Cell Subtype Mechanisms Underlying Stress Susceptibility and Resilience

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Summary/Abstract Repeated stress alters the structure and function of brain reward circuitry leading to disruption of the motivated pursuit of rewards. Stress can be a major risk factor or trigger episodes of psychiatric disorders, which are hallmarked by altered motivational processing observed in major depressive disorder, bipolar disorder, schizophrenia, and post-traumatic stress disorder. The nucleus is a critical brain hub for altered cellular and molecular actions underlying motivated behaviors in rodents and many of these adaptations are observed in postmortem NAc of individuals with mental illness, such as depression. Previously we uncovered dendritic atrophy, which correlated with disrupted activity and excitatory function, in NAc dopamine receptor 1 expressing medium spiny neurons (D1-MSNs), of mice displaying reduced social interaction and anhedonia after chronic social defeat stress (CSDS). While our group has delineated intrinsic mechanism that drive these morphological adaptations, the extrinsic factors are unknown. Mounting evidence implicates microglia, which play a role in shaping neuron dendritic adaptations, in social defeat stress outcomes. Thus, the parent grant investigates microglia mechanisms that may regulate D1-MSN dendritic atrophy in social stress models in both sexes. However, the proposed studies in the parent grant do not address the temporal dynamics that microglia initiate mechanisms to drive the D1-MSN atrophy during stress. Data we are generating from the parent grant suggest that microglia around D1-MSNs, in stressed animals, are phagocytic. However, these data also implicate reduced D1-MSN-microglia contact and reduced microglia density surrounding D1-MSNs suggesting that microglia have already impacted D1-MSNs at this time point where atrophy is observed. Based on this data, we hypothesize that microglia display a temporal increase in contact with NAc D1-MSNs and activation of phagocytic markers throughout social stress exposure, which will be assessed in this diversity supplement. In this proposal a set of experimental Aims and a training plan are devised to provide technical training in neuron-microglia morphological analysis and gene expression of microglia across a temporal profile of stress exposure. The technical training is accompanied by conceptual training in microglia biology, reward circuit biology, and molecular neuroscience. Additional, training and career development are outlined in the proposal to foster the candidate’s growth toward applying for a F99/K00 and completing the milestones of the PhD thesis.