of misfolded proteins. These neurofilament proteins, which serve normal physiological functioning in

NEWS & REVIEWS healthy individuals, are hyper-phosphorylated and take on a pathological phenotype. In addition, these proteins contain unique patterns of bound ubiquitin, a protein used to mark in targets for degradation by proteasomes (Gibb & Lees, 1988; McKeith, 2002). Lewy bodies are

(Gibb & Lees, 1988; McKeith, 2002).

Because the frontal lobe (in the forebrain) is associated with personality, emotions, and behavior, LBD patients may experience drastic changes in personality (Cipriani, Borin, Del Debbio, & Di Fiorino, 2015).

The symptoms of Lewy Body De-

Figure 1. Progressive hippocampal atrophy in dementia-afflicted brain, indicated by increase in size of the adjacent lateral ventricles. (Figure & caption adapted from Johnson et al., 2012) found not just in LBD patients but also in patients with progressive supranuclear palsy, multiple systems atrophy, Alzheimer’s disease, Parkinson’s disease, and corticobasal degeneration (Weiner, 1999). Research described by McKeith suggests that the difference between Lewy Body Dementia and other major neurological disorders lies in the location of the Lewy bodies. In Parkinson’s disease, Lewy bodies develop in the brain stem and the substantia nigra, leading to movement disorders. In addition to these areas, in LBD, Lewy bodies develop in the paralimbic and neocortical areas of the brain. This leads to a substantial decrease in vital neurotransmitter signaling along with degeneration in the brain stem and basal forebrain

mentia are often almost identical to those of other major neurological and neurodegenerative diseases, making diagnosis based on observation very difficult. However, autopsies can reveal the presence of Lewy bodies in both the substantia nigra and neocortical areas a hallmark of LBD. It is possible to diagnose LBD in living patients if other neurological disorders with similar symptoms are eliminated through further testing. Unfortunately, according to the Lewy Body Dementia Association, it takes patients an average of three doctors and more than 18 months of trial testing in order to be accurately diagnosed.

As reported by the Mayo Clinic, Lewy Body Dementia has no cure, and patients receive treatment that

only alleviate the individual symptoms that they experience. Medications may include antipsychotics to stop hallucinations, cholinesterase inhibitors to help increase neurotransmitter concentrations, and medications for patients with movement problems (McKeith et al., 1995). If patients with LBD patients remain misdiagnosed, they will be provided with ineffective treatment, which may possibly cause adverse reactions and further exacerbate problems. As with many disorders, early diagnosis is key to treatment, even if the treatment only currently consists of alleviating symptoms to improve quality of life. As awareness for LBD is raised, a more effective treatment may be discovered to stop and even reverse the damaging effects of Lewy Body Dementia.

References: Cipriani, G., Borin, G., Del Debbio, A., & Di Fiorino, M. (2015). Personality and dementia. The Journal of Nervous and Mental Disease, 203(3), 210-214.

Gibb, W. R., & Lees, A. J. (1988). The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease.

Journal of Neurology, Neurosurgery, and Psychiatry, 51, 745-752.

Johnson, K.A., Fox N.C., Sperling, R.A., Klunk W.E.(2012). Brain Imaging in Alzheimer’s Disease. Cold Spring Harbor Perspectives in Medicine, 2(4) McKeith, I. (2002). Dementia with Lewy bodies. The British Journal of Psychiatry, 180(2), 144-147.

McKeith, I., Galasko, D., Wilcock, G., & Byrne, E. J. (1995). Lewy Body Dementia - Diagnosis and Treatment. British Journal of Psychiatry, 167, 709-717.

McKeith, I., Mintzer, J., Aarsland, D., Burn, D., Chiu, H., Cohen-Mansfield, J., . . . Reid, W. (2004). Dementia with Lewy bodies.

The Lancet Neurology, 3(1), 19-28.

Weiner, M. F. (1999). Dementia Associated With Lewy Bodies: Dilemmas and Directions. Archives of Neurology, 56(12), 1441-1442.

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SENIOR SPOTLIGHT

Joseph An

Annie Erickson

“Activation of high fat diet derived microglia destabilizes neuronal cytoskeletal elements” p. 11

“Caffeine differentially modulates cognition in healthy and impaired rats” p. 13

Alex Farhang

Ian Pengra

“Elucidating the neural signals underlying song evaluation in zebra finches” p. 15

“FoxP2 brain expression in a vocal teleost fish: comparison with tetrapods” p.17

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SENIOR SPOTLIGHT

INTERVIEW

to efforts in making clearer insight feels like I’m putting my acquired into what is causing the disease knowledge and skills to good use.

