Lateral Hypothalamus Circuits in Stress-Induced Blunting of Alcohol Aversion& Escalation of Alcohol Self-Administration

下丘脑外侧回路在压力引起的酒精厌恶减弱中的作用

• 批准号: 10676196
• 负责人: Marcus Matthias Weera
• 金额: $ 12.9万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676196
• 关键词: Acute; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Applications Grants; Area; Award; Bobcat; Brain; Cessation of life; Computer Analysis; Data; Development; Dose; Exhibits; Exposure to; Faculty; Fiber; Foundations; Funding; Future; Genetic; Glutamates; Goals; Habenula; Heavy Drinking; Human; Hypothalamic structure; Immunohistochemistry; Individual; Individual Differences; Institution; Investigation; Lateral; Maintenance; Measures; Mediating; Mediator; Mentors; Neurobiology; Neurons; Neurosciences; Odors; Phase; Photometry; Positioning Attribute; Prevention; Principal Investigator; Procedures; Psyche structure; Public Health; Publishing; Rattus; Research; Rewards; Role; Secure; Self Administration; Signal Transduction; Stimulus; Stress; Stress and Coping; Stressful Event; Techniques; Testing; Training; Training Support; Urine; Work; alcohol abuse therapy; alcohol effect; alcohol misuse; alcohol sensitivity; alcohol use disorder; behavior test; career; career development; coping; data submission; economic cost; experimental study; genetic testing; improved; in vivo; indexing; neural circuit; neuromechanism; new therapeutic target; novel; paired stimuli; programs; research and development; response; skill acquisition; stress reactivity; tenure track; traumatic stress

Project Summary Traumatic stress can lead to alcohol misuse and alcohol use disorder (AUD). In particular, avoidance coping after stress (i.e., persistent mental and/or physical avoidance of stress-related stimuli) is associated with higher rates of alcohol misuse. Using an animal model, we have shown that exposure to predator odor stress produces persistent avoidance of predator odor-paired stimuli in a subset of rats, termed ‘Avoiders’. Importantly, Avoider rats show long-lasting increases in alcohol self-administration after stress, similar to findings in humans. The neurobiology underlying this phenomenon remains an open area of investigation. This K99/R00 award includes a comprehensive career development and research plan based on Dr. Marcus Weera’s preliminary data showing that Avoider rats exhibit increased tolerance to the aversive effects of alcohol, which is hypothesized to facilitate increased alcohol self-administration in these rats. Our preliminary data also show that Avoider rats exhibit blunted activation of lateral habenula (LHb)-projecting lateral hypothalamus (LHA) neurons by aversive doses of alcohol. The scientific goal of this K99/R00 award is to test the central hypothesis that LHA-LHb neurons mediate stress-induced tolerance to alcohol aversion and stress-induced escalation of alcohol self-administration in Avoider rats via three aims. In Aim 1, we predict that Avoider rats show blunted activation of LHA-LHb and LHb neurons in response to an aversive dose of alcohol, as measured by Fos immunohistochemistry and in vivo fiber photometry. In Aim 2, we predict that in vivo chemogenetic stimulation of LHA-LHb neurons rescues stress- induced blunting of LHb activity and stress-induced tolerance to alcohol aversion in Avoider rats, as measured by in vivo fiber photometry and alcohol conditioned place aversion, respectively. In Aim 3, we predict that in vivo chemogenetic stimulation of LHA-LHb neurons rescues stress-induced blunting of LHb activity and stress- induced escalation of alcohol responding in Avoider rats, as measured by in vivo fiber photometry and operant alcohol self-administration, respectively. Results from these studies will improve our understanding of the neural circuits underlying stress-induced changes in sensitivity to alcohol’s aversive effects and in alcohol self- administration. The career development goal of this K99/R00 award is to provide the principal investigator, Dr. Marcus Weera, with additional technical training and professional development, and to help him establish an independently-funded research program. During the K99 portion of the award, under the guidance of an expert team of mentors, Dr. Weera will expand his technical and analytical repertoire to include in vivo fiber photometry and computational analysis of photometry data. He will also search for and secure a tenure-track faculty position. During the R00 portion of the award at his new institution, Dr. Weera will use his acquired skills to build upon these studies, gathering rigorous data for submission of an R01 application. The work and training supported by this award will be critical for the PI’s successful transition to an independent research career studying the neurobiology underlying individual differences in stress and alcohol responsiveness.

项目摘要 创伤性压力会导致滥用酒精和饮酒障碍（AUD）。特别是避免应对 压力之后（即，与压力相关的刺激的持续性心理和/或身体避免）与较高的 滥用酒精的速度。使用动物模型，我们表明暴露于捕食者气味应力会产生 持续避免在一部分大鼠中避免捕食气味的刺激，称为“避开者”。重要的是，Avoider 大鼠在压力后表现出持久的饮酒自我给药的增加，类似于人类的发现。这 这种现象基础的神经生物学仍然是开放的投资领域。该K99/R00奖项包括 基于Marcus Weera博士的初步数据的全面职业发展和研究计划 避免大鼠对酒精的厌恶作用表现出更高的耐受性，这是可以促进的 在这些大鼠中增加了酒精自给自足。我们的初步数据还表明Avoider大鼠展出 侧面Habenula（LHB）的激活通过厌恶剂量的侧面下丘脑（LHA）神经元的激活 酒精。该K99/R00奖的科学目标是测试LHA-LHB神经元介导的中心假设 压力引起的对酒精厌恶的耐受性和应力引起的酒精自我给药的升级 Avoider大鼠通过三个目标。在AIM 1中，我们预测Avoider大鼠显示LHA-LHB和LHB的激活钝化 通过FOS免疫组织化学和体内纤维测量，神经元响应厌食剂量的酒精剂量 光度法。在AIM 2中，我们预测LHA-LHB神经元反应应激的体内化学发生模拟 如测量的 分别通过体内纤维光度法和条件性位置厌恶。在AIM 3中，我们预测体内 LHA-LHB神经元的化学发生模拟反应应力引起的LHB活性和应激的钝化 通过体内纤维光度法和操作员测量的Avoider大鼠的酒精响应升级 酒精自我管理。这些研究的结果将改善我们对神经的理解 应力引起的电路对酒精厌恶作用和酒精自我自我的敏感性变化 行政。该K99/R00奖的职业发展目标是为主要研究员提供博士提供。 马库斯·韦拉（Marcus Weera），还有其他技术培训和专业发展，并帮助他建立 独立资助的研究计划。在奖励的K99部分期间，在专家的指导下 导师团队，Weera博士将扩大他的技术和分析曲目，包括体内纤维光度法 和光度数据的计算分析。他还将搜索并确保担任终身教师职位。 在他的新机构的奖项的R00部分期间，Weera博士将利用他获得的技能来建立 这些研究，收集严格的数据以提交R01应用程序。支持的工作和培训 该奖项对于PI的成功过渡到独立研究职业至关重要 神经生物学在压力和酒精反应性方面的个体差异是基本的。