Epigenetic Regulation of Microglia Dopamine System Interactions

摘要 青春期是风险和寻求回报行为增加的时期，74%的成年人使用药物 精神障碍从17岁开始使用，许多滥用药物通过多巴胺(DA)系统起作用。 这使得了解青少年DA系统的发展对揭示其病因具有重要意义 物质使用障碍。在大鼠中，青春期是核内电路精炼的关键窗口 伏隔核(NAC)，一个富含多巴胺(DA)的大脑区域，与奖励有关。小胶质细胞，一种常驻免疫 大脑的细胞，不仅提供神经免疫支持，而且修剪突触和受体。我们最近 在大鼠身上证实，多巴胺D1受体(D1R)在青春期达到峰值，并下降到成年期，以及 这种下降在男性中是通过依赖小胶质细胞的吞噬机制发生的，而在女性中不是。重要的是，这 NAC中D1R的下调调节了男性青少年社交游戏行为的终止。它不是 知道是什么调节了NAC中的小胶质细胞修剪行为。已知小胶质细胞的吞噬作用 染色质重塑引起的大脑区域改变了所需基因的转录可及性。此外， 突触的小胶质细胞吞噬作用已被证明依赖于神经元的活动。我的中央 假说是NAC小胶质细胞染色质重组在整个青少年发育过程中起着调节作用 基因组可及性和吞噬基因的表达，介导D1R吞噬引导社会行为 在男性身上。我预测这会以依赖DA活动的方式发生。为了检验这些假设，在目标1中，我将 用小胶质细胞表征基因组可及性和基因表达，相关吞噬基因可及性 表达贯穿整个青春期的发展。这将提供一种新的基线表征 通过发育和性别之间的小胶质细胞，潜在地识别动态基因的敏感期 监管。在目标2中，我将确定典型的小胶质细胞是否需要向NAC发出多巴胺能信号。 吞噬细胞活动和染色质组织，影响社会行为。这将证明是否 青春期小胶质细胞对多巴胺受体的修剪依赖于神经元的活动，并具有 对行为的后果。总而言之，这些数据允许强大的未来方向调查 药物滥用对小胶质细胞发育和功能的影响

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