Project Summary This proposal will explore a new axis of dopaminergic regulation–microglial expression of the dopamine receptor DRD1 and their modulation of neuronal activity and excitability in response to changing dopamine levels. Microglia, the resident immune cells of the central nervous system, exhibit a wide array of functions, some stereotypical of macrophages and some unique to the brain. Recent research from our lab and others has demonstrated that one such function is to modulate neuronal activity, but how and why they do so is still under investigation. Microglia exhibit a high degree of regional heterogeneity in form and function, perhaps to account for the diversity of local cues and demands of different brain regions. A growing body of literature suggests that microglia possess the ability to express receptor transcripts for and respond to an array of neurotransmitters and neuropeptides, and that expression of these may vary by region, activity, or disease state. Our lab has uncovered a unique subpopulation of microglia that express the dopamine receptor DRD1 (D1) in the striatum. Dopamine is a neurotransmitter involved in reward, motivation, voluntary motor behavior, and substance use disorders. How, when, and why microglial DRD1 expression emerges remains unclear, and I will confront each of these questions with my proposed experiments. I will trace the ontogeny of microglial DRD1 through development using several transgenic mouse models to investigate when microglial DRD1 expression begins, from where D1+ microglia originate, if not the striatum, and if expression/maintenance is dependent upon dopaminergic input. I will also use cutting-edge microglia transplant techniques to determine if microglia can acquire DRD1 in the striatum, which will provide important evidence for the role of local cues in microglial phenotypic determination, an open question in the field. Additionally, preliminary data from our lab have demonstrated that D1+ microglia may be able to modulate the neuronal and behavioral response to dopamine. Ablation of microglia overall and D1+ microglia specifically both amplify the locomotor response to chronic cocaine, which increases dopamine levels by blocking reuptake. Changing dopamine levels are characteristic of a number of physiological, developmental, and environmental events. In this proposal, I will explore two that are associated with an adaptation of striatal medium spiny neuron excitability: juvenile dopaminergic development and chronic cocaine. Based on our data, I hypothesize that D1+ microglia sense and respond to dopamine in order to tune neuronal excitability to changing dopamine levels throughout the lifetime. Exploring the role of D1+ microglia in dopaminergic signaling is critical to understanding the dopaminergic dysfunction that characterizes numerous neuropsychiatric and neurological disorders, including substance use disorder, Parkinson’s disease, depression, and ADHD, and could provide novel...