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

青少年药物诱导的神经免疫信号对性别特异性社会发展和奖励学习的影响。

基本信息

批准号：
10370665
负责人：
Ashley M Kopec
金额：
$ 48.67万
依托单位：
ALBANY MEDICAL COLLEGE
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：
2022-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370665
关键词：
Adolescence Adolescent Adult Affect Area Behavior COVID-19 pandemic Data Development Drug Exposure Drug usage Epidemic Exposure to Familiarity Female Food Goals Immune Impairment Learning Learning Disorders Life Longevity Measures Mediating Memory Disorders Mental disorders Microglia Modeling Molecular Morphine Neuroimmune Nucleus Accumbens Opioid Outcome Phagocytes Phagocytosis Pharmaceutical Preparations Proteins Rattus Relapse Resources Rewards Risk Risk Factors Signal Transduction Social Behavior Social Development Social Interaction Social outcome Stimulus Substance Use Disorder Synapses Testing adolescent drug use brain cell classical conditioning conditioned place preference disorder risk drug reward early adolescence male opioid misuse opioid mortality opioid use postnatal preadolescence preference prescription opioid receptor sex social social deficits social factors social influence synaptic pruning

项目摘要

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.

项目摘要药物使用障碍（SUD），尤其是涉及阿片类药物的药物，已经达到了流行水平。泡沫假设是学习和记忆障碍：药物“奖励”与其他中性重新遇到类似的刺激时，刺激会促进或恢复药物使用（复发）。复发利率为40-60％，表明先前学习的药物协会是康复者持续的风险来自泡沫。社会介导的学习无处不在，社会因素也调节药物使用。但是，社会因素如何影响与药物相关的学习及其表达一旦建立，尚不清楚。伏隔核（NAC）奖励区域对于药物联想学习和社会影响都至关重要过度行为。我们确定小胶质细胞，居民的大脑免疫力，媒体社会发展通过吞噬作用或雄性大鼠早期NAC核中突触蛋白的“修剪”，在雄性大鼠和女性的青春期前。青春期药物使用会增加生活后来生活的风险和社会功能障碍。实际上，即使是青少年处方阿片类药物的使用也会增加现年生活中的阿片类药物。阿片类吗啡直接激活小胶质细胞上的pro-脑受体，包括NAC小胶质细胞。这些数据增加了可能性青少年的阿片类药物使用可以通过改变小胶质细胞介导的NAC和社会发展来增加SUD风险，反过来又对奖励学习的社会影响力。在此提案中，我们将限制短期吗啡暴露于每个特定性别的NAC核心修剪期在青春期，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，以及（3）社会介导的奖励学习。我们的核心假设是青春期吗啡暴露于NAC核心的小胶质细胞介导的修剪加剧，导致社会发展异常和增强对奖励学习的社会影响力。该提案将是第一个检查机械的提案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 - 在终生的SUD风险和其他精神健康障碍的特定青春期脆弱性时期受到影响。