Joseph An ‘16 and how to treat it.

What else are you involved in on What major and college are you Describe any current or previous campus? affiliated with? research projects.

I am an editor-in-chief of the I am a Biological Sciences maI am currently working on the Cornell Synapse. On the weekjor in the College of Agricultrual nature of the interaction between ends, I have commitments as a and Life Sciences. microglia and neurons in the praise team member for Bethany Alzheimer’s disease model. In Christian Campus Church, an Where are you from? my previous research project I organization comprised of mostly I grew up in Long Island, NY studied a neurotrophic parasite Cornell students. but after graduating from high Toxoplasma gondii, which causschool I moved to Queens, NY . es severe neurological disease in What do you enjoy doing for immunocompromised individufun? Hobbies? Interests?

What department and/or field als. I helped find what genes the My primary hobby is music. I do you conduct research in? parasite significantly altered in the enjoy singing and playing the piaWho is your professor and suhost cell in order to alter the host no, guitar, and cello. When I have pervisor? environment. extended periods of free time, I My research is in the Departlike to record and produce my ment of Microbiology and Immu- What are the potential applicaown music as well. I also like to go nology. My Lab PI is Dr. Margaret tions of your research project? weight-lifting at Teagle Hall after Bynoe and my supervisor/mentor The project helps support the class to take my mind off things. is Dr. Do-Geun Kim. idea that diet, and not a genetic predisposition to Alzheimer’s dis- What are your long term ambiWhat is the specific focus of your ease, is sufficient to cause neurotions or goals? What’s next after research project? nal damage long before character- college?

I am looking at the high-fat istic amyloid-beta plaques form, My long-term goal is to bediet murine model of Alzheimer’s as established by a previous paper come a physician that will be able disease, specifically on neurons published by the lab. Restrictions to push clinical and translational as well as microglia, the innate on diets containing high levels of boundaries through research. immune cells of the brain. saturated fats should be placed on However, I now know that, like high risk individuals (old age and science, nothing is quite set in Why is your research project rel- afflicted family members). This stone. I am open to finding anevant or important to the neuro- may prove to be a valuable tool in other route in order to make a science community? preventing cumulative build-up of meaningful impact. I am going to Alzheimer’s disease is the neuronal damage before irrevers- be working at the National Cancer sixth-leading cause of death in ible damage occurs to the brain.

Institute at the NIH as a post-bacthe U.S., and the number of those calaureate. I am joining Dr. Richafflicted is projected to increase What is your favorite part about ard Hodes’ lab, which specializes exponentially as populations con- working in a laboratory? in the study of adaptive immunity, tinue to age. There is still no cure I love the novelty of laboratory including thymic development or even an approved treatment for work—every day is unique, unlike and T cell/B cell lymphoma.

Alzheimer’s disease, likely because what it can be for classes. Laboof lack of understanding of the ratory work is also in many ways disease’s pathophysiology. My the application of what I’ve been project will hopefully contribute learning as a student thus far, so it 11 Volume 10 © 2016 Cornell Synapse

SENIOR SPOTLIGHT

Activation of high fat diet derived microglia destabilizes neuronal cytoskeletal elements Joseph An ‘16 Bynoe Lab, Microbiology & Immunology lzheimer’s disease (AD) is the sixth-leading cause of death in the U.S and is characterized by high brain amyloid-beta (Aβ) plaque load, hyper-phosphorylated tau (pTau) inclusions, and cell death-mediated brain atrophy. The etiology of AD is still unknown, and in order to move beyond palliative treatments that can only alleviate symptoms, greater insight into the pathophysiology must be made. The historically prominent postulate for neuronal death in AD speculates that the superfluous build-up of cytotoxic amyloid-beta (Aβ) peptide is the primary driving factor for AD pathogenesis. However, more recent models suggest that Aβ plaques, although they may exacerbate pathogenesis due its cytotoxicity, is instead the byproduct of cell stress and death rather than its direct cause.

Microglia are resident immune cells as well as glial cells of the central nervous system (CNS) that survey the brain for any disruptions in homeostasis. When these highly-sensitive cells sense indications of trauma or infection, microglia take on a more prominent effector role

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by becoming immunologically activated. In the high-fat diet (HFD) model of late-onset Alzheimer’s disease, microglia are in an activated state months before overt symptoms appear. It is not clearly known, however, whether these microglia are ameliorating disease progression by being neuroprotective or if they are accelerating neuropathology. If these microglia are indeed pathological to an AD patient, interventions may be implemented in order to dampen or silence the their role in disease.

