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.

项目概要 创伤性压力会导致滥用酒精和酒精使用障碍（AUD），特别是回避应对。 压力后（即持续精神和/或身体避免与压力相关的刺激）与更高的 通过动物模型，我们发现暴露于捕食者的气味压力会产生酒精滥用率。 一部分老鼠持续回避捕食者气味配对的刺激，被称为“回避者”，重要的是，回避者。 老鼠在受到压力后表现出长期持续的自我饮酒增加，这与人类的研究结果相似。 这种现象背后的神经生物学仍然是一个开放的研究领域，该 K99/R00 奖项包括在内。 基于 Marcus Weera 博士的初步数据显示的全面职业发展和研究计划 回避型大鼠对酒精的厌恶作用表现出更高的耐受性，这有助于促进 我们的初步数据还表明，回避型大鼠表现出酒精自我摄入量增加。 厌恶剂量的外侧缰核（LHb）投射的外侧下丘脑（LHA）神经元的激活减弱 该 K99/R00 奖项的科学目标是检验 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压力引起的自我饮酒的升级 回避型大鼠的三个目标 在目标 1 中，我们预测回避型大鼠的 LHA-LHb 和 LHb 激活减弱。 通过 Fos 免疫组织化学和体内纤维测量神经元对厌恶剂量酒精的反应 在目标 2 中，我们预测 LHA-LHb 神经元的体内化学遗传学刺激可以缓解压力。 诱导的 LHb 活性减弱和应激诱导的回避大鼠对酒精厌恶的耐受性（测量结果） 分别通过体内纤维光度测定和酒精条件位置厌恶，在目标 3 中，我们预测体内。 LHA-LHb 神经元的化学遗传学刺激可挽救应激诱导的 LHb 活性减弱和应激- 通过体内纤维光度法和操作法测量，诱导回避大鼠的酒精反应升级 这些研究的结果将分别提高我们对神经的理解。 压力引起的对酒精厌恶效应的敏感性和酒精自我调节变化的潜在电路 该 K99/R00 奖项的职业发展目标是为首席研究员 Dr. Marcus Weera 接受了额外的技术培训和专业发展，并帮助他建立了 在K99部分的奖励期间，在专家的指导下独立资助的研究项目。 Weera 博士的导师团队将扩展他的技术和分析能力，包括体内光纤光度测定 他还将寻找并获得终身教授职位。 在他的新机构获得 R00 奖项期间，Weera 博士将利用他获得的技能 这些研究为提交 R01 申请收集了严格的数据，并得到了支持的工作和培训。 该奖项对于 PI 成功过渡到独立研究生涯至关重要 神经生物学揭示了压力和酒精反应的个体差异。