Role of Neuropeptides in Stress-Induced Escalation of Alcohol Drinking

创伤性应激障碍影响数百万美国人，每年花费数十亿美元。酒精使用 疾病（AUD）影响约12%的世界人口，在美国每年造成250万人死亡， 每年花费2200亿美元。创伤后应激障碍（PTSD）使发生AUD的风险增加三倍。 PTSD和AUD通过增加慢性疾病的发病率来增加人类的死亡率。PTSD诊断 也与人类慢性疼痛的发病率较高有关。目前的创伤后应激障碍治疗策略， AUD和慢性疼痛是次优的。拟议工作的目标是：1）测试创伤压力对 中央杏仁核（CeA）中分子鉴定的神经元的活动，这些神经元投射到奖励/厌恶和疼痛 中心和2）测试特定的CeA投射细胞在介导酒精奖励/厌恶的应激效应中的作用 以及感觉伤害感受和疼痛回避。 我们将使用已建立的创伤应激动物模型，其中大鼠暴露于捕食者气味（即， 山猫尿），然后索引以避免气味配对的上下文;该模型基于以下事实： 回避是人类创伤后应激障碍的标志性症状类似于人类的创伤性压力 我们发表的数据显示，在酒精中毒后，避免者表现出饮酒和痛觉过敏的升级。 应力我们将使用这个模型来测试介导创伤应激反应的电路和分子机制， 行为特异性目的1测试创伤应激激活LH投射CeA CRFR 1+细胞的预测 并抑制饮酒的雄性和雌性CRFR 1：cre大鼠中投射vlPAG的CeA CRFR 1+细胞。具体 目的2测试了抑制LH投射的CeA CRFR 1+细胞将逆转应激诱导的增加的预测 在雄性和雌性CRFR 1：cre大鼠中，酒精自我给药和酒精厌恶减少。具体 目的3测试vlPAG投射的CeA CRFR 1+细胞的活化将逆转应激诱导的CRFR 1+细胞的活化的预测。 雄性和雌性CRFR 1：cre大鼠的痛觉过敏和疼痛回避增加。我们会用脑切片 电生理学、解剖追踪、逆行神经标记和分子生物学技术， 结合基于电路和药理学的方法来测试应激对CRFR 1：cre行为的影响， 我们实验室培育的老鼠

Traumatic stress disorders affect millions of Americans and cost the U.S. billions of dollars annually. Alcohol use disorder (AUD) affects ~12% of the world population, contributing to >2.5 million deaths per year in the U.S. and costing the U.S. $220 billion annually. Post-traumatic stress disorder (PTSD) triples the risk for developing AUD. PTSD and AUD increase mortality in humans by increasing the incidence of chronic disease. PTSD diagnoses are also associated with higher incidence of chronic pain in humans. Current treatment strategies for PTSD, AUD and chronic pain are sub-optimal. The goal of the proposed work is to 1) test traumatic stress effects on the activity of molecularly identified neurons in central amygdala (CeA) that project to reward/aversion and pain centers and 2) test the role of specific CeA projection cells in mediating stress effects on alcohol reward/aversion and sensory nociception & pain avoidance. We will use an established animal model of traumatic stress in which rats are exposed to predator odor (i.e., bobcat urine), then indexed for avoidance of the odor-paired context; this model is predicated on the fact that avoidance is a hallmark symptom of PTSD in humans. Similar to what is seen in humans with traumatic stress disorders, our published data show that Avoiders exhibit escalation of alcohol drinking and hyperalgesia after stress. We will use this model to test circuit and molecular mechanisms mediating traumatic stress effects on behavior. Specific Aim 1 tests the prediction that traumatic stress activates LH-projecting CeA CRFR1+ cells and inhibits vlPAG-projecting CeA CRFR1+ cells in alcohol-drinking male and female CRFR1:cre rats. Specific Aim 2 tests the prediction that inhibition of LH-projecting CeA CRFR1+ cells will reverse stress-induced increases in alcohol self-administration and reductions in alcohol aversion in male and female CRFR1:cre rats. Specific Aim 3 tests the prediction that activation of vlPAG-projecting CeA CRFR1+ cells will reverse stress-induced hyperalgesia and increases in pain avoidance in male and female CRFR1:cre rats. We will use brain slice electrophysiology, anatomical tract-tracing, retrograde neural labeling and molecular biology techniques, combined with circuit-based and pharmacological approaches to test stress effects on behavior in CRFR1:cre rats developed by our lab.