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。长期饮酒会导致大脑神经适应性改变 暴露，但这种耐受性背后的神经机制是未知的。电路中的信号受损 编码厌恶是可能的候选机制。头内侧被盖核（RMTg）的特点是 因为它涉及厌恶，包括发出乙醇的厌恶特性的信号。父母补助金的目的 旨在检验以下假设：在离散的RMTg投射神经元中，依赖诱导的可塑性 内侧前额叶皮层（mPFC）的子区域促进了对乙醇厌恶特性的长期耐受。 这一假设得到了以下事实的支持： mPFC和RMTg。然而，RMTg也接受来自前岛叶皮层（AIC）的输入。AIC是 关键地参与处理内感受信息以指导对环境刺激的行为反应 包括那些与奖赏和厌恶相关的。特别是，AIC功能的丧失会导致行为性 对令人厌恶的刺激反应的缺陷。虽然这种神经回路的功能尚不清楚，但我们的数据显示， 实验室认为，AIC和RMTg都在传递关于厌恶属性的信号