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.

项目概要 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是 缺乏，至少部分是由于对戒断症状背后的机制了解甚少。这 喙内侧被盖核 (RMTg) 是一个 GABA 能区域，对中脑发挥抑制控制作用 生物胺能和胆碱能细胞核。最近，我们实验室的工作表明 cFos 显着增强 慢性间歇性乙醇 (CIE) 暴露大鼠 RMTg 中的表达是近期神经元活动的标志物 急性戒断12小时。此外，我们还发现 RMTg 的药理抑制作用会减弱 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 多动症未知。外侧缰核 (LHb) 为 RMTg 和 RMTg 提供密集的谷氨酸能输入 与 RMTg 表现出显着的功能重叠。此外，我们的初步数据显示， 急性戒断期间，RMTg 投射的外侧缰核 (LHb) 神经元中的 cFos 表达增加。 总之，这些数据使我们假设 LHb 输入到 RMTg 在调节中发挥机械作用 长期接触乙醇的戒断症状。当前提案中的实验旨在 通过使用体内化学遗传学双向选择性操纵 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、冲动的选择。其他工作将使用离体切片电生理学来探索 在从长期乙醇暴露中戒断期间，该回路中发生的生理神经适应。 这些实验的结果将为该神经回路在调节症状中的作用提供新的线索。 戒断并由此延伸有可能发现新的神经生物学靶点来治疗 酒精使用障碍。