Long Lasting Effects of Early Life Stress on the Brain and Epigenome

Omar Kassem

Abstract

Stable caregiving in early life is critical for normal social and emotional development. Exposure to chronic or extreme stress early in life has been associated with increased risk for psychiatric disorders, especially affective disorders. Early life stress (ELS) has long-lasting impacts on the development and function of diverse brain regions that are involved in emotional processing, cognitive functions, and social behavior. Despite the adverse effects of ELS on brain development, the neural underpinnings of those effects are not yet well characterized. This review highlights ELS-provoked changes in networks wiring, the cellular impacts on neuron excitability and myelination, and the epigenetic modifications that contribute to those changes. Understanding those neurobiological aberrations aids in understanding the increased risk for psychopathology that has been reported in children exposed to ELS and provides insights into potential

Introduction

Brain development and maturation are modulated by an interaction between environmental inputs and genes. It is well established that exposure to stress at different ages leads to different outcomes, with early stages of development being associated with more severe and long-lasting effects [1]. Early childhood is a critical period of brain development, which renders it highly vulnerable to disorganizing environmental influences. Sustained or adverse

early-life stress (ELS), such as childhood trauma or caregiver deprivation, modifies the expression of multiple neurotransmitters and other molecules that affect neuron and network development in specific brain regions, potentially causing long-term structural and functional changes [2]. Brain regions involved in emotional processing, such as the amygdala, cognitive regions such as the hippocampus and prefrontal cortex, as well as networks involved in social behaviors seem

to be particularly responsive and vulnerable to the impact of stress [1,3,4,5,6]. ELS-induced long-lasting changes in these regions would be expected to increase susceptibility to emotional disorders and psychiatric illnesses, which has been reported in many epidemiological human studies [7,8]. Although the associations that were statistically inferred from epidemiological studies are highly indicative of the impact of ELS, it is difficult to prove causality and elucidate the biological mechanisms underlying this influence in humans. Therefore, many subsequent studies have used animal models to investigate the biological underpinnings of ELS consequences. Studies in animal models, especially rodents, have revealed that ELS can provoke changes on various levels including changes in neuron excitability and myelination, rewiring of networks, and epigenetic modifications that are in some cases transgenerational [2,9,10,11]. Thus, integrating findings from circuitry, cellular, and genetic studies is essential to fully understand this process. Understanding the neural underpinnings of the relationship between ELS and the mental health of the victims is of great value in the pursuit of possible treatments and interventions. Moreover, a better understanding of caregiver-related stress effects on child development provides many useful insights for improving orphanage systems.

Impact of ELS through disruption of the maturation of brain networks and circuitry The long-term effects of ELS stem from the fact that developmental processes that organize circuits and connectivity patterns are still occurring. In humans, the development of the hippocampus and limbic circuit, which are involved in cognitive and emotional functions, takes place largely shortly after birth and continues for years into adolescence. Therefore, unlike the effects of stress on adult cognitive functions that are reversible, ELS can often permanently impact these processes and systems, yet behavioral and pharmacological interventions can still be effective [12,13,14].. An epidemiological study conducted on post-institutionalized adolescents showed that chronic early life stress, being raised in orphanages, is associated with a reduced volume of prefrontal cortex and hippocampus [15]. Remarkably, this study was conducted on adolescents years after exposure but the impact of ELS was still significant. Further studies in mice have provided more insight into the underlying neural changes in those regions in response to stress. The main physiological model of memory formation in the brain is through adjusting synaptic weights in networks to encode memories. Several studies have

demonstrated that ELS interferes with synaptic plasticity and induces dendritic as well as spine atrophy [13,16,17]. The cumulative effect of these alterations causes the loss of functional synapses, which contributes to cognitive deficits. These influences on neural networks are mediated by multiple molecules including stress-associated glucocorticoid hormones, neurotransmitters, and neuropeptides. Better characterization of the stress toolbox has enhanced our ability to pharmacologically intervene and manage stress symptoms [18,19]. Similarly, ELS, especially in the form of caregiver deprivation, has been shown to affect the development of the amygdala, which is highly involved in emotion processing, affective valuation, and learning [20]. One key study did an fMRI scan of brain activity of children adopted from orphanages in a behavioral paradigm where they were instructed to “go” to a neutral cue, and “not go” to a rare threat cue [3]. Results showed that ELS-exposed preadolescents took longer to approach a cue when anticipating a potential threat, indicating that the disorganized care of the orphanage experience can alter emotional and behavioral regulation. FMRI data showed that only activity in the amygdala differentiated the ELS-exposed children from the control group

when anticipating an aversive stimulus. These findings help explain the epidemiological association between the institutional rearing of children and psychiatric disorders, especially internalizing ones such as anxiety and disruptive disorders [21,22]. Moreover, these results gesture towards the critical importance of providing stable caregiver affection in orphanages, and families, to ensure the healthy mental development of children. ELS neuron-level effects

