Epigenetic Regulation of Microglia Dopamine System Interactions

摘要

ABSTRACT Adolescence is a time of increased risk and reward seeking behaviors, and 74% of adults with a substance use disorder initiated use by 17 years of age, with many drugs of abuse acting through the dopamine (DA) system. This makes understanding DA system development in adolescence of great importance to uncover the etiology substance use disorders. In the rat, adolescence is a critical window of circuit refinement in the nucleus accumbens (NAc), a dopamine (DA) rich brain region associated with reward. Microglia, the resident immune cell of the brain, not only provides neuroimmune support but prunes synapses and receptors. We recently demonstrated in rats that dopamine d1 receptor (D1r) peaks in adolescence and declines into adulthood, and this decline occurs via a microglial-dependent phagocytic mechanism in males but not females. Importantly, this downregulation of D1r in the NAc mediates termination of adolescent social play behavior in males. It is not known what regulates microglial pruning behavior in the NAc. It is known that microglia phagocytosis across brain regions due to chromatin remodeling altering transcriptional accessibility of required genes. Moreover, microglial phagocytosis of synapses has been demonstrated to be dependent on neuronal activity. My central hypothesis is that NAc microglial chromatin reorganization throughout adolescent development regulates genomic accessibility and expression of phagocytic genes, mediating D1r phagocytosis directing social behavior in males. I predict this occurs in a DA activity-dependent manner. To test these hypotheses, in Aim 1 I will characterize genomic accessibility and gene expression with microglia, correlating phagocytic gene accessibility expression through across adolescent development. This will provide a novel baseline characterization of microglia through development and between sexes, potentially identifying sensitive periods of dynamic gene regulation. In Aim 2 I will determine if dopaminergic signaling to the NAc is required for typical microglial phagocytic activity and chromatin organization, impacting social behavior. This will demonstrate whether microglial pruning of dopamine receptors during adolescence is dependent on neuronal activity and has consequences for behavior. Collectively these data allows for powerful future directions investigating effects of drugs of abuse on microglial development and function