Project Summary: Stress alters the structure and function of brain reward circuitry leading to disruption of reward and motivation. Stress can be a major risk factor or trigger episodes of psychiatric disorders, which encompass altered motivational behavior; including major depressive disorder, bipolar disorder, schizophrenia, and post traumatic stress disorder. Current studies emphasize a need to approach psychiatric diseases from a combined circuit and molecular perspective to link candidate molecules to dysfunctional cell subtypes. Our previous work provided an initial foundation for understanding nucleus accumbens, a major brain reward region, medium spiny neuron (MSN) subtypes in response to stress. However, there is a critical need for a comprehensive understanding that encompasses intrinsic molecular regulators of these MSN subtype adaptations and the extrinsic regulators (such as microglia) that help to shape these structural adaptations in mice susceptible to stress, as well as those displaying resilient response to stress. In this proposal we will completely characterize structural adaptations in D1-MSN subpopulations, microglia, and the interaction between the two in stress susceptible and resilient conditions of both sexes using chronic social defeat stress (CSDS) and chronic witness defeat stress (CWDS) paradigms. We will manipulate microglia and D1-MSN subpopulations to determine how these alterations affect the other cell type, D1-MSN circuit activity, and ultimately stress vulnerable or resilient behavior including reward value behaviors. Finally, using cell subtype RNA-seq we will determine how microglia impact stress mediated molecular adaptations in D1-MSN subtype populations and how D1-MSNs impact stress mediated microglia adaptations. Collectively our studies can provide improved understanding of NAc cell subtype mechanisms in susceptible and resilient subjects. Our studies could uncover future therapeutic avenues aimed at mimicking stress resilient mechanisms or combating stress susceptible mechanisms in psychiatric motivational symptoms