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

杏仁核输出在压力引起的饮酒增加中的作用

• 批准号: 10264773
• 负责人: Marcus Matthias Weera
• 金额: $ 3.37万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2021-02-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264773
• 关键词: Affect; Alcohol consumption; Alcohols; American; Amygdaloid structure; Anatomy; Attenuated; Behavior; Biological; Brain; CRF receptor type 1; Cells; Cessation of life; Corticotropin-Releasing Hormone; Development; Disease; Engineering; Exposure to; Female; Funding; General Population; Goals; Human; Hypothalamic structure; Immunohistochemistry; Incidence; Individual; Individual Differences; Lateral; Mediating; Mediator of activation protein; Modeling; Neurobiology; Neurons; Odors; Outcome; Output; Pharmaceutical Preparations; Positioning Attribute; Post-Traumatic Stress Disorders; Prevalence; Prevention strategy; Public Health; Rattus; Receptor Signaling; Research Personnel; Rewards; Role; Signal Transduction; Stimulus; Stress; Techniques; Testing; Training; Trauma; Traumatic Stress Disorders; Work; alcohol reward; alcohol use disorder; combat; comorbidity; conditioned place preference; cost; design; economic cost; epidemiology study; experimental study; exposed human population; indexing; innovation; male; meetings; motivated behavior; nerve supply; neuroadaptation; receptor; skill acquisition; stress reactivity; symptom cluster; targeted treatment; therapeutic target; traumatic stress; treatment strategy

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.

项目摘要 酒精使用障碍（AUD）是影响数百万美国人的主要公共卫生问题。创伤性 应激障碍与AUD高度共病，并可促进AUD的发展。大鼠研究， 我们的实验室已经证明，创伤性（捕食者气味）压力会产生压力诱导的条件性地点回避 在一个被称为“回避者”的应激大鼠亚组中， 人类的压力反应存在差异。捕食者气味应激诱导的神经适应的比较 在回避者和非回避者大鼠中的研究表明，通过CRF-1的促肾上腺皮质激素释放因子（CRF）信号传导 中央杏仁核（CeA）中的CRFR 1受体代表了捕食者气味应激的一种机制， 改变行为然而，尚不清楚CeA中CRF-CRFR 1信号传导中的应激诱导的可塑性是否 在Avoider大鼠中介导应激诱导的饮酒升级，也不知道改变CRFR 1 CeA中的信号传导通过门控特定CeA输出的活性来介导应激后行为。在此，我提议 测试1）CeA CRF-CRFR 1信号传导，2）CeA投射到外侧下丘脑（LH），和3）CeA CRFR 1+投射到LH，在避免大鼠中饮酒和奖励的应激诱导升级中。我们 最重要的假设是CeA β LH CRFR 1+神经元介导创伤应激诱导的 饮酒和奖励。我将结合免疫组织化学化学遗传学和解剖学 技术来检验这个假设。在具体目标1中，我将测试回避大鼠将表现出更大的 在捕食者气味应激后，与非回避者和对照大鼠相比，CeA β LH CRFR 1+神经元的激活。在特定 目的2，我将检验以下假设：1）抑制CeA β LH CRFR 1+神经元将减弱应激诱导的 在Avoider大鼠中增加饮酒和酒精奖励，以及2）刺激CeA β LH CRFR 1神经元 会增加未经历压力的大鼠的饮酒量和酒精奖励。我会用新设计的雄性 雌性CRFR 1：Cre大鼠用于所有实验。拟议的工作将提供有关脑回路的信息 介质和潜在的药物靶点，用于治疗合并的AUD和创伤性应激障碍。在 此外，该项目将为一位有前途的年轻酒精神经科学家提供重要培训。