To test this question, wild-type C57BL/6 male mice at 12 weeks of age were placed under a one or two month duration of high-fat diet (HFD) or standard chow diet (SD) treatment. Primary microglia were isolated from enzymatically digested brains and seeded in vitro. After complete confluence was reached, the conditioned medium was collected and an enzyme-linked immunosorbent assay (ELISA) was performed to measure cytokine secretion levels. Primary neurons were seeded on well-plates and were incubated with microglia or microglial conditioned media (1:1000 dilution) and were stained for phosphorylated Tau (pTau), microtubule-associated protein 2 (MAP2),

ABSTRACT NMDA receptor, and beta-actin.

Analysis of data revealed that the 2 month HFD-derived microglia had a 12-fold increased tumor-necrosis factor alpha (TNFα), increased interleukin-1-beta (IL-1β), and decreased interleukin-4 (IL-4) secretion. Neurons incubated with microglia conditioned media had increased expression of pTau, and decreased expression of MAP2, NMDAR and beta-actin. Dendritic atrophy was observed as measured by shortening of dendritic processes. Co-incubation of neuron under conditioned media with anti-TNFα antibody rescued the neurons from signs of cytoskeletal stress.

Because neuron morphology is critically tied with the function of neurons, compromised expression of cytoskeletal proteins can be used as markers for decreased viability of neurons. The simultaneous upregulation of the pro-inflammatory cytokines TNFα and IL-1 β and downregulation of anti-inflammatory cytokines IL-4 indicate that microglia in the AD model brain may be in a prominently pro-inflammatory state, and that their secretions may be inducing stress and perhaps even apoptotic signaling.

Figure 1. Brightfield imaging of primary microglia after complete confluence in culture. As opposed to the SD microglia, those derived from the HFD brain were immunologically activated marked by hypertrophic growth and retraction of their dendritic processes into the soma. © 2016 Cornell Synapse

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SENIOR SPOTLIGHT

INTERVIEW Annie Erickson ‘16 What major and college are you affiliated with?

I am a Human, Biology, Health & Society (HBHS) major in the College of Human Ecology.

Where are you from?

I grew up and completed high school in Pittsburgh, PA. Have you conducted research in any other laboratories? How do your experiences compare?

Yes, a lab in the Nutritional Sciences Department. It was a very different experience from the work I currently do.

What department and/or field do you conduct research in?

Who is your professor and supervisor?

My research is in human development and cognitive neuroscience. My lab PI is Dr. Eve De Rosa.

What is the specific focus of your research project?

This past year, I worked on completing my senior thesis. Specifically, I am studying the neurochemical basis of caffeine’s effect on cognition.

Describe any current or previous research projects.

We are having rats do a simple cognitive task. We give them either caffeine or saline injections for one or four days and assess them. This allows us to see if there’s a difference between acute and chronic dosage. During the experiment, my research partner and I are condition-blind.

On the fifth day we stop the caffeine treatment and give scopolamine, which blocks the action of acetylcholine and impairs the rats’ memories. We are looking to see if caffeine acts via this cholinergic system and attenuates the memory loss.

What are the potential applications of your research project?

It would definitely be helpful to know how caffeine affects the brains of people who consume it, especially in an environment like Cornell or in other places that similarly have a high-caffeine intake lifestyle.

I interact very closely with two helpful lab managers.

What have you learned from your research experience? What skills have you taken away?

I think I come out of this experience as a more patient person.

I have grown in my ability to troubleshoot problems and think critically. I definitely learned a great deal of laboratory skills and techniques, including how to work with animals.

What else are you involved in on campus?

I organize lab tours for the Cornell Undergraduate Society for Neuroscience (CUSN), TA for an Environmental Psychology class, and volunteer at the inpatient wing at Cayuga Medical Center.

What do you enjoy doing for fun? Hobbies? Interests?

I enjoy being outdoors and participate in related activites such as hiking and kayaking.

What are your long term ambiWhat is your favorite part about tions or goals? What’s next after working in a laboratory? college?

I love the research community After graduating, I plan on dowhere there is open opportunity ing one to two years of full-time to exchange newfound ideas. I research and then going to gradualso find the entire experimental ate school to get a Ph.D. Next year process exciting and rewarding I will be working in Dr. Mazen Why is your research project rel- because of its novelty.

