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 饮酒障碍（AUD）是影响数百万美国人的主要公共卫生问题。创伤性 应力障碍与AUD高度合并，可以为AUD的发展做出贡献。大鼠研究 我们的实验室表明，创伤性（捕食者气味）应力会产生应力引起的条件避免 并在压力大鼠的一部分中升级酒精，称为避开者，概括了个人 人类看到的压力反应性差异。比较捕食者气味应激诱导的神经适应 在Avoider和非avaider大鼠中，大鼠透露了crf-1的释放皮质激素释放因子（CRF）信号 中央杏仁核（CEA）中的受体（CRFR1）代表一种机制 改变行为。但是，尚不清楚CRF-CRFR1信号中的应力诱导的可塑性是否在CEA中 介导压力引起的Avoider大鼠饮酒的升级，也不知道CRFR1是否改变 CEA中的信号传导通过门控特定CEA输出的活性来介导后压力行为。在这里，我建议 测试1）CEA CRF-CRFR1信号的作用，2）CEA投影对下丘脑（LH）和3）CEA CRFR1+向LH投影，在压力引起的饮酒和奖励升级的情况下。我们的 总体假设是CEALHCRFR1+神经元介导了创伤性应力诱导的升级 饮酒和奖励。我将使用免疫组织化学，化学遗传学和解剖学的组合 检验该假设的技术。在特定目标1中，我将测试Avoider大鼠将显示更大的假设 与非ave子相比，CEALHCRFR1+神经元的激活和捕食者气味应力后的控制大鼠的激活。具体 AIM 2，我将测试以下假设：1）抑制CEALHCRFR1+神经元将减轻压力诱导的 在Avoider大鼠中升级饮酒和酒精奖励，以及2）刺激CEALHCRFR1神经元 在没有压力的大鼠中会增加饮酒和酒精奖励。我将使用新设计的男性和 女性CRFR1：用于所有实验的CRE大鼠。拟议的工作将提供有关大脑电路的信息 介质和潜在的药物靶标，用于治疗合并的AUD和创伤应激障碍。在 此外，该项目将为承诺年轻的酒精神经科学家提供重要的培训。