Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure

慢性乙醇暴露后皮质纹状体传递的突触前调节

• 批准号: 10241461
• 负责人: Kari Johnson
• 金额: $ 24.86万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241461
• 关键词: Addictive Behavior; Alcohol abuse; Alcohol consumption; Alcohols; Animal Behavior; Behavior; Behavioral; Behavioral Assay; Behavioral Paradigm; Brain region; CNR1 gene; Chemosensitization; Chronic; Cognition; Communication; Corpus striatum structure; Coupled; Data; Development; Discrimination; Dorsal; Drug Modelings; Electrophysiology (science); Ethanol; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Glutamates; Goals; Habits; Human; Impairment; Learning; Long-Term Depression; Mediating; Modeling; Motor Activity; Mus; Operant Conditioning; Pathologic; Pharmaceutical Preparations; Pharmacology; Physiological; Positioning Attribute; Proteins; Rattus; Receptor Activation; Regulation; Research; Rodent; Role; Self Administration; Signal Transduction; Slice; Specificity; Synapses; Synaptic Transmission; Techniques; Testing; Thalamic structure; Therapeutic; Toxin; Training; Viral; Visual; Withdrawal; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol use disorder; base; career development; chronic alcohol ingestion; classical conditioning; clinical development; designer receptors exclusively activated by designer drugs; experience; flexibility; innovation; insight; interest; metabotropic glutamate receptor 2; mu opioid receptors; neuroadaptation; novel; novel therapeutics; optogenetics; positive allosteric modulator; pre-clinical; preference; presynaptic; receptor; receptor function; response; synaptic depression; transmission process; vapor

Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure Chronic ethanol exposure causes pathological changes in behavior, including alterations in cognition and a transition from flexible, goal-directed alcohol use to inflexible, habitual alcohol seeking. The dorsal striatum, which is responsible for motor activity, action learning, and habit formation, undergoes changes in synaptic modulation in response to chronic alcohol exposure. Inhibition of excitatory transmission by presynaptic G protein-coupled receptors (GPCRs) such as metabotropic glutamate receptor 2 (mGlu2) that couple to Gi/o proteins is impaired by chronic alcohol. I will explore how alcohol changes GPCR modulation of specific synapses, and relate these alterations to behavioral adaptations. My central hypothesis is that reductions in presynaptic GPCR function following chronic alcohol exposure disrupt normal cortical regulation of striatal function such that dorsolateral striatum-dependent learning is facilitated. Results of the following studies will provide insight into the therapeutic utility of targeting presynaptic GPCRs such as mGlu2 for AUDs. Aim 1. Determine the input-specificity of the disruption of mGlu2-mediated modulation of glutamatergic synaptic transmission in the dorsal striatum. I will use slice electrophysiology and optogenetic techniques to identify specific excitatory projections to the dorsal striatum that are impacted by chronic alcohol exposure. Aim 2. Evaluate the effect of alcohol-induced changes in corticostriatal Gi/o-coupled GPCR function on dorsal striatum-mediated learning. I will use an innovative, genetically-encoded, toxin-based technique to test the hypothesis that disruption of presynaptic GPCR function in corticostriatal circuits mimics the enhancing effect of chronic alcohol exposure on dorsal striatum-dependent learning. I will also test the hypothesis that activation of presynaptic Gi/o-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in corticostriatal circuits will reverse alcohol-induced enhancement of striatum-dependent learning. Aim 3. Assess the impact of presynaptic corticostriatal inhibition by Gi/o-coupled GPCRs on habitual alcohol seeking. I will use pharmacological and chemogenetic strategies to study effects of presynaptic GPCR activation (mGlu2 or DREADD) on habitual alcohol seeking. Training: I will gain extensive experience with models of chronic alcohol exposure, including chronic intermittent ethanol vapor exposure (CIE) (Aims 1 and 2) and operant ethanol self-administration (Aim 3). I will also learn sophisticated models of instrumental learning to look at alcohol-induced changes in cognition (Aim 2) and habitual alcohol seeking behavior (Aim 3). Training in behavioral assays will allow me to apply my interest in GPCR modulation of synaptic transmission to unanswered questions about how synaptic modulation influences animal behavior. I will also receive career development training that will maximize my ability to transition to an independent position and make significant scientific contributions to the alcohol field.

慢性乙醇暴露后皮质纹状体传递的突触前调节 慢性乙醇暴露会导致行为病理变化，包括认知改变 从灵活的、有目标的饮酒到不灵活的、习惯性的饮酒的转变。背部 负责运动活动、行动学习和习惯形成的纹状体发生了变化 对慢性酒精暴露的突触调节。抑制兴奋性传递 突触前 G 蛋白偶联受体 (GPCR)，例如代谢型谷氨酸受体 2 (mGlu2) 长期饮酒会损害与 Gi/o 蛋白的耦合。我将探讨酒精如何改变 GPCR 的调节 特定的突触，并将这些改变与行为适应联系起来。我的中心假设是 长期酒精暴露后突触前 GPCR 功能的降低会扰乱正常的皮质调节 纹状体功能，从而促进背外侧纹状体依赖性学习。结果如下 研究将深入了解针对突触前 GPCR（例如 mGlu2）用于 AUD 的治疗效用。 目标 1. 确定 mGlu2 介导的谷氨酸能调节破坏的输入特异性 背侧纹状体的突触传递。我将使用切片电生理学和光遗传学技术 确定受长期酒精暴露影响的背侧纹状体的特定兴奋性投射。 目标 2. 评估酒精引起的皮质纹状体 Gi/o 耦合 GPCR 功能变化对 背侧纹状体介导的学习。我将使用一种创新的、基因编码的、基于毒素的技术来 检验皮质纹状体回路中突触前 GPCR 功能的破坏模拟了增强的假设 慢性酒精暴露对背侧纹状体依赖性学习的影响。我还将检验以下假设 突触前 Gi/o 耦合设计受体的激活仅由设计药物激活 皮质纹状体回路中的（DREADD）将逆转酒精引起的纹状体依赖性学习的增强。 目标 3. 评估 Gi/o 耦合 GPCR 抑制突触前皮质纹状体对习惯性行为的影响 寻求酒精。我将使用药理学和化学遗传学策略来研究突触前的影响 习惯性饮酒时 GPCR 激活（mGlu2 或 DREADD）。 培训：我将获得长期酒精暴露模型的丰富经验，包括慢性酒精暴露模型 间歇性乙醇蒸气暴露 (CIE)（目标 1 和 2）和操作性乙醇自我给药（目标 3）。我会 还学习工具学习的复杂模型，以观察酒精引起的认知变化（目标 2) 和习惯性饮酒行为（目标 3）。行为分析培训将使我能够应用我的 对突触传递的 GPCR 调节的兴趣以及关于突触调节如何进行的未解答的问题 影响动物行为。我还将接受职业发展培训，以最大限度地提高我的能力 过渡到独立地位并为酒精领域做出重大科学贡献。