Kheirbek’s lab at USCF, where I evant or important to the neurowill be studying the neural circuitscience community?

What is your role in the research ry of emotion using novel techA tremendous amount of project? Do you work by yourself niques. research has been done on figuror are you under the supervision ing out the effects of caffeine on of a graduate student? sleep-wake cycles, but not much I don’t work directly under a work has looked into the effects of graduate student, but my undercaffeine on cognition. graduate research partner and 13 Volume 10 © 2016 Cornell Synapse

SENIOR SPOTLIGHT

ABSTRACT

Caffeine differentially modulates cognition in healthy and impaired rats Annie Erickson ‘16 De Rosa Lab, Human Development affeine is one of the most widely consumed psychoactive drugs in the world.

Its stimulating effects are well described, but recent studies suggest it may also be neuroprotective against cognitive decline through its interactions with the neuromodulator acetylcholine. Here we examined rats’ performance in two different cognitive tasks after acute (one day) and chronic caffeine (four days) administration (10 mg/kg). The first task tested discrimination of a novel object from a familiar object (novel object recognition: NOR) and the

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second tested discrimination of two familiar objects based on the timing of exposure (temporal object recognition: TMOR.) We found acute caffeine administration, compared to saline controls, selectively impaired NOR, while chronic caffeine eliminated this effect. This is perhaps an effect of caffeine-induced anxiety upon first caffeine administration.

Following the chronic caffeine treatment, rats were administered the scopolamine or methyl-scopolamine (0.2 mg/kg), and tested on the same cognitive measures. Scopolamine, a muscarinic acetylcholine antagonist (mAchA), is known to induce memory deficits. Methyl-scopolamine, a mAchA that can-

not cross the blood brain barrier, was used as a control for the non-cognitive, peripheral effects of mAchAs. We found chronic caffeine pretreatment, compared to chronic saline pretreatment, appeared to have a mildly, but not significant, protective effect on scopolamine-induced memory impairment in TMOR, but not NOR. These results indicate caffeine selectively modulates cognition depending on type of cognitive task, duration of caffeine treatment, and existing cognitive impairment.

Furthermore, these findings also suggest the related roles of caffeine and the cholinergic system in healthy and impaired cognition.

Figure 1. Scoring of cognitive tests was defined by a discrimination ratio, where a score of 1 is perfect discrimination (good memory), 0 no discrimination, and -1 poor discrimination. a. There was a significant difference of caffeine administration in the NOR task after acute (day 1) caffeine (p=0.0333), which was significantly improved by day 4 (p=0.0410). b. Chronic treatment of caffeine has a mildly protective effect on scopolamine induced memory deficits in the TMOR task. © 2016 Cornell Synapse

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SENIOR SPOTLIGHT

INTERVIEW Alex Farhang ‘16 What major and college are you are you affiliated with?

I am a Biological Sciences major concentrating in Neurobiology and Behavior in the College of Agricultural and Life Sciences.

Where are you from?

I grew up and went to high school in Los Angeles, CA.

first-ever recordings of dopamine neurons during birdsong hopes to answer this question. These are the same cells that are dysfunctional in Parkinson’s disease and may shed light on brain pathologies. Also, recording projections from the basal forebrain may provide insight into the computations preceding dopamine’s role as an reward prediction error signal.

What is your favorite part about working in a laboratory?

My lab has a very friendly and collaborative environment. It is exciting working with others to investigate interesting questions in the field of neuroscience.

What have you learned from your research experience? What skills have you taken away?

I’ve had exposure to every stage of research from grant writing, to data analysis, and manuscript review. I’ve also learned many electrophysiological, microfabrication techniques, and many aspects of scientific writing and presenting that will be useful in my career.

Have you conducted research in any other laboratories? How do your experiences compare?

I spent a summer at JPL working on quantum well infrared photodetectors. Surprisingly, my work there helped prepare me What else are you involved in on for my current lab. A lot of the campus? hardware manufacturing skills I’m an outreach chair for the carried over, as I am now involved Cornell Undergraduate Society for in fabricating motorized brain What is the specific focus of your Neuroscience (CUSN) as well as a implants. research project?

Cornell Undergraduate Research My project’s aim is to underBoard (CURB) peer mentor.

What organizations or activities stand neural mechanisms undo you find most meaningful? derlying song learning in zebra What do you enjoy doing for Why? finches. It’s known that dopamine fun? Hobbies? Interests?

