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

项目总结 由于出现戒断症状，相当多的人努力保持清醒。 在早期戒酒期间。尽管如此，治疗戒断的药物疗法有 缺乏，至少部分是由于对戒断症状的潜在机制缺乏了解。这个 被盖旋转内侧核(RMTg)是对中脑施加抑制性控制的GABA能区 生物胺能核和胆碱能核。最近，我们实验室的工作显示，CFO显著增强 慢性间歇乙醇(CIE)暴露大鼠RMTg中神经元近期活性标志的表达 急性戒断12小时。此外，我们还表明，RMTg的药理抑制作用减弱 戒断引起的焦虑样行为。然而，驱动这种假定的RMTG的精确神经电路 多动症是未知的。外侧缰核(LHb)提供密集的谷氨酸能输入到RMTG和 与RMTG在功能上有显著重叠。此外，我们的初步数据显示， 急性戒断时RMTg投射外侧缰核(LHb)神经元CFos表达增加。 综上所述，这些数据使我们假设RMTG的LHb输入在调节过程中起着机械性的作用 长期接触酒精后的戒断症状。当前提案中的实验旨在 通过使用体内化学遗传学双向和选择性地操作LHb-RMTg来检验这一假设 戒断症状的行为测试中的活动，包括焦虑样行为、机械性疼痛 敏感和冲动的选择。其他工作将使用体外切片电生理学来探索 在慢性酒精暴露的戒断过程中，在这个回路中发生的生理性神经适应。 这些实验的发现将为这一神经回路在调节高血压症状中的作用提供新的线索。 停药，进而有可能发现新的神经生物学靶点，用于治疗 酒精使用障碍。

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.