Role of RMTg afferents in mechanisms of withdrawal from chronic ethanol exposure

RMTg 传入神经在慢性乙醇暴露戒断机制中的作用

• 批准号: 10717194
• 负责人: Elizabeth J Glover
• 金额: $ 44.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717194
• 关键词: Acute; Affect; Alcohol consumption; Alcohols; Attenuated; Behavioral; Brain; Brain region; Cell Nucleus; Chronic; Consumption; Data; Decision Making; Development; Electrophysiology (science); Ethanol; Exhibits; Genetic; Glutamates; Habenula; Health; Hour; Human; Hyperactivity; Hyperalgesia; Impaired cognition; Impulsivity; Individual; Lateral; Link; Literature; Measures; Mechanics; Mediating; Methodology; Midbrain structure; Neurobiology; Neurons; Pain; Physiological; Physiology; Play; Public Health; Rattus; Regulation; Relapse; Role; Signal Transduction; Slice; Symptoms; Testing; Time; Viral; Withdrawal; Withdrawal Symptom; Work; acute symptom; alcohol abstinence; alcohol abuse therapy; alcohol exposure; alcohol use disorder; anxiety-like behavior; behavior test; cholinergic; design; drug development; emotional symptom; experimental study; flexibility; genetic approach; in vivo; innovation; insight; negative affect; neural; neural circuit; neuroadaptation; neurobiological mechanism; neurotransmission; optogenetics; pain sensitivity; pharmacologic; physical symptom; preclinical study; relapse prevention; sobriety; symptom treatment; therapeutic target; withdrawal-induced anxiety

PROJECT SUMMARY A significant number of individuals struggle to maintain sobriety as a result of withdrawal symptoms that emerge during early abstinence from alcohol. Despite this, pharmacotherapeutics for the treatment of withdrawal are lacking, at least in part, due to poor understanding of the mechanisms underlying symptoms of withdrawal. The rostromedial tegmental nucleus (RMTg) is a GABAergic region that exerts inhibitory control over midbrain bioaminergic and cholinergic nuclei. Recently, work from our lab revealed significantly enhanced cFos expression, a marker of recent neuronal activity, in the RMTg of chronic intermittent ethanol (CIE) exposed rats 12 hours into acute withdrawal. In addition, we showed that pharmacological inhibition of the RMTg attenuates withdrawal-induced anxiety-like behavior. However, the precise neural circuits that drive this putative RMTg hyperactivity is unknown. The lateral habenula (LHb) provides dense glutamatergic input to the RMTg and exhibits significant functional overlap with the RMTg. In addition, our preliminary data reveals a significant increase in cFos expression in RMTg-projecting lateral habenula (LHb) neurons during acute withdrawal. Together, these data lead us to hypothesize that LHb inputs to the RMTg play a mechanistic role in regulating symptoms of withdrawal from chronic ethanol exposure. Experiments in the current proposal are designed to test this hypothesis by using in vivo chemogenetics to bidirectionally and selectively manipulate LHb-RMTg activity during behavioral tests of withdrawal symptoms including anxiety-like behavior, mechanical pain sensitivity, and impulsive choice. Additional work will use ex vivo slice electrophysiology to explore the physiological neuroadaptations that occur in this circuitry during withdrawal from chronic ethanol exposure. Findings from these experiments will shed new light onto the role of this neural circuit in regulating symptoms of withdrawal and by extension have the potential to uncover new neurobiological targets for the treatment of alcohol use disorder.

项目摘要 由于出现戒断症状，相当多的人难以保持清醒 在早期戒酒期间。尽管如此，用于治疗戒断的药物治疗仍然存在。 缺乏，至少部分原因是对戒断症状的机制缺乏了解。的 头内侧被盖核（RMTg）是GABA能区，对中脑施加抑制性控制 生物胺能和胆碱能核。最近，我们实验室的工作显示， 慢性间歇性乙醇（CIE）暴露大鼠的RMTg中最近神经元活动的标志物 急性戒断12小时后。此外，我们发现RMTg的药理学抑制减弱了 戒断引起的焦虑样行为然而，驱动这种假定的RMTg的精确神经回路 多动症是未知的。外侧缰核（LHb）向RMTg提供密集的突触能输入， 显示出与RMTg显著的功能重叠。此外，我们的初步数据显示， 在急性戒断过程中，RMTg投射外侧缰核（LHb）神经元中cFos表达增加。 总之，这些数据使我们假设，LHb输入RMTg在调节中发挥机械作用。 慢性酒精暴露后的戒断症状本提案中的实验旨在 通过使用体内化学遗传学双向和选择性地操纵LHb-RMTg来检验这一假设 戒断症状行为测试期间的活动，包括焦虑样行为、机械性疼痛 敏感和冲动的选择额外的工作将使用离体切片电生理学来探索 生理神经适应发生在这个电路在退出慢性乙醇暴露。 这些实验的发现将为这种神经回路在调节脑缺血症状中的作用提供新的线索。 撤药和延伸有可能发现新的神经生物学靶点，用于治疗 酒精使用障碍