I’ve found my involvement in activity is crucial to learn for an I enjoy hiking and kayaking. research to be the most enriching external reward like food or juice, aspect of my time here at Corbut is unclear whether it is also What are your long term ambinell. I felt that the work was very involved in internally-guided tions or goals? What’s next after meaningful and my experience learning (song). My project hopes college? has led me to pursue a career in to elucidate this as well as invesI plan on pursuing a Ph.D. in research. tigate potential inputs to these neuroscience and hope to eventudopamine neurons. ally start a lab of my own. After What is your role in the research graduation I will be working as project? Do you work by yourself Why is your research project rel- a research specialist in Dr. Evan or are you under the supervision evant or important to the neuro- Feinberg’s Lab at UCSF for two of a graduate student? science community? years investigating problems in I ‘hunt’ for neurons while birds Dopamine’s role in external sensory integration. sing using a remote-controlled reward learning has been known motorized microdrive housing for several years, however it has recording electrodes. I work in never been shown to be important collaboration with two postdocs for other types of learning. Our and one graduate student.

15 Volume 10 © 2016 Cornell Synapse What department and/or field do you conduct research in?

Who is your professor and supervisor?

I work with Dr. Jesse Goldberg in the Department of Neurobiology and Behavior where we are trying to understand the brain mechanisms of motor learning.

SENIOR SPOTLIGHT

ABSTRACT

Elucidating the neural signals underlying song evaluation in zebra finches Alex Farhang ‘16 Goldberg Lab, Neurobiology & Behavior any of our behaviors like playing the piano or even speaking are not innately programmed, but are acquired through years of practice involving trial and error learning. These behaviors are not motivated by an external, appetitive reward but are instead completed to reach an internally represented goal. In external reward paradigms, rewards increase the firing rate of dopamine neurons in the ventral tegmental area; the absence of reward when the animal expected it results in a suppression of dopamine firing.

However, the dopamine’s role and the neural mechanisms underlying

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internally-guided behavior remain unclear. Songbirds provide a powerful model system for studying internally guided learning as they have a discrete neural circuit for song learning. Also, birdsong offers the advantage of studying ethologically relevant learning as it relates to an internal goal with the absence of external reward. In this experiment, we recorded dopamine neurons in singing zebra finches while they experienced both vocal errors and successes. They exhibited phasic suppression upon errors and activation at the precise moment when an error would have occurred, but did not. This provides evidence that the canonical dopaminergic reward prediction error is a specific example of a neural computation capa-

ble of comparing expected to actual performance outcomes. To understand the mechanisms underlying this computation, I recorded from inputs to the ventral tegmental area from the basal forebrain. I found neurons encoding the timing of the song-motor performance and response to perceived vocal error. Together, these signals could process information necessary for the construction of a representation of expected song quality. This representation could be involved in driving dopamine neurons’ phasic activation upon perceived a vocal success.

The basal forebrain is a highly evolutionarily conserved structure common to all vertebrates. Thus these findings could provide insight into general principles of how internally-guided behaviors are acquired.

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Figure 1. A) Model of the zebra finch song system. VTA and BF were sites of recording. B) Sample neuron recorded from BF. From top: Spectrogram displaying song on a ‘good’ trial and corresponding neural trace.

Spectrogram displaying song on a ‘bad’ trial and corresponding neural trace. Raster plot displaying action potentials as ticks over separate song trials (yellow marks the time of auditory error). Firing rate histogram of ‘good’ (blue) and ‘bad’ (red) trials.

Note the time-locked firing pattern and the increase in firing rate on ‘bad’ trials right after the yellow highlight.

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SENIOR SPOTLIGHT

INTERVIEW Ian Pengra ‘16 What major and college are you are you affiliated with?

I am a Biological sciences major in the College of Agriculture and Life Sciences.

Where are you from?

My hometown is Berkeley, CA. What else are you involved in on campus?

I am currently a member of the Von Cramm Cooperative.

What department and/or field do you conduct research in?

Who is your professor and supervisor?

I work with Dr. Andrew Bass and Margaret Marchaterre as my PI and my lab supervisor, respectively, in the Department of Neurobiology and Behavior.

Why is your research project relevant or important to the neuroscience community?

I suggest that to link verbal communication to this “language gene” one has to look outside of pathways that are intuitively connected to vocalization because it is expressed in non-vocal regions of all vertebrate lineages investigated so far. Descriptive studies like this project are useful for gauging the promise of such unintuitive pathways, and I propose that acoustic and hormonal pathways might have significant functional dependence on FoxP2. Either of these pathways could be responsible for vocal deficits seen in animals with disturbed FoxP2 activity.

What is your favorite part about working in a laboratory?

I enjoy the passion of everyone around me who works sometimes through droning along on a cold, gray Ithaca winter “day”, someWhat is the specific focus of your times while manically bouncing research project? in excitement about an awesome My project aims to figure to new thing they just heard a talk what extent is FoxP2 specifically about, and sometimes contentedly a “language gene”, and to what chatting about everyday life. extent are its expression patterns in the brain conserved across all What do you enjoy doing for vertebrates. fun? Hobbies? Interests?

I like to make things. Last What are the potential applicasemester a friend and I made a tions of your research project? kiddie pool raft and rode it a mile My project will extend basic down Fall Creek and into Cayuga science knowledge of the FoxP2 lake. “Made” might be an overgene, which will ultimately allow statement because it barely looked broadening of the way we think and worked like a raft. about language and how it is controlled and manipulated.

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What are your long term ambitions or goals? What’s next after college?

In the long term, I want to go into the research field of brain-machine interfaces. I don’t really know where taking that path will take me, but until then I am thinking of taking a gap year to work and travel and then go to graduate school.

What organizations or activities do you find most meaningful?

Why? I find the research I do at the Bass Lab the most meaningful.

Research is an awesome way to indulge a deep curiosity and marvel at the beautiful and literally incomprehensible deep patterns that weave through our everyday existence, but it also allows us to use it as a sharp edge to cut through this web of complexity in order to find better understand what is going on in the world.

What is your role in the research project? Do you work by yourself or are you under the supervision of a graduate student?

I worked with my lab supervisor to establish an in situ hybridization protocol, a technique that have never been previously performed in the Bass Lab. Additionally, I collected experimental data and worked with my reseasrch advisor to wrap my head around how to think critically about the data I produced. Otherwise I worked very independently.

SENIOR SPOTLIGHT

ABSTRACT

FoxP2 brain expression in a vocal teleost fish: comparison with tetrapods Ian G.G. Pengra ‘16 Bass Lab, NB&B

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ocal communication is our defining feature as humans.

Motivated by studies of a monogenic speech deficit in humans, several studies over the past two decades have focused on the potential role of a forkhead-domain transcription factor, FOXP2, in the development of speech and more broadly vocalization. Behavioral studies in mice and zebra finches have suggested that disturbing FoxP2 disturbs learned and unlearned vocalization. However, FoxP2 is expressed in many regions of the brain in mice and songbirds, implying greater functional significance beyond vocalization that might be shared with

other vertebrate groups. Reports on FoxP2 expression among teleost fish, the most species-rich group of living vertebrates, have been limited in scope. Furthermore, there have been no descriptive studies comparing the neuroanatomical distribution of FoxP2 between diverse vertebrate lineages. We used in situ hybridization to map the expression patterns of FoxP2 mRNA in a highly vocal fish, the plainfin midshipman Porichthys notatus, and then compared this pattern to that in mice and birds and to previously examined steroid signaling regions containing androgen receptors, aromatase, or estrogen receptors. We found that nearly every region that expressed FoxP2 in midshipman also expressed it in homologous brain regions in mice or zebra finch-

es. We also found significant overlap between FoxP2 expression and expression of several steroid hormone receptors. This suggests that the last common ancestor of this vocal fish, birds, and mice expressed FoxP2 in these same brain regions, which further implies that disturbance of FoxP2 disrupts an evolutionarily ancient substrate upon which a wide array of targets could have become dependent, including vocalization. This also suggests that FoxP2 could wear many more functional “hats” than vocal behavior, and that unexpected pathways such as hormonal signaling pathways that have previously been overlooked as causal factors for speech deficits seen in FoxP2 mutants might be responsible for some part of the speech-deficient phenotype we see in FoxP2 mutants like the KE family.

Table 1. Expression patterns of FoxP2 across diverse vertebrate lineages Each column represents brain regions of one vertebrate lineage (blue = Porichthys notatus; peach = Mus musculus; green = Taeniopygia guttata). Rows represents homologous brain regions in each lineage in terms of their respective nomenclature.

Colored cells indicate expression of FoxP2 in that brain region,in that species, and white cells indicate its absence.

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