Role of prelimbic input to the rostromedial tegmental nucleus in encoding sensitivity to the aversive properties of ethanol

项目总结 个人对酒精的有益和令人厌恶的特性的主观反应会增加他们患酒精症的风险 出现酒精使用障碍(AUD)。例如，对厌恶属性不那么敏感的个体 酒精通常会限制饮酒，更有可能酗酒并患上AUD。条件性味觉 厌恶(CTA)是一种允许临床前研究人员探测对厌恶特性的敏感性的测试 毒品。使用这种分析方法，我们的初步数据显示在敏感度上存在显著的个体差异。 与临床人群中观察到的乙醇的厌恶特性相似。具体来说，一些 个体表现出强烈的乙醇诱导的CTA(CTA敏感)，而其他人对乙醇表现出最小的CTA (抗CTA)。尽管有强有力的证据表明，对乙醇的主观反应与心脏病风险之间存在联系 此外，编码对乙醇的厌恶特性敏感的神经生物学底物很差 明白了。我们实验室最近的研究表明，旋转内侧被盖核(RMTg)发出信号 乙醇的厌恶特性。驱动RMTG参与传递酒精厌恶信号的神经回路 未知，但我们实验室的数据表明，内侧前额叶皮质的初步(PL)细分为 一个潜在的消息来源。PL和RMTG都与对厌恶刺激的行为反应有关，我们 已经发现PL向RMTG发送密集的投影。我们还发现这个投射被激活了 在暴露于令人厌恶的刺激时，这一回路的刺激会驱使逃避。总而言之，这让我们 假设投射RMTg的PL神经元对乙醇的厌恶特性编码敏感，并且 回路活动的差异导致了个体对乙醇的主观反应的差异。我们将测试 这一假设涉及三个具体目标。在目标1中，我们将CTA与体内纤维光度法相结合进行比较 CTA敏感和抗性个体的PL-RMTg活性。在目标2中，我们将使用全细胞膜片钳 电生理学检查投射RMTg的PL神经元在跨CTA的生理学差异 表型。在目标3中，我们将在投射RMTg的PL神经元中进行全基因组RNA测序，以评估 CTA敏感和抗性个体之间的翻译差异。总之，这些实验将提供 对乙醇厌恶特性的神经生物学基础的新的机械论见解，同时也 为申请者提供神经科学概念创新和前沿方法方面的新培训 研究。

PROJECT SUMMARY An individual’s subjective response to alcohol’s rewarding and aversive properties contribute to their risk for developing alcohol use disorder (AUD). For example, individuals who are less sensitive to the aversive properties of alcohol, which typically limit drinking, are more likely to drink heavily and develop AUD. Conditioned taste aversion (CTA) is an assay that allows preclinical researchers to probe sensitivity to the aversive properties of drugs. Using this assay, our preliminary data reveal the presence of significant individual differences in sensitivity to the aversive properties of ethanol similar to that which is observed in clinical populations. Specifically, some individuals exhibit strong ethanol-induced CTA (CTA-sensitive), whereas others exhibit minimal CTA to ethanol (CTA-resistant). Despite strong evidence for a relationship between subjective response to ethanol and risk for AUD, the neurobiological substrates that encode sensitivity to ethanol’s aversive properties are poorly understood. Recent work from our lab suggests that the rostromedial tegmental nucleus (RMTg) signals the aversive properties of ethanol. The neural circuits driving engagement of the RMTg to signal ethanol aversion are unknown, but data from our lab point toward the prelimbic (PL) subdivision of the medial prefrontal cortex as a potential source. The PL and RMTg are both implicated in the behavioral response to aversive stimuli, and we have discovered that the PL sends dense projections to the RMTg. We also found that this projection is activated during exposure to aversive stimuli, and that stimulation of this circuit drives avoidance. Together, this leads us to hypothesize that RMTg-projecting PL neurons encode sensitivity to the aversive properties of ethanol and that differences in circuit activity contribute to individual differences in subjective response to ethanol. We will test this hypothesis across three specific aims. In Aim 1, we will combine CTA with in vivo fiber photometry to compare PL-RMTg activity in CTA-sensitive and -resistant individuals. In Aim 2, we will use whole-cell patch-clamp electrophysiology to examine differences in the physiology of RMTg-projecting PL neurons across CTA phenotypes. In Aim 3, we will conduct whole-genome RNA-sequencing in RMTg-projecting PL neurons to assess translational differences in CTA-sensitive and -resistant individuals. Together, these experiments will provide new mechanistic insight into the neurobiology underlying sensitivity to ethanol’s aversive properties, while also providing the applicant with new training in conceptually innovative and cutting-edge approaches in neuroscience research.