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。

基本信息

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
项目类别：
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

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

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项目摘要

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”电路在期间经历了重要的发育可塑性青少年，包括多巴胺D1和D2（D1/D2R）受体的细化伏隔核（NAC）。我们最近在雄性大鼠中证明了小胶质细胞 - 中枢神经系统的原发性免疫细胞在雕刻开发电路中发挥作用 - engulf和在青春期NAC开发的精确窗口中，消除D1RS，以响应接收器补充蛋白C3的“标记”；而小胶质细胞对D1RS的这种发展是对于发展正常奖励驱动行为（社交游戏）至关重要。而且，大鼠在青春期（但不成年）期间接收重复的吗啡成年后，小胶质功能的变化并增加了吗啡的恢复。而且，前青少年吗啡暴露期间用神经胶质调节剂治疗可防止这种增加恢复原状，暗示小胶质细胞的关键作用。基于小胶质细胞的突触神经活动的变化，导致我们假设在男性中（1）小胶质细胞雕刻NAC D1RS 由于多巴胺（DA）活性改变，在正常青少年期间接收器标记为“吃我”信号C3；（2）显着影响DA信号传导的因素在青少年期间NAC内部可能会持续改变奖励处理 - 包括成瘾责任 - 通过更改D1RS的小胶质修剪。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）将导致长期奖励驱动的行为失调。重要的是，D1R细化是通过女性的未知机制，与小胶质细胞C3相互作用无关为了成瘾，尚未评估。为了探索女性的推定机制，我们将另外评估D2R的变化，并检查其他推定的分子标签/“ eat-me” 信号。