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制 慢性乙醇暴露导致行为的病理变化，包括认知的改变 以及从灵活的、有目的的饮酒转变为不灵活的、习惯性的饮酒。背 纹状体负责运动活动、动作学习和习惯形成， 突触调制对慢性酒精暴露的反应。兴奋性传递的抑制 突触前G蛋白偶联受体（GPCR）如代谢型谷氨酸受体2（mGlu 2）， 与Gi/o蛋白偶联的蛋白质被慢性酒精损害。我将探讨酒精如何改变GPCR调制 特定的突触，并将这些变化与行为适应联系起来。我的核心假设是 慢性酒精暴露后突触前GPCR功能的降低破坏了正常的皮质调节 纹状体的功能，从而促进背外侧纹状体依赖性学习。以下结果 研究将提供对靶向突触前GPCR如mGlu 2用于AUD的治疗效用的深入了解。 目标1.确定mGlu 2介导的谷氨酸能调节的破坏的输入特异性 背侧纹状体的突触传递。我会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，这是由慢性酒精暴露的影响。 目标二。评估酒精诱导的皮质纹状体Gi/o偶联GPCR功能变化对 背侧纹状体介导的学习。我会用一种创新的基因编码的毒素技术 检验皮质纹状体回路中突触前GPCR功能的破坏模拟了 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一个假设， 突触前Gi/o偶联设计者受体的激活（仅由设计者药物激活） （DREADDs）在皮质纹状体回路将逆转酒精诱导的纹状体依赖性学习的增强。 目标3。评估Gi/o偶联GPCR对习惯性突触前皮质纹状体抑制的影响 酒精寻求我将使用药理学和化学发生学的策略来研究突触前神经元的作用。 GPCR激活（mGlu 2或DREADD）对习惯性酒精寻求的影响。 培训：我将获得广泛的经验与模型的慢性酒精暴露，包括慢性 间歇性乙醇蒸汽暴露（CIE）（目的1和2）和操作性乙醇自我给药（目的3）。我会 我还学习了复杂的工具学习模型，以观察酒精引起的认知变化（Aim 2)和习惯性饮酒行为（目标3）。行为分析方面的培训将使我能够运用我的 对突触传递的GPCR调制的兴趣到关于如何突触调制的未回答的问题 影响动物的行为。我还将接受职业发展培训，以最大限度地发挥我的能力， 过渡到一个独立的位置，并作出重大的科学贡献，酒精领域。

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.