Microglial pruning of dopamine receptors and opioid abuse.

多巴胺受体的小胶质细胞修剪和阿片类药物滥用。

• 批准号: 10596602
• 负责人: Staci D Bilbo
• 金额: $ 38.82万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596602
• 关键词: Acute; Adolescence; Adolescent; Adult; Age; Alcohol consumption; Behavior; Biological; Brain; COVID-19 pandemic; Cells; Cessation of life; Complement; Development; Disease; Dopamine; Dopamine Receptor; Drug Exposure; Drug abuse; Drug usage; Eating; Elderly; Excision; Female; Genetic; Human; Immune; Inflammatory; Life; Longevity; Mediating; Membrane; Microglia; Molecular; Morphine; Neurobiology; Neurons; Nucleus Accumbens; Opioid; Phagocytosis; Pharmaceutical Preparations; Play; Rattus; Reporting; Rewards; Risk; Risk Taking; Rodent; Rodent Model; Role; Self Administration; Signal Transduction; Social Behavior; Social Environment; Social Interaction; Social isolation; Stress; Synapses; System; Testing; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Weaning; addiction; addiction liability; brain cell; critical period; developmental plasticity; early adolescence; experience; illicit drug use; male; mouse model; neural; opioid abuse; opioid epidemic; peer; prescription opioid misuse; prevent; receptor; resilience; response; reward circuitry; reward processing; sex; social; twelfth grade; young adult

The dopaminergic “reward” circuitry undergoes significant developmental plasticity during adolescence, including the refinement of dopamine D1 and D2 (D1/D2r) receptors within the nucleus accumbens (NAc). We have recently demonstrated in male rats that microglia – the primary immune cells of the CNS that also play a role in sculpting developing circuits – engulf and eliminate D1rs during a precise window of adolescent NAc development in response to receptor “tagging” by complement protein C3; and that this developmental pruning of D1rs by microglia is critical for the development of normal reward-driven behavior (social play). Moreover, rats that receive repeated morphine during adolescence (but not young adulthood) show persistent changes in microglial function and increased reinstatement to morphine as adults; and, pre- treatment with a glial modulator during adolescent morphine exposure prevents this increased reinstatement, implicating a critical role for microglia. Microglia refine synapses based on changes in neural activity, leading us to hypothesize that, in males (1) microglia sculpt NAc D1rs during normal adolescence as a consequence of altered dopamine (DA) activity which leads to receptor tagging by the “eat me” signal C3; and (2) factors that significantly impact DA signaling within the NAc during adolescence could persistently alter reward processing - including addiction liability - by changing microglial pruning of D1rs. We will use 3 aims to test the hypothesis that dopaminergic input to the NAc leads to complement C3 “tagging” of D1r and phagocytosis by microglia and that disruptions of this normal input (e.g. by social isolation stress) will lead to dysregulated long-term reward-driven behaviors. Importantly, D1r refinement occurs via unknown mechanisms in females, independent of microglia-C3 interaction, and the implications for addiction have not been assessed. To explore putative mechanisms in females we will additionally assess changes in D2r, and examine additional putative molecular tags/ “eat-me” signals.

多巴胺能“奖励”电路在发育过程中经历了显着的发育可塑性 青春期，包括多巴胺 D1 和 D2 (D1/D2r) 受体的细化 我们最近在雄性大鼠中证明了伏隔核（NAc）。 中枢神经系统的初级免疫细胞在塑造发育中的回路中也发挥着作用——吞噬和 在青少年 NAc 发育的精确窗口期间消除 D1rs 以响应受体 补体蛋白 C3 进行“标记”；小胶质细胞对 D1rs 的发育修剪是 此外，对于正常奖励驱动行为（社交游戏）的发展至关重要。 在青春期（但不是成年初期）重复接受吗啡表现出持续性 成年后小胶质细胞功能的变化和吗啡恢复的增加； 在青少年吗啡暴露期间使用神经胶质调节剂治疗可防止这种增加 恢复，表明小胶质细胞在细化突触方面发挥着关键作用。 神经活动的变化，使我们发现，在男性中 (1) 小胶质细胞塑造 NAc D1rs 在正常青春期，由于多巴胺 (DA) 活性，导致 “吃我”信号 C3 的受体标记；以及 (2) 显着影响 DA 信号传导的因素 青春期的 NAc 内可能会持续改变奖励处理——包括成瘾 责任 - 通过改变 D1rs 的小胶质细胞修剪，我们将使用 3 个目标来检验以下假设： NAc 的多巴胺能输入导致 D1r 的补体 C3“标记”和吞噬作用 小胶质细胞和这种正常输入的破坏（例如通过社会隔离压力）将导致 重要的是，D1r 的细化是通过长期奖励驱动的行为发生的。 女性中的未知机制，独立于小胶质细胞-C3 相互作用，及其影响 为了探索女性的成瘾机制，我们将进行评估。 另外评估 D2r 的变化，并检查其他假定的分子标签/“吃我” 信号。