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 创伤性压力会导致酒精滥用和酒精使用障碍（AUD）。特别是回避应对 压力后（即，持续的精神和/或身体回避压力相关的刺激）与较高的 酒精滥用率。使用动物模型，我们已经表明，暴露于捕食者气味压力产生 在一组大鼠中，持续回避捕食者气味配对刺激，称为“回避者”。重要的是，避免 大鼠在压力后自我饮酒的持续增加，与人类的发现相似。的 这种现象背后的神经生物学仍然是一个开放的研究领域。此K99/R 00奖项包括 一个全面的职业发展和研究计划的基础上博士马库斯Weera的初步数据显示， 回避型大鼠对酒精的厌恶作用表现出更高的耐受性，这被假设为促进了 增加这些大鼠的酒精自我给药。我们的初步数据还显示， 抑制外侧缰核（LHb）投射外侧下丘脑（LHA）神经元的激活 酒精这个K99/R 00奖项的科学目标是测试LHA-LHb神经元介导的中心假设。 压力诱导的对酒精厌恶的耐受性和压力诱导的自我饮酒的升级 通过三个目标避免老鼠。在目的1中，我们预测Avoider大鼠显示LHA-LHb和LHb的钝化激活 通过Fos免疫组织化学和体内纤维测定， 测光在目标2中，我们预测体内LHA-LHb神经元的化学发生刺激可以缓解应激， 在Avoider大鼠中诱导LHb活性的钝化和应激诱导的对酒精厌恶的耐受性， 分别采用在体纤维光度法和酒精条件性位置厌恶法。在目标3中，我们预测在体内 LHA-LHb神经元的化学发生刺激挽救了应激诱导的LHb活性钝化， 在Avoider大鼠中诱导酒精反应的升级，如通过体内纤维光度法和操作性测量的 酒精的自我管理，分别。这些研究的结果将提高我们对神经系统的理解。 压力引起的对酒精厌恶效应的敏感性变化和酒精自我调节的潜在回路， 局这个K99/R 00奖的职业发展目标是提供主要研究者，博士。 Marcus Weera，额外的技术培训和专业发展，并帮助他建立一个 独立资助的研究项目。在K99部分的奖项，在专家的指导下， Weera博士的导师团队将扩展他的技术和分析技能，包括体内纤维光度测定 和光度数据的计算分析。他还将寻找并确保终身教职。 在他的新机构的R 00部分奖励期间，Weera博士将利用他获得的技能， 这些研究，收集严格的数据提交R 01申请。支持的工作和培训 该奖项将是关键的PI的成功过渡到一个独立的研究生涯研究 压力和酒精反应的个体差异的神经生物学。