Epigenetic Regulation of Microglia Dopamine System Interactions

小胶质细胞多巴胺系统相互作用的表观遗传调控

• 批准号: 10677275
• 负责人: Madeline J Clark
• 金额: $ 4.03万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2026-03-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677275
• 关键词: 17 year old; Adolescence; Adolescent; Adolescent Development; Adult; Animal Experiments; Animals; Automobile Driving; Behavior; Biological Assay; Biology; Brain region; Chromatin; Chromatin Remodeling Factor; Control Animal; Control Groups; Cues; DNA; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Down-Regulation; Epigenetic Process; Etiology; Exhibits; Female; Fiber; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Histones; Immune; Immunohistochemistry; Knowledge; Mediating; Microglia; Motivation; Neuroimmune; Neurons; Nucleus Accumbens; Phagocyte Bactericidal Dysfunction; Phagocytes; Phagocytosis; Play; Process; Property; Rattus; Regulation; Regulator Genes; Rewards; Risk; Role; Sampling; Signal Transduction; Social Behavior; Stimulus; Substance Use Disorder; Synapses; Systems Development; Testing; Time; Transposase; Ventral Tegmental Area; Work; brain cell; brain reward regions; chromatin remodeling; comparison control; density; dopamine system; drug of abuse; epigenetic regulation; genomic locus; glial cell development; male; neural; novel; p38 Mitogen Activated Protein Kinase; phagocytosis receptor; receptor; receptor density; sex; social; synaptic pruning; transcriptome sequencing

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

摘要 青春期是一个增加风险和寻求奖励行为的时期，74%的成年人使用药物， 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DA系统在青春期的发展非常重要，以揭示病因 药物使用障碍。在大鼠中，青春期是细胞核回路精细化的关键窗口 多巴胺（DA）丰富的大脑区域，与奖励有关。小胶质细胞，常驻免疫细胞 脑细胞，不仅提供神经免疫支持，而且修剪突触和受体。我们最近 在大鼠中证明多巴胺d1受体（D1r）在青春期达到峰值，并在成年期下降， 这种下降通过小胶质细胞依赖性吞噬机制在雄性中发生，但在雌性中不发生。重要的是这 NAc中D1r的下调介导了男性青少年社会游戏行为的终止。不 我们知道是什么调节了NAc中的小胶质细胞修剪行为。已知小胶质细胞吞噬跨膜细胞， 由于染色质重塑改变了所需基因的转录可及性，此外，委员会认为， 已经证明突触的小胶质细胞吞噬作用依赖于神经元活性。我的中枢 一种假说认为，在整个青少年发育过程中，NAc小胶质细胞染色质重组调节 吞噬基因的基因组可及性和表达，介导D1r吞噬作用，指导社会行为 在男性中。我预测这是以DA活性依赖的方式发生的。为了验证这些假设，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， 通过青少年的发展来表达。这将提供一种新的基线表征， 小胶质细胞通过发展和性别之间，潜在地确定敏感时期的动态基因 调控在目标2中，我将确定多巴胺能信号传导到NAc是否是典型的小胶质细胞所必需的。 吞噬活性和染色质组织，影响社会行为。这将证明， 青春期多巴胺受体的小胶质细胞修剪依赖于神经元活动， 行为的后果。总的来说，这些数据为未来研究 滥用药物对小胶质细胞发育和功能的影响