Epigenetic programming of the juvenile social brain : risk and resilience conferred by biological sex

Author / Creator

Kigar, Stacey, dissertant

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Online

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Summary

The data presented in the following chapters of this dissertation are meant to address open questions about how the early environmental milieu shapes an individual's epigenetic landscape-and, in tu...

The data presented in the following chapters of this dissertation are meant to address open questions about how the early environmental milieu shapes an individual's epigenetic landscape-and, in turn, may manifest as risk or resilience to certain mental health disorders. We hypothesized that experiential and hormonal influences on biological sex during development may produce differences in the epigenome, and that these differences play an important role in gating risk or resilience to a number of neurological and psychiatric disorders. One intriguing hypothesis is that the framework belying sex differences in the brain, consisting of differences in methylation and demethylation patterns, confer risk and resilience to mental health disorders. In our attempt to elucidate these mechanisms, we focused primarily on the amygdala given its seminal role in the formation of socioemotional and anxiety behaviors; we were furthermore interested in this region as disturbances in its activity are implicated in the etiology of a wide variety of psychiatric disorders. We present evidence suggesting that mRNA expression within the amygdala of the DNA demethylation factor, Gadd45b, is involved in the patterning of social behaviors. Furthermore, we describe amygdalar sex differences in Gadd45b expression during a critical period of neonatal brain development, and suggest this pathway may be a useful target in investigating the etiology of social deficits associated with some mental heath disorders. Importantly, we provide the first evidence, to our knowledge, of the function and existence of 6-methyladenine (6mA) as a novel epigenetic regulator in the mammalian brain. Specifically, we demonstrate that 6mA is present in the gene promoter of serotonin receptor type 2a (Htr2a), and that its presence predicts levels of gene expression. We furthermore show that this epigenetic modification exhibits stable, developmental sex differences and stress responsivity in a novel, variable predator odor exposure (POE) paradigm of early life stress. Additionally, we characterize anxiety-like behavior in our neonatally predator odor exposed animals and find long-term changes; as Htr2a and the serotonergic system have a well-known role in the development of anxiety disorders, we suggest that 6mA may represent a valuable biomarker and pharmacological target in the their treatment. Given the unchallenged assumption of 5-methylcytosine (5mC) as the primary epigenetic regulator in the mammalian genome, we hope this research opens up new and exciting avenues into the investigation of stress-induced neuropathologies.

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