Like humans, mice subjected to stress can be divided into two phenotypes. Susceptible animals succumb to maladaptive symptoms such as anhedonia and social avoidance, while resilient animals continue to behave indistinguishably from controls. The mechanisms that drive this divergent stress-response remain elusive. Understanding the functional relationship between individual variability in functional and structural connectivity and stress-response is a critical first step in early identification of at-risk individuals and preventative approaches that actively enhance resilience. We will address this relationship at multiple scales of resolution: the whole-brain functional connectivity level using cFos co-activation mapping, the mesoscale structural connectome level using viral-mediated trans-synaptic tracing, the synaptic level using single-cell 3D reconstruction of dendritic spines, and the circuit level using viral-mediated identification and chemogenetic control of a corticolimbic pathway. Multiscale circuits will be studied using a ?time-course? approach, which will provide mechanistic insight into how the functional and structural wiring diagram prior to a stressor contributes to the development of divergent stress-responses. Our behavioral toolbox includes acute and chronic social defeat stress resulting in subpopulations of resilient and susceptible mice, and novel non-stressful predictors of each phenotype. In our preliminary studies, the basolateral amygdala (BLA) and its input from the prelimbic cortex (PL), two regions involved in emotional regulation, have emerged as key players mediating divergent stress-responses.
In Aim 1, we will define the contribution of individual variability in BLA connectivity prior to stress-exposure to BLA functional and structural reorganization during acute stress.
In Aim 2, we will assess if individual variability in functional and structural BLA connectivity becomes exacerbated following chronic stress.
In Aim 3, we will test the hypothesis that circuit rewiring prior to stress-exposure can alter future stress- responses.

Public Health Relevance

Depression is a highly debilitating and prevalent disease, with largely ineffective treatments. The focus of the current proposal is to understand the individual variability in neurocircuitry that mediates selective vulnerability and resilience in an animal model of social stress. The ultimate goal of this research is to identify at-risk individuals, and develop new therapeutics aimed at enhancing resilience.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Simmons, Janine M
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Takahashi, Aki; Chung, Jia-Ru; Zhang, Song et al. (2017) Establishment of a repeated social defeat stress model in female mice. Sci Rep 7:12838