Sex Differences in Endocannabinoid Regulation of Behavioral Flexibility

项目摘要 大约30%的人尝试滥用药物过渡到成瘾，这表明个体差异 吸毒前的经历会增加成瘾的脆弱性。信号跟踪和目标跟踪表型， 预测不同的药物复发脆弱性，已经在人类和啮齿动物中建模。符号追踪大鼠 在药物体验之前表现出增强的线索敏感性，这预示着线索驱动的药物寻求增加， 与目标追踪者相比，提示诱导的复发增加。男性和女性在成瘾方面也有所不同 在脆弱性方面，妇女的吸毒情况更加严重，复发的可能性更高。女性 大鼠更有可能是符号追踪者，这表明需要研究符号追踪大鼠的性别差异， 了解女性独特的神经生物学脆弱性。信号追踪者和女性是相似的 当奖励结果被贬低时，我发现减少大麻素1受体 背内侧纹状体（DMS）中的CB 1 R信号使雌性符号追踪大鼠变得灵活，但 而在雄性符号追踪大鼠中则相反。CB 1 R在眶额皮质（OFC）上表达，输入DMS 以及对DMS中的GABA能中间神经元和中型棘神经元的影响。该项目将侧重于 性和符号跟踪的交叉点，研究DMS内源性大麻素对行为灵活性的调节。我 假设CB 1 R介导OFC-DMS传递减少阻止了女性体征的灵活性- 跟踪大鼠，而CB 1 R介导的GABA能传递减少促进男性标志的灵活性， 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大鼠之间DMS内CB 1 R的基于表达的差异。第二，我会用 化学遗传学和切片电生理学来研究OFC-DMS投射对行为的贡献。 灵活性和CB 1 R激活对该投射的影响。通过这些实验，我的目标是揭示 关键的分子和电路为基础的机制，有助于损害的灵活性， 成瘾的脆弱性。

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.