Cell-type and whole-brain dynamics underlying operant social stress resiliency

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Project Summary Prolonged elevated levels of stress are comorbid with many neuropsychiatric illnesses such as major depressive disorder (MDD), and can have devastating effects on individuals, their caretakers, and healthcare professionals. MDD is typically demarcated as exhibiting emotions of sadness, significant loss of motivation, and can be defined by social deficits. A growing literature indicates that major depressive disorder is influenced by dysregulation in limbic brain regions including stress and reward circuitry. Despite a significant clinical awareness, direct preclinical characterization of affective disorder circuitry and associated neuronal mechanisms inclusive of sex as a biological variable are currently absent, and notably do not include social decision making and motivation as behavioral metrics. Therefore, the aim of my proposal is to obtain the necessary computational, behavioral and anatomical training to identify, interrogate, and manipulate neural populations that modulate these complex social behaviors. This project will focus on identifying nucleus accumbens (NAc) circuit and cell type specific mechanisms that regulate resiliency to operant social stress (OSS), and then further interrogate the afferent projections driving these populations. OSS incorporates social decision making and social reward as metrics for social stress resiliency. The choice of this brain region is based on converging preliminary data, implicating that the NAc dopamine receptor (Drd) 1 and Drd2 medium spiny neurons (MSNs) confer opposing roles in regulating resiliency to social stress. NAc circuit and cell-type specific activation will be identified using a combination of whole brain clearing, Fos (a marker of neuronal activity) immunohistochemistry, and retrograde viral tracing. Because of the limited temporal resolution of Fos during these behaviors, awake-behaving fiber photometry recordings will be used to observe how NAc MSNs encode varying levels of susceptibility and resiliency to OSS in real-time. Next, the causal significance of the NAc and its afferent projections will be examined using region, circuit, and cell type specific optogenetic manipulations. Understanding the neural mechanisms driving operant social stress in a sex-dependent manner will allow for the development of more specific and effective treatments for affective mood disorders such as major depressive disorder (MDD).