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.

慢性酒精暴露对皮质纹状体传递的突触前调节 长期接触酒精会导致行为的病理变化，包括认知方面的改变 从灵活的、目标导向的饮酒过渡到僵化的、习惯性的饮酒。背部 负责运动活动、动作学习和习惯养成的纹状体，在 突触调节对慢性酒精暴露的反应。对兴奋性传递的抑制 突触前G蛋白偶联受体(GPCRs)，如代谢性谷氨酸受体2(MGlu2) 与Gi/o蛋白的偶联受到慢性酒精的损害。我将探索酒精如何改变gpr的调节。 特定的突触，并将这些变化与行为适应联系起来。我的中心假设是 慢性酒精暴露后突触前GPCR功能降低扰乱正常皮质调节 纹状体功能的改变，从而促进背外侧纹状体依赖的学习。以下结果 研究将为靶向突触前GPCR的治疗作用提供洞察力，例如mGlu2对AUDS的治疗作用。 目的1.确定mGlu2介导的谷氨酸能调制中断的输入特异性 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 以确定特定的兴奋性投射到背侧纹状体的影响，长期酒精暴露。 目的2.评价酒精对大鼠皮质纹状体Gi/o偶联GPCR功能的影响。 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 验证这样的假设，即皮质纹状体回路突触前GPCR功能的中断模仿了突触前GPCR功能的增强 慢性酒精暴露对背侧纹状体依赖学习的影响。我还将检验这一假设 特制药物对突触前Gi/O偶联设计受体的激活作用 皮质纹状体环路中的DREADDS将逆转酒精诱导的纹状体依赖学习的增强。 目的3.评估Gi/o偶联GPCRs对习惯性的突触前皮质纹状体抑制的影响 酗酒。我将使用药理学和化学发生学策略来研究突触前的作用 习惯性饮酒的GPCR激活(mGlu2或DREADD)。 培训：我将在慢性酒精暴露模型方面获得丰富的经验，包括慢性 间歇性乙醇蒸气暴露(CIE)(目标1和2)和可操作性乙醇自我给药(目标3)。这就做 还要学习复杂的工具性学习模型，以观察酒精诱导的认知变化(目标 2)和习惯性寻酒行为(目标3)。行为分析方面的培训将使我能够应用我的 对突触传递的GPCR调制感兴趣，关于突触如何调制的问题尚未回答 影响动物的行为。我还将接受职业发展培训，以最大限度地提高我的能力 过渡到一个独立的立场，并对酒精领域做出重大的科学贡献。