Many studies have attempted to understand the neuronlevel impacts of ELS that mediate the observed cortical activity changes and behavioral phenotype. The two main influences that have been characterized are changes in the electrical properties and myelination of neurons [23,24,25]. One study used adolescent social isolation of rats to investigate the electrical properties of basolateral amygdala pyramidal cells. This study revealed that the stressed group showed a significant increase in neuron excitability, meaning that neurons were more easily and frequently firing, in comparison to control rats. This effect was mediated by a decrease in SK potassium channel activity. Using a drug to enhance SK channel activity to normalize neuron excitability was found to attenuate anxiety-related behaviors, which provides insights into the potential of pharmacological interventions that could elevate symptoms. Another study by Tanti et al [27] attempted to investigate the effect of altered brain activity of the brain during early development, and how that could induce long-term changes similar to those observed in children that face early childhood adversity. This study showed that pharmacological reduction of the activity of the prefrontal cortex of mice during development reproduces the cellular and behavioral defects induced by repeated ELS: increased behaviors associated with anxiety and depression, a persistent decrease in neuronal activity, and early differentiation of oligodendrocyte precursors (OPCs), cells that will be responsible for producing the myelin surrounding neurons. Conversely, restoring normal neuronal activity in the prefrontal cortex in mice undergoing early maternal separation leads to the disappearance of short-term memory deficits, behavioral alterations associated with the depressive state, and oligodendrocyte development. However, behavioral disorders associated with anxiety persisted. This difference in effect on anxiety disorders and depressive disorders could be due to a spatial bias of the viral injection they used to modulate activity, as it could have modified activity in only a subset of emotional circuits involved. Furthermore, the pharmacogenetic technique used to modulate neuronal activity does not reproduce the physiological state of developing neural networks. These differences could contribute to the persistence of anxiety behaviors. The same study revealed that ELS is associated with changes in myelination and oligodendrocyte maturation. ELS induces premature differentiation of oligodendrocyte precursors into mature oligodendrocytes. These results suggest that early emotional stress could lead to expedited maturation in brain regions associated with emotion processing, which comes with a short-term advantage, that being processing the immediate emotional disturbances, and a long-term deficit. The decrease in OPCs could lead to a decrease in quantity and plasticity of myelination later in life. This falls in line with human studies associating institutionalized rearing with a decline in white matter volume [26], which is related to the volume of the fatty myelin layer surrounding axons. Additionally, early maturation of OPCs has been reported in young adults who were sexually assaulted in childhood [27], which further supports the hypothesis that early life ELS effects on the epigenome Epigenetics refers to the regulation of gene expression without altering the genetic code itself. This change in regulation is achieved by changing the 3D structure of chromatin. By making the DNA more tightly or loosely packed, epigenetic machinery can regulate the accessibility of the genome, thus, regulating the expression of genes. Epigenetic modifications involve adding a chemical modification to the DNA or histone proteins, which the DNA is wrapped around, to change its chemical properties and 3D shape in the cell. These modifications are added by a writer protein and removed by an eraser. The study of epigenetic changes in the nervous system, called Neuroepigenetics, has provided a lot of insight into the mechanisms of gene regulation in neurons, especially during development. One key study by Kronman et al found that early-life stress in mice induces epigenetic changes, dimethylation of lysine 79 of histone H3 (H3K79me2), in D2-type medium spiny neurons in the depressionassociated region nucleus accumbens, renders mice more vulnerable to stress later in life [11]. When ELS-exposed mice faced a second stress event in adulthood they exhibited more depression-like behaviors than control mice, including lower social interaction, decreased exploration, and greater immobility in a swim test. They then used a viral vector to genetically interfere with the function of the writer (Dot1l) and eraser (Kdm2b) enzymes of the implicated epigenetic modification. Inducing increased modification through overexpression of Dot1lor knockdown of Kdm2b induced depression-like behaviors in control mice, in other words inducing an ELS-like phenotype. Conversely, knocking down Dot1l or overexpressing Kdm2b reversed the depression-like behaviors in response to stress, showing that interventions on an epigenetic level could be a potential therapeutic approach to remedy the long term effects of ELS. Although the effects of ELS could be reversed with genetic manipulation in mice, such an intervention is not very practical in humans. Drugs that inhibit protein functions are much more feasible for human applications. The authors tested the effect of using a drug that inhibits Dotl1 enzyme to interfere with ELS disruptions. Treated mice showed reduced modification levels in their genome and improved behavioral performance, social interaction scores. These results provided important insights into the potential of using epigenetic drugs to remedy disruptions in the brain and reverse some of those long-lasting effects.

Conclusion and future directions

Overall, these studies demonstrate that early life stress has profound effects on the developing brain including disrupting critical networks, disrupted electrical properties, and myelination of neurons. These effects are at least partly mediated by epigenetic modifications that change the 3D shape of DNA, thus regulating gene expression in neurons. These ELS effects are often long-lasting and increase susceptibility to mental and psychiatric disorders, which has been repeatedly shown to be a significant influence on institutionally reared children. A better understanding of the biological underpinnings of ELS disruptions has provided significant insights into prospective therapeutic approaches that could reverse those long-lasting effects, such as epigenetic and pharmacological intervention. Moreover, studies on early-life caregiver deprivation and social isolation emphasize the importance of providing a

at a young age, which should be incorporated into institutional rearing organizations. There are many future research directions that would provide a more comprehensive understanding of this phenomenon and provide insights into minimizing its impact on children. Elucidating the nature and underlying biology of sex-specific consequences of early-life stress is one important question that has been posed by epidemiological studies that show higher prevalence in females. Many behavioral cognitive therapies have been shown to promote rectifying changes in the brain, the potential of such treatments for reversing the ELS-induced biological and neurological changes is also one issue that hasn’t been studied. Also, many epigenetic studies have revealed that some epigenetic modifications could be transgenerational, potentially making future generations more vulnerable to disruptions that parents experienced. The question of whether epigenetic changes that happen in response to early life adversity could be inherited is another interesting perspective that could have implications for parents with a history of ELS. Finally, the studies discussed here provide evidence for the accelerated maturation of emotion circuitry following ELS. Whether this altered developmental pattern comes at the cost of lagged development of other systems is still unknown and is of great importance for improving the lives of individuals with histories of ELS.

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