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.

项目摘要 成瘾研究强调已经上瘾的人群，而不是最初的MA暴露的影响。这是 对厌恶药物影响的高初始敏感性很可能导致避免药物，并降低 瘾。谷氨酸能侧Habenula（LHB）的激活投射到背侧Raphe（DR）5-羟色胺 （5-HT）和GABA中间神经元与几种刺激引起的厌恶感有关，但 从未检查过它们在药物引起的厌恶中的作用。该建议利用老鼠 有选择地繁殖高（MAHDR）和低（MALDR）的自愿甲基苯丙胺（MA）摄入风险， 统称为MA饮酒（MADR）线条。选择响应和对厌恶的敏感性的差异 MA（MALDR> MAHDR）的效果非常可重现。对MA诱导的厌恶的敏感性低 与Mahdr线中的高自愿MA摄入相对应，而相反的关系则在 Maldr线。我的初步数据证实，急性MA给药在LHB中诱导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 与它们对MA诱导的厌恶的高灵敏度有关。我提出了LHB介导的影响的转变 直接兴奋性和间接抑制输入到DR 5-HT神经元上 对MADR线中的MA引起的厌恶的敏感性。我的建议将检查DR的直接LHB突触 5-HT和GABA神经元使用全细胞贴片钳电生理学和光遗传学，以及 确定使用病毒表达的Dreadds抑制LHB-DR电路是否阻止了MA-的获取 在Maldr小鼠中诱导的位置厌恶。总的来说，这些研究将增强我们对 谷氨酸从LHB传播到DR 5-HT和GABA神经元以及电路操纵的影响 关于对MA厌恶的敏感性。该项目将补充我的全面，结构化的培训计划 与我的共同赞助商Drs一起开发。理查兹和英格拉姆。除了前体内的高级培训 电生理学，化学遗传学，光遗传学和行为遗传学，我将进一步巩固并扩展 我在编程，实验设计，数据传播和科学写作方面的技能。我会深入 了解成瘾和药物引起的厌恶的可能保护作用。另外，我还有 开始并将继续从事改善我作为导师能力的活动。总体而言 拟议的培训将为我提供所需的工具和技能，以进一步发展我的职业生涯 成瘾领域的学术研究员。