Sex Differences in Endocannabinoid Regulation of Behavioral Flexibility

内源性大麻素对行为灵活性调节的性别差异

• 批准号: 10606290
• 负责人: Catherine A. Stapf
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-13 至 2026-01-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606290
• 关键词: Affect; Automobile Driving; Behavior; Behavioral; Brain; CNR1 gene; Cells; Chronic; Clinical; Clinical Research; Corpus striatum structure; Cue-induced relapse; Cues; Data; Development; Disease; Dorsal; Drug Exposure; Drug usage; Electrophysiology (science); Endocannabinoids; Equilibrium; Female; Food; Genetic; Genetic Transcription; Glutamates; Goals; Human; Impairment; Individual; Individual Differences; Interneurons; Mediating; Messenger RNA; Modeling; Molecular; Motivation; Neurobiology; Neurons; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Population; Probability; Rattus; Receptor Activation; Receptor Signaling; Regulation; Relapse; Reporting; Research; Rewards; Rodent; Sex Differences; Slice; Substance Use Disorder; Synapses; Testing; Vulnerable Populations; Woman; addiction; brain circuitry; cocaine craving; cocaine relapse; cocaine use; craving; cue reactivity; drug of abuse; drug relapse; endocannabinoid signaling; experience; experimental study; flexibility; gamma-Aminobutyric Acid; mRNA Expression; male; men; neurotransmitter release; optogenetics; patch clamp; pre-clinical; preclinical study; presynaptic; prevent; sex; transmission process

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.

项目概要 大约 30% 尝试滥用药物的人会转变为成瘾，这表明个体差异 吸毒之前的经历会导致成瘾脆弱性。标志跟踪和目标跟踪表型 预测不同的药物复发脆弱性，已在人类和啮齿动物中进行建模。体征追踪老鼠 在药物体验之前表现出增强的提示敏感性，这预示着提示驱动的药物寻求会增强 与目标追踪器相比，提示诱发的复发增加。男性和女性的成瘾程度也不同 脆弱性，妇女吸毒的情况更加严重，而且复发的可能性也更高。女性 老鼠更有可能成为信号追踪者，这表明需要研究信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 当奖励结果贬值时，就变得不灵活。我发现减少大麻素 1 受体 背内侧纹状体 (DMS) 中的 (CB1R) 信号使雌性信号追踪大鼠变得灵活，但 对雄性体征追踪大鼠产生相反的效果。 CB1R 在 DMS 的眶额皮层 (OFC) 输入上表达 以及 DMS 中的 GABA 能中间神经元和中型多棘神经元。该项目将重点关注 性与体征追踪的交叉点，调查 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 传输减少会阻碍女性信号的灵活性 跟踪大鼠，而 CB1R 介导的 GABA 能传输减少可促进雄性信号的灵活性 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。其次，我将使用 化学遗传学和切片电生理学研究 OFC-DMS 预测对行为的贡献 灵活性以及 CB1R 激活对此预测的影响。通过这些实验，我的目的是揭示 导致相关灵活性受损的关键分子和电路机制 具有成瘾脆弱性。