Project Summary/Abstract Microglia are the tissue resident macrophages in the brain that perform diverse functions to maintain brain homeostasis. Microglia phagocytose dying cells and debris, secrete growth factors, and prune afunctional synapses. In order for this homeostasis to be maintained, microglia need to sense cognate changes in neuronal activity. One exciting possible mechanism by which microglia sense changes in neural activity is by expressing receptors for the neurotransmitters present in their microenvironment. In this way, microglia could sample fluctuations in local neurotransmitter levels, infer changes in neural activity, and corresponding modify overall neural activity to maintain circuit homeostasis. Accordingly, I found that a subset of microglia in the striatum express the dopamine 1 receptor (D1R). Dopaminergic innervation is crucial for psychomotor functioning, and dysregulation is associated with neurological and neuropsychiatric disorders. I hypothesize that the unique subpopulation of D1R-expressing microglia in the striatum may actively sense changes in dopamine levels and relay these changes to striatal neurons by modulating their activity. This project will investigate how D1R signaling influences microglial gene expression and function and assess how abrogating the microglial response to dopamine impacts medium spiny neurons and dopamine-dependent behaviors. I will use cutting-edge molecule and genetic techniques coupled with behavioral paradigms to fully assess the role of this D1R+ microglial subpopulation. The data obtained in this project will help uncover novel mechanisms of cognate microglia-neuron communication and help us understand how microglia sense and respond to specific changes in neural activity. Identifying the function of D1R signaling in microglia may reveal how microglia contribute to dopamine system dysfunction in neuropsychiatric disorders and addiction.