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变化 创伤后应激障碍(PTSD)是一种以一系列症状为特征的严重焦虑症 包括侵入性记忆、高度唤醒和反应性。适应不良的恐惧学习是可能的原因之一 疾病病理学的基本机制。内源性大麻素是一种脂质神经调节剂，控制着几种 PTSD患者的记忆和情绪等生理过程被发现发生了变化。创伤后应激障碍患者 表现出循环中内源性大麻素的减少和大麻素受体1水平的增加。因此，大麻素 受体激动剂已被用于缓解创伤后应激障碍的症状。近一半患有创伤后应激障碍的患者 符合酒精使用障碍(AUD)的标准。酒精暴露已被证明会增加 内源性大麻素存在于大脑的几个区域。这增加了内源性大麻素减少的可能性 信号传递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 小脑与恐惧学习、情绪学习和奖励有关。我的初步结果显示，恐惧 条件反射增加单酰甘油(MAGL)活性增加内源性大麻素的降解 小脑。相比之下，长期接触酒精会降低MAGL的活性。我们的中心假设是恐惧 条件反射提高了MAGL的活性，降低了欧洲央行的语气，这促进了恐惧记忆的保留，而 随后的酒精暴露会逆转小脑的这些变化。目的1探讨大鼠脑缺血再灌注损伤的机制 MAGL活性增加。目标2将研究酒精暴露降低MAGL活性的机制 采用去极化抑制激发和酶活性测定。Aim 2也将调查这一影响 长期酒精暴露对恐惧记忆保持的影响。这项研究将提供有关创伤后应激障碍的机械性见解 并存的AUD，这可能导致开发新的治疗方法来治疗这种并存。

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.