Sex Differences in Endocannabinoid Regulation of Behavioral Flexibility

项目摘要 大约30%的尝试滥用药物的人转变为成瘾，这表明个体差异 吸毒前的经历会导致上瘾的易感性。手势跟踪和目标跟踪表型 预测明显的药物复发脆弱性，已经在人类和啮齿动物身上建立了模型。手势跟踪大鼠 在药物体验之前表现出更高的线索敏感度，这预示着线索驱动的药物寻求和 与目标追踪者相比，线索诱导的复发率更高。男性和女性在成瘾方面也不同。 妇女易受伤害，表现为吸毒加剧，复发的可能性更高。女性 老鼠更有可能是手势跟踪者，这表明有必要研究手势追踪老鼠的性别差异 了解女性独特的神经生物学脆弱性。手势追踪者和雌性类似 当有回报的结果贬值时，这种做法不灵活。我发现减少大麻素1受体 背内侧纹状体(DMS)中的(CB1R)信号使雌性大鼠手势跟踪变得灵活，但 对追踪手势的雄性大鼠的影响正好相反。CB1R在DMS的眶前皮质(OFC)输入上表达 DMS内的GABA能中间神经元和中等棘神经元。该项目将重点放在 性行为和手势跟踪的交叉，研究DMS内源性大麻素对行为灵活性的调节。我 假设CB1R介导的OFC-DMS传递的减少阻止了女性手势的灵活性- 跟踪大鼠，而CB1R介导的GABA能传递的减少促进了男性体征的灵活性- 追踪老鼠。首先，我将使用切片电生理学和RNAScope来了解功能和 雄性和雌性ST大鼠DMS内CB1R的表达差异。第二，我将使用 化学遗传学和脑片电生理学研究OFC-DMS投射对行为的贡献 灵活性以及CB1R激活对这一投射的影响。通过这些实验，我的目标是发现 导致相关灵活性受损的关键分子和基于电路的机制 容易上瘾的人。

Project Summary Around 30% of individuals who try drugs of abuse transition to addiction, suggesting that individual differences prior to drug experience contribute to addiction vulnerability. Sign-tracking and goal-tracking phenotypes which predict distinct drug relapse vulnerabilities, have been modelled in humans and rodents. Sign-tracking rats show enhanced cue sensitivity prior to drug experience which predicts heightened cue-driven drug seeking and increased cue-induced relapse as compared to goal-trackers. Men and women also differ in their addiction vulnerability, where women show enhanced escalation of drug use and higher probability to relapse. Female rats are more likely to be sign-trackers, suggesting a need to study sex differences in sign-tracking rats to understand the unique neurobiological vulnerabilities in females. Sign-trackers and females are similarly inflexible when rewarding outcomes are devalued. I have found that decreasing cannabinoid 1 receptors (CB1R) signaling in the dorsomedial striatum (DMS) makes female sign-tracking rats flexible, but has the opposite effect in male sign-tracking rats. CB1R are expressed on orbitofrontal cortex (OFC) inputs to the DMS and on GABAergic interneurons and medium spiny neurons in the DMS. This project will focus on the intersection of sex and sign-tracking, investigating DMS endocannabinoid regulation of behavioral flexibility. I hypothesize that a CB1R-mediated decrease in OFC-DMS transmission prevents flexibility in female sign- tracking rats, while a CB1R-mediated decrease in GABAergic transmission promotes flexibility of male sign- tracking rats. First, I will use slice electrophysiology and RNAscope to understand the functional and expression-based differences in CB1R within the DMS between male and female ST rats. Second, I will use chemogenetics and slice electrophysiology to investigate the contribution of OFC-DMS projection to behavioral flexibility and the influence of CB1R activation on this projection. Through these experiments, I aim to uncover critical molecular and circuit-based mechanisms that contribute to impairments in flexibility that are associated with addiction vulnerability.