Role of Lateral Habenula- Dorsal Raphe Circuit on MA-Induced Aversion

外侧缰核-中缝背侧回路对 MA 诱发厌恶的作用

• 批准号: 10601869
• 负责人: Samantha Rios
• 金额: $ 4.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2025-02-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601869
• 关键词: 18 year old; Acute; Adult; Animal Model; Antibodies; Aversive Stimulus; Behavior; Behavioral Genetics; Bilateral; Breeding; Cells; Cementation; Complement; Data; Development; Dorsal; Electrophysiology (science); Exhibits; Experimental Designs; Genetic; Genetic Models; Glutamates; Goals; Habenula; Health; Intake; Interneurons; Intervention; Lateral; Learning; Maps; Measures; Mediating; Mentors; Methamphetamine; Methamphetamine use disorder; Mus; Neurons; Optics; Oregon; Other Genetics; Perception; Pharmaceutical Preparations; Play; Population; Preparation; Probability; Reporting; Reproducibility; Research; Research Personnel; Resources; Rewards; Risk; Risk Reduction; Role; Science; Scientist; Serotonin; Signal Transduction; Slice; Stimulus; Structure; Synapses; System; Testing; Tracer; Training; Universities; Viral; Writing; addiction; attenuation; behavior test; career; conditioning; data dissemination; design; designer receptors exclusively activated by designer drugs; drinking; experience; extracellular; gamma-Aminobutyric Acid; improved; insight; methamphetamine effect; methamphetamine exposure; methamphetamine use; new therapeutic target; optogenetics; patch clamp; recruit; regional difference; response; skills; tool; transmission process

Project Summary Addiction research emphasizes already addicted populations and not the effects of initial MA exposure. It is likely that high initial sensitivity to aversive drug effects results in drug avoidance and reduces the probability of addiction. Activation of glutamatergic lateral habenula (LHb) afferents projecting to dorsal raphe (DR) serotonin (5-HT) and GABA interneurons are implicated in the perception of aversion induced by several stimuli, but have never been examined for their role in drug-induced aversion. This proposal takes advantage of mice selectively bred for high (MAHDR) and low (MALDR) risk for voluntary methamphetamine (MA) intake, collectively known as the MA drinking (MADR) lines. Selection response and differential sensitivity to aversive effects of MA (MALDR>MAHDR) have been highly reproducible. Low sensitivity to MA-induced aversion corresponds with high voluntary MA intake in the MAHDR line, whereas the opposite relationship is found in the MALDR line. My preliminary data confirm that acute MA administration induces cFos expression in the LHb of MALDR mice, but not MAHDR mice. This suggests that MA activates the LHb in MALDR mice, which may be related to their high sensitivity to MA-induced aversion. I propose a shift in the influence of LHb-mediated direct excitatory and indirect inhibitory inputs onto DR 5-HT neurons is responsible for the difference in sensitivity to MA-induced aversion in the MADR lines. My proposal will examine direct LHb synapses onto DR 5-HT and GABA neurons using whole-cell patch-clamp electrophysiology and optogenetics, as well as determine whether inhibition of the LHb-DR circuit using virally-expressed DREADDs blocks acquisition of MA- induced place aversion in MALDR mice. Collectively, these studies will enhance our understanding of glutamate transmission from the LHb onto DR 5-HT and GABA neurons and the effects of circuit manipulation on sensitivity to MA aversion. This project will complement a comprehensive and structured training plan that I have developed with my co-sponsors Drs. Richards and Ingram. In addition to advanced training in ex-vivo electrophysiology, chemogenetics, optogenetics, and behavioral genetics, I will further cement and expand on my skills in programming, experimental design, data dissemination and scientific writing. I will gain a deep understanding of addiction and the possible protective role of drug-induced aversion. Additionally, I have begun and will continue to engage in activities that are improving my abilities as a mentor. As a whole, the proposed training will provide me the tools and skillset needed to further the development of my career as an academic researcher in the addiction field.

项目概要 成瘾研究强调已经成瘾的人群，而不是最初接触 MA 的影响。这是 最初对令人厌恶的药物作用的高度敏感性可能会导致药物回避并降低药物的可能性 瘾。激活投射到中缝背侧 (DR) 血清素的谷氨酸能外侧缰核 (LHb) 传入神经 (5-HT) 和 GABA 中间神经元与多种刺激引起的厌恶感有关，但是 从未研究过它们在药物引起的厌恶中的作用。这个提议利用了老鼠的优势 针对自愿摄入甲基苯丙胺 (MA) 的高风险 (MAHDR) 和低风险 (MALDR) 进行选择性培育， 统称为 MA 饮用线 (MADR)。选择反应和对厌恶的不同敏感性 MA (MALDR>MAHDR) 的效果具有高度可重复性。对 MA 引起的厌恶的敏感性较低 与 MAHDR 线中的高自愿 MA 摄入量相对应，而相反的关系见于 MALDR 线。我的初步数据证实，急性 MA 给药会诱导 LHb 中的 cFos 表达 MALDR 小鼠，但不是 MAHDR 小鼠。这表明 MA 激活 MALDR 小鼠的 LHb，这可能 与他们对 MA 引起的厌恶高度敏感有关。我建议改变 LHb 介导的影响 DR 5-HT 神经元的直接兴奋性和间接抑制性输入是造成差异的原因 MADR 线中对 MA 引起的厌恶的敏感性。我的建议将检查 DR 上的直接 LHb 突触 使用全细胞膜片钳电生理学和光遗传学的 5-HT 和 GABA 神经元，以及 确定使用病毒表达的 DREADD 抑制 LHb-DR 电路是否会阻止 MA-的获得 诱导 MALDR 小鼠的地方厌恶。总的来说，这些研究将增强我们对 谷氨酸从 LHb 传递到 DR 5-HT 和 GABA 神经元以及电路操作的影响 对 MA 厌恶的敏感性。该项目将补充我所制定的全面且结构化的培训计划 与我的共同发起人 Drs 一起开发。理查兹和英格拉姆。除了离体高级训练外 电生理学、化学遗传学、光遗传学和行为遗传学，我将进一步巩固和扩展 我在编程、实验设计、数据传播和科学写作方面的技能。我将获得深刻的 了解成瘾和药物引起的厌恶可能的保护作用。另外，我有 开始并将继续从事提高我作为导师能力的活动。总体而言， 拟议的培训将为我提供进一步发展我的职业生涯所需的工具和技能 成瘾领域的学术研究员。