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: 10388826
• 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/10388826
• 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 D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Exposure; Drug abuse; Drug usage; Eating; Elderly; Excision; Female; 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; base; brain cell; critical period; developmental plasticity; early adolescence; experience; illicit drug use; male; mouse model; opioid abuse; opioid epidemic; peer; prescription opioid misuse; prevent; ranpirnase; receptor; relating to nervous system; 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“奖赏”回路在发育过程中经历了显著的发育可塑性。 青春期，包括多巴胺D1和D2（D1/D2 r）受体的细化， 丘脑核（NAc）。我们最近在雄性大鼠中证明， 中枢神经系统的初级免疫细胞也在塑造发育中的回路中发挥作用-吞噬和 在青少年NAc发育的精确窗口期消除D1 rs，以响应受体 补体蛋白C3的“标记”;小胶质细胞对D1 rs的这种发育修剪， 对正常奖励驱动行为（社交游戏）的发展至关重要。此外， 在青春期（但不是年轻的成年期）反复接受吗啡， 小胶质细胞功能的变化和成年后对吗啡的恢复增加; 在青少年吗啡暴露期间用神经胶质调节剂治疗可以防止这种增加 恢复，暗示小胶质细胞的关键作用。小神经胶质细胞根据 神经活动的变化，使我们假设，在男性（1）小胶质细胞雕刻NAc D1 rs 在正常青春期，由于多巴胺（DA）活动的改变，导致 受体标记的“吃我”信号C3;和（2）因素，显着影响DA信号 在青春期，NAc内的神经元可能会持续地改变奖励过程--包括成瘾 责任-通过改变D1 rs的小胶质细胞修剪。我们将使用3个目标来检验假设， 向NAc的多巴胺能输入导致补体C3对D1 r的“标记”，并通过 小胶质细胞，这种正常输入的中断（例如，社会孤立压力）将导致 长期奖励驱动的行为失调。重要的是，D1 r细化通过以下方式进行： 女性中未知的机制，独立于小胶质细胞-C3相互作用，及其影响 成瘾性还没有被评估。为了探索女性的假定机制，我们将 额外评估D2 r的变化，并检查额外的推定分子标签/“eat-me” 信号.