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: 10525080
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525080
• 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; Glutamates; Goals; Habenula; Heavy Drinking; Human; Hypothalamic structure; Immunohistochemistry; Individual; Individual Differences; Institution; Investigation; Lateral; Lead; Maintenance; Measures; Mediating; Mediator of activation protein; 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; base; behavior test; career; career development; coping; data submission; economic cost; experimental study; improved; in vivo; indexing; neural circuit; neuromechanism; new therapeutic target; novel; paired stimuli; programs; research and development; response; skills; 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 创伤应激可导致酒精滥用和酒精使用障碍(AUD)。特别是，回避应对 在压力(即，持续的精神和/或身体上对与压力相关的刺激的回避)与更高的 酒精滥用的比率。使用动物模型，我们已经证明暴露在捕食者气味压力下会产生 持续回避捕食者气味配对刺激的一组大鼠，被称为“回避者”。重要的是，Avoider 与人类的研究结果类似，大鼠在压力后酒精自我管理的能力出现了长期的增长。这个 这种现象背后的神经生物学仍然是一个开放的研究领域。这个K99/R00奖项包括 基于马库斯·维拉博士的初步数据显示的全面职业发展和研究计划 Avoider大鼠对酒精的厌恶作用表现出更强的耐受性，这被认为是为了促进 这些大鼠的酒精自我给药增加。我们的初步数据还显示，Avoider老鼠表现出 厌恶剂量对外侧缰核(LHb)投射下丘脑外侧(LHA)神经元的钝化激活 酒精。这项K99/R00奖的科学目标是检验LHA-LHb神经元在 应激诱导对酒精厌恶的耐受和应激诱导的酒精自我给药的升级 通过三个目标避鼠。在目标1中，我们预测Avoider大鼠表现出LHA-LHb和LHb的钝性激活 用Fos免疫组织化学和体内纤维检测神经元对厌恶剂量酒精的反应 测光学。在目标2中，我们预测体内对LHA-LHb神经元的化学生成刺激可以拯救应激- Avoider大鼠LHb活性的诱导钝化和应激诱导的酒精厌恶耐受性 分别采用体内纤维光度法和酒精条件性位置厌恶法。在目标3中，我们预测在活体内 化学刺激LHa-LHb神经元挽救应激诱导的LHb活性钝化和应激- 用体内纤维光度法和操纵剂测定Avoider大鼠酒精反应的诱导升级 分别为酒精自我给药。这些研究的结果将提高我们对神经的理解。 应激引起的对酒精厌恶效应的敏感性和酒精自身的回路变化 行政管理。这一K99/R00奖项的职业发展目标是为首席研究员Dr。 Marcus Weera，提供额外的技术培训和专业发展，并帮助他建立 独立资助的研究项目。在K99颁奖期间，在一位专家的指导下 导师团队，维拉博士将扩大他的技术和分析能力，包括体内纤维光度测定 测光数据的计算分析。他还将寻找并获得一个终身教职的职位。 在他的新机构的R00颁奖部分，维拉博士将利用他获得的技能在 这些研究为提交R01申请收集了严格的数据。所支持的工作和培训 这一奖项将对国际和平研究所成功过渡到独立研究生涯至关重要 压力和酒精反应的个体差异背后的神经生物学。