Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol

项目总结 长期接触酒精与对酒精的厌恶特性产生耐受性有关，这 用来限制饮酒。相比之下，人们对酒精的有益特性的反应仍然存在，这些特性促进了饮酒 保持不变。由于长期饮酒，大脑经历了一系列神经适应性变化，但 这种耐受性背后的神经机制尚不清楚。编码厌恶的电路中的信号受损 是一种可能的候选机制。被盖旋转内侧核(RMTg)以其受累为特征 在厌恶方面，包括发出乙醇的厌恶特性的信号。前额叶(PL)内侧皮质 (MPFC)与RMTg有重要的功能相似之处，包括促进厌恶学习和 调节对厌恶刺激的行为反应。邻近的mPFC的次边缘(IL)亚区 通过促进厌恶反应的消退，对PL mPFC产生相反的影响。我们的工作揭示了一个 从mPFC到RMTg的密集投射跨越PL和IL亚区。我们的研究结果来自 研究RMTG的功能mPFC输入的实验支持这些电路在调节中的作用 厌恶的反应。这些数据让我们假设，特定于子区域和特定线路的依赖 RMTg投射的mPFC神经元的可塑性促进了对乙醇厌恶特性的慢性耐受。这个 目前提案中描述的AIMS将使用创新的、特定于电路的策略来验证这一假设。目标 1将使用体内纤维光度法来测量RMTg投射的PL和IL mPFC中钙信号的变化 在容忍度发展过程中的投入。目标2将使用体内闭环光遗传学来剖析这些效应 对RMTG的PL和IL mPFC输入的双向操作对慢性耐受性的测量 乙醇的令人厌恶的特性。目标3将使用全细胞膜片钳切片电生理学和病毒- 识别依赖诱导的突触和结构可塑性变化的中介交叉法 对乙醇令人厌恶的特性的潜在耐受性。这些研究的结果将提供至关重要的洞察 导致无节制饮酒的电路特有的神经机制。在此过程中，我们的发现 有可能发现治疗酒精使用障碍的新治疗靶点。

PROJECT SUMMARY Chronic alcohol exposure is associated with the development of tolerance to alcohol’s aversive properties, which serve to limit drinking. In contrast, the response to alcohol’s rewarding properties, which promote drinking, remain unchanged. The brain undergoes a host of neuroadaptive changes as a result of chronic alcohol exposure but the neural mechanisms underlying this tolerance are unknown. Impaired signaling in circuits encoding aversion is a likely candidate mechanism. The rostromedial tegmental nucleus (RMTg) is characterized for its involvement in aversion including signaling the aversive properties of ethanol. The prelimbic (PL) medial prefrontal cortex (mPFC) shares important functional similarities with the RMTg including facilitation of aversion learning and regulating the behavioral response to aversive stimuli. The neighboring infralimbic (IL) subregion of the mPFC exerts opposing effects to PL mPFC by facilitating extinction of aversive responding. Our work has uncovered a dense projection from the mPFC to the RMTg that spans both PL and IL subregions. Our findings from experiments investigating the function mPFC inputs to the RMTg support a role for these circuits in regulating aversive responding. These data lead us to hypothesize that subregion- and circuit-specific dependence-induced plasticity in RMTg-projecting mPFC neurons facilitates chronic tolerance to ethanol’s aversive properties. The aims described in the current proposal will use innovative, circuit-specific strategies to test this hypothesis. Aim 1 will use in vivo fiber photometry to measure changes in calcium signal in RMTg-projecting PL and IL mPFC inputs during the development of tolerance. Aim 2 will use closed-loop in vivo optogenetics to dissect the effects of bidirectional manipulation of PL and IL mPFC inputs to the RMTg on measures of chronic tolerance to ethanol’s aversive properties. Aim 3 will use whole-cell patch-clamp slice electrophysiology and a virally- mediated intersectional approach to identify dependence-induced changes in synaptic and structural plasticity underlying tolerance to ethanol’s aversive properties. The results of these studies will provide crucial insight into the circuit-specific neural mechanisms that contribute to uncontrolled alcohol drinking. In doing so, our findings have the potential to uncover new therapeutic targets for the treatment of alcohol use disorder.