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

项目摘要 成瘾研究强调已经成瘾的人群，而不是最初接触MA的影响。是 很可能，对厌恶药物作用的高初始敏感性导致药物回避，并降低了 成瘾中缝背核5-羟色胺投射的多巴胺能外侧缰核（LHb）传入的激活 （5-HT）和GABA中间神经元参与了由几种刺激引起的厌恶感的感知，但 从未被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 选择性饲养高（MAHDR）和低（MALDR）风险的自愿甲基苯丙胺（MA）摄入， 统称为MA饮用（MADR）线。选择反应和对厌恶的不同敏感性 MA的作用（MALDR>MAHDR）具有高度可重复性。对MA诱导的厌恶反应敏感性低 对应于MAHDR线中的高自愿MA摄入量，而相反的关系被发现， MALDR线我的初步数据证实，急性MA给药诱导LHb中cFos表达， MALDR小鼠，而不是MAHDR小鼠。这表明MA激活MALDR小鼠的LHb，这可能 这可能与他们对MA引起的厌恶的高度敏感性有关。我建议改变LHb介导的 直接兴奋性和间接抑制性输入到DR 5-HT神经元是负责的差异， 对MADR系中MA诱导的厌恶的敏感性。我的建议将检查直接LHb突触到DR 5-HT和GABA神经元使用全细胞膜片钳电生理学和光遗传学，以及 确定使用病毒表达的DREADD抑制LHb-DR回路是否阻断MA的获取。 在MALDR小鼠中诱导位置厌恶。总的来说，这些研究将加强我们对 谷氨酸从LHb向DR 5-HT和GABA神经元的传递及回路操作的影响 对MA厌恶的敏感性。该项目将补充一个全面和结构化的培训计划， 是和我的共同赞助人理查兹博士和英格拉姆博士一起开发的除了在体外进行高级培训外， 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大 我在编程、实验设计、数据传播和科学写作方面的技能。我将获得一个深刻的 了解成瘾和药物引起的厌恶可能的保护作用。另外，我有 我已经开始并将继续参与提高我作为导师能力的活动。全体确能 建议的培训将为我提供进一步发展职业生涯所需的工具和技能， 成瘾领域的学术研究者

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.