The effect of adolescent drug-induced neuroimmune signaling in sex-specific social development and reward learning.

项目摘要 物质使用障碍，特别是涉及阿片类药物的物质使用障碍，已达到流行病的程度。泡沫 被假设为学习和记忆障碍：药物“奖励”与其他中性 当再次遇到类似的刺激时，刺激促进继续或恢复药物使用（复发）。复发 患病率为40- 60%，这表明之前了解到的药物关联对康复者来说是一个持续的风险 从SUD社会介导的学习在物种中无处不在，社会因素也会调节药物使用。 然而，社会因素如何影响药物相关的学习，以及它的表达一旦建立，是不清楚的。 神经核（NAc）奖赏区对药物联想学习和社会影响都至关重要 而不是行为我们确定，小胶质细胞，大脑的常驻免疫细胞，介导社会发展 通过吞噬作用，或“修剪”，在雄性大鼠青春期早期的NAc核心的突触蛋白，和 青春期前的女性青少年吸毒增加了SUD风险和以后生活中的社会功能障碍;事实上， 即使是在青春期使用处方类阿片也会增加以后生活中的类阿片滥用。阿片类吗啡直接 激活包括NAc小胶质细胞在内的小胶质细胞上的促吞噬细胞受体。这些数据表明 青少年阿片类药物使用通过改变小胶质细胞介导的NAc和社会发育增加SUD风险， 进而影响社会对奖励学习的影响。 在本提案中，我们将限制每个性别特异性NAc核心修剪期的短期吗啡暴露 以确定（1）吗啡如何影响正在进行的发育突触修剪活动，（2）社会 发展;（3）社会中介奖励学习。我们的核心假设是青少年的吗啡 暴露加剧了小胶质细胞介导的NAc核心修剪，导致异常的社会发展， 社会对奖励学习的影响增加。这项建议将是第一个审查一个机械的 青少年的社会发展与成年后的奖励学习之间的关系，并可能确定性别- 特定的青少年脆弱期，在此期间，一生中的SUD风险和其他精神健康疾病可能 受到影响。

PROJECT SUMMARY Substance use disorders (SUDs), particularly those involving opioids, have reached epidemic levels. SUDs are hypothesized to be learning and memory disorders: the association of drug ‘reward’ with otherwise neutral stimuli promotes continued or reinstated drug use (relapse) when similar stimuli are re-encountered. Relapse rates are 40-60%, suggesting that previously learned drug associations are a constant risk for those recovering from SUDs. Socially-mediated learning is ubiquitous across species, and social factors also modulate drug use. However, how social factors influence drug-associated learning, and its expression once established, is unclear. The nucleus accumbens (NAc) reward region is critical for both drug associative learning and for social influence over behavior. We determined that microglia, the resident immune cells of the brain, mediate social development via phagocytosis, or “pruning,” of synaptic proteins in the NAc core during early adolescence in male rats, and pre-adolescence in females. Adolescent drug use increases SUD risk and social dysfunction later in life; in fact, even prescription opioid use in adolescence increases opioid misuse later in life. The opioid morphine directly activates a pro-phagocytic receptor on microglia, including on NAc microglia. These data raise the possibility that adolescent opioid use increases SUD risk by changing microglia-mediated NAc and social development, and in turn social influence over reward learning. In this proposal, we will restrict short-term morphine exposure to each sex-specific NAc core pruning period in adolescence to determine (1) how morphine affects ongoing developmental synaptic pruning activity, (2) social development, and (3) socially-mediated reward learning. Our core hypothesis is that adolescent morphine exposure exacerbates microglia-mediated pruning in the NAc core, causing abnormal social development and increased social influence over reward learning. This proposal will be the first to examine a mechanistic relationship between social development in adolescence and reward learning in adulthood, and may identify sex- specific adolescent periods of vulnerability during which lifetime SUD risk and other mental health disorders can be influenced.