The Role of Amygdala Outputs in Stress-Induced Escalation of Alcohol Drinking

项目总结 酒精使用障碍(AUD)是影响数百万美国人的一个主要公共健康问题。创伤性的 应激障碍与AUD高度并存，并可促进AUD的发展。在中国的老鼠研究 我们的实验室表明，创伤性(捕食者气味)应激会产生应激诱导的条件性位置回避。 在一组被称为回避者的应激大鼠中，酒精饮用量增加，概括了这个个体 人类在应激反应方面的差异。捕食气味应激诱导的神经适应的比较 在Avoider和非Avoider大鼠中已发现促肾上腺皮质激素释放因子(CRF)通过CRF-1信号转导 中央杏仁核(CEA)中的受体(CRFR1)代表捕食者气味应激的一种机制 改变行为。然而，目前尚不清楚应激是否诱导CEA中CRF-CRFR1信号的可塑性 介导应激诱导的饮酒增加，目前也不清楚CRFR1是否改变 CEA中的信号通过门控特定CEA输出的活动来调节应激后的行为。在此，我建议 测试1)CEA CRF-CRFR1信号，2)CEA投射到下丘脑外侧(LH)，以及3)CEA的作用 CRFR1+向黄体生成素的投射，在应激诱导的饮酒和奖励增加中。我们的 最重要的假说是CEA、、LHCRFR+神经元介导创伤性应激诱导的脑内神经递增。 酗酒和奖励。我将使用免疫组织化学、化学遗传学和解剖学的组合 检验这一假说的技术。在特定的目标1中，我将测试这样的假设，即Avoider大鼠将表现出更大的 捕食气味应激后大鼠CEA、、LHCRFR1+神经元的激活程度明显高于非回避组和对照组。具体而言 目的2，我将验证以下假设：1)抑制CEA、、LHCRFR+神经元将减弱应激诱导的 酒精饮酒和酒精奖赏的递增，以及2)刺激CEA--L-CRFR-1神经元 会增加压力幼稚大鼠的饮酒和酒精奖励。我会用新设计的男性和 雌性CRFR1：CRE大鼠，用于所有实验。这项拟议的工作将提供有关大脑回路的信息 治疗共病的AUD和创伤性应激障碍的介体和潜在的药物靶点。在……里面 此外，该项目将为一位有前途的年轻酒精神经学家提供重要培训。

PROJECT SUMMARY Alcohol use disorder (AUD) is a major public health problem that affects millions of Americans. Traumatic stress disorders are highly co-morbid with AUD and can contribute to the development of AUD. Rat studies in our lab have shown that traumatic (predator odor) stress produces stress-induced conditioned place avoidance and escalated alcohol drinking in a subset of stressed rats, termed Avoiders, recapitulating the individual differences in stress reactivity seen in humans. Comparisons of predator odor stress-induced neuroadaptations in Avoider and Non-Avoider rats have revealed that corticotropin-releasing factor (CRF) signaling via CRF-1 receptors (CRFR1) in the central amygdala (CeA) represents one mechanism by which predator odor stress alters behavior. However, it is not known whether stress-induced plasticity in CRF-CRFR1 signaling in CeA mediates stress-induced escalation of alcohol drinking in Avoider rats, nor is it known whether altered CRFR1 signaling in CeA mediates post-stress behavior by gating the activity of specific CeA outputs. Here, I propose to test the role of 1) CeA CRF-CRFR1 signaling, 2) CeA projections to lateral hypothalamus (LH), and 3) CeA CRFR1+ projections to LH, in stress-induced escalation of alcohol drinking and reward in Avoider rats. Our overarching hypothesis is that CeALH CRFR1+ neurons mediate traumatic stress-induced escalation of alcohol drinking and reward. I will use a combination of immunohistochemistry, chemogenetics, and anatomical techniques to test this hypothesis. In Specific Aim 1, I will test the hypothesis that Avoider rats will show greater activation of CeALH CRFR1+ neurons than Non-Avoider and Control rats after predator odor stress. In Specific Aim 2, I will test the hypotheses that 1) inhibition of CeALH CRFR1+ neurons will attenuate stress-induced escalation of alcohol drinking and alcohol reward in Avoider rats, and 2) stimulation of CeALH CRFR1 neurons will increase alcohol drinking and alcohol reward in stress-naïve rats. I will use the newly-engineered male and female CRFR1:Cre rats for all experiments. The proposed work will provide information regarding brain circuit mediators and potential drug targets for the treatment of co-morbid AUD and traumatic stress disorders. In addition, this project will provide important training to a promising young alcohol neuroscientist.