Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol

项目摘要 长期酒精暴露与对酒精厌恶特性的耐受性的发展有关， 限制饮酒。相反，对酒精的奖励属性的反应，促进饮酒， 不变大脑经历了一系列神经适应性变化，这是长期酒精暴露的结果， 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受损信号 是一个可能的候选机制。头内侧被盖核（RMTg）的特点是参与 包括发出乙醇的厌恶属性的信号。前边缘（PL）内侧前额叶皮层 （mPFC）与RMTg具有重要的功能相似性，包括促进厌恶学习， 调节对厌恶刺激的行为反应。mPFC的相邻边缘下（IL）亚区 通过促进厌恶反应的消退对PL mPFC产生相反的作用。我们的工作揭示了 从mPFC到RMTg的密集投影跨越PL和IL亚区。我们的发现来自 研究输入到RMTg的mPFC功能的实验支持这些电路在调节 厌恶的回应这些数据使我们假设，亚区和电路特异性依赖诱导 RMTg投射mPFC神经元的可塑性促进了对乙醇厌恶性质的慢性耐受。的 本提案中所述的目标将使用创新的、针对具体电路的战略来检验这一假设。目的 1将使用体内纤维光度法测量RMTg投射PL和IL mPFC中钙信号的变化 在宽容的发展过程中。AIM 2将使用闭环体内光遗传学来剖析影响 双向操纵PL和IL mPFC输入到RMTg的慢性耐受性措施， 乙醇令人厌恶的特性Aim 3将使用全细胞膜片钳切片电生理学和病毒- 介导的交叉途径，以确定依赖诱导的突触和结构可塑性的变化 对乙醇的厌恶特性的潜在耐受性。这些研究的结果将提供关键的洞察力， 导致不受控制的饮酒的特定回路神经机制。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.