Alcohol exposure reverses fear conditioning-induced change in endocannabinoid signaling

酒精暴露逆转恐惧条件反射诱导的内源性大麻素信号传导的变化 创伤后应激障碍（PTSD）是一种严重的焦虑症，其特征是一系列症状 包括侵入性记忆、过度兴奋和反应性。适应不良的恐惧学习可能是 疾病病理学的潜在机制。内源性大麻素，脂质神经调质，控制几个 发现PTSD患者的生理过程如记忆和情绪发生改变。PTSD患者 表现出较低的循环内源性大麻素和增加的大麻素受体1水平。因此，大麻素 受体激动剂已用于减轻PTSD的症状。近一半的PTSD患者 符合酒精使用障碍（AUD）的标准。酒精暴露会增加 内源性大麻素在大脑的几个区域。这增加了内源性大麻素减少的可能性， 信号传导不仅与创伤后应激障碍有关，还可能导致酒精强化。越来越多的证据表明 小脑参与恐惧学习，情绪学习和奖励。我的初步结果显示 调节增加单酰基甘油（MAGL）活性，增加内源性大麻素的降解 小脑相反，慢性酒精暴露会降低MAGL活性。我们的核心假设是恐惧 条件反射提高了MAGL的活性，降低了eCB的张力，从而促进了恐惧记忆的保留， 随后的酒精暴露逆转了小脑的这些变化。目的1探讨 增加MAGL活性。目的2将研究酒精暴露降低MAGL活性的机制 使用激发的去极化抑制和酶活性测定。AIM2也将研究 长期饮酒对恐惧记忆保留的影响。这项研究将提供有关PTSD机制的见解 合并AUD，这可能导致开发针对该合并症的新疗法。

Alcohol exposure reverses fear conditioning-induced change in endocannabinoid signaling Post-traumatic stress disorder (PTSD) is a severe anxiety disorder characterized by a cluster of symptoms including intrusive memories and hyper-arousal and reactivity. Maladaptive fear learning is one of the possible mechanisms underlying disease pathology. Endocannabinoids, lipid neuromodulators, control several physiological processes such as memory and mood are found to be altered in PTSD patients. PTSD patients exhibit lower circulating endocannabinoids and increased level of cannabinoid receptor 1. Hence, cannabinoid receptor agonists have been used to alleviate symptoms of PTSD. Nearly half of patients suffering from PTSD meet the criteria for alcohol use disorder (AUD). Alcohol exposure has been shown to increase endocannabinoids in several areas of the brain. This raise the possibility that decrease in endocannabinoid signaling is not only involved in PTSD, but may also cause alcohol reinforcement. Mounting evidence has implicated cerebellum in fear learning, emotional learning, and reward. My preliminary results show that the fear conditioning increases monoacyl glycerol (MAGL) activity increasing endocannabinoid degradation in the cerebellum. In contrast, chronic alcohol exposure decreases MAGL activity. Our central hypothesis is that fear conditioning elevates MAGL activity and reduces eCB tone, which promotes retention of fear memories, while subsequent alcohol exposure reverses these changes in the cerebellum. Aim 1 investigate the mechanisms of increased MAGL activity. Aim 2 will study the mechanisms by which alcohol exposure reduces MAGL activity using depolarization suppression of excitation and enzyme activity assay. Aim 2 will also investigate the effect of chronic alcohol exposure on fear memory retention. This study will provide mechanistic insight about PTSD comorbid AUD, which may lead to development of new therapeutics for this comorbidity.