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Peripheral and Central Mechanisms of Stress Vulnerability and Resilience false
By:Madeline Leah Pfau
Published on 2017 by

Despite the high prevalence of stress-related disorders, effective new treatments have been slow to emerge. A promising area of research involves the study of resilience, the adaptive maintenance of normal physiology and behavior in the face of psychological stress. Stress resilience and its converse, susceptibility, are increasingly considered consequences of the integrated response of numerous bodily systems, including the central nervous, endocrine, and immune systems. A growing body of evidence supports a role for epigenetic regulation by microRNAs, small RNAs that do not encode proteins but instead suppress the expression of target mRNAs, in depression and antidepressant response. This dissertation focuses on mechanisms contributing to behavioral vulnerability and resilience to stress in the central nervous and peripheral immune systems, with a particular emphasis on post-transcriptional regulation by microRNAs. In chapter two, I characterize sex differences in nucleus accumbens genome-wide transcriptional and post-transcriptional profiles following exposure to subchronic variable stress, a stress paradigm that produces depression-like behavior in female, but not male, rodents, thus recapitulating the enhanced susceptibility of adult women to depression. I find that male and female mice show minimal overlap in stress-regulated genes, microRNAs, and enriched functional pathways. Despite the resistance of male mice to stress-induced behavioral and neuroendocrine decrements, males mount a robust transcriptional and post-transcriptional response to stress, indicating that resilience likely results from the engagement of active mechanisms. In chapter three, I explore intrinsic mechanisms within peripheral blood leukocytes contributing to stress-induced inflammation and depression. I find that, following exposure to repeated social defeat stress, mice susceptible to stress-induced depression-like behavior exhibit increased frequency of circulating Ly6chigh inflammatory monocytes. Peripheral depletion of Ly6chigh monocytes is antidepressant, indicating a functional role for this leukocyte subtype in stress response. Inflammatory monocytes of susceptible and resilient mice display different patterns of microRNA expression, and my preliminary evidence indicates that downregulation of the microRNA-106b~25 cluster in the peripheral immune system promotes behavioral resilience to defeat. Collectively, my findings demonstrate that susceptibility and resilience are associated with unique molecular signatures. These findings inform our understanding of stress-related disorders and resilience to them, and identify microRNAs as potential therapeutic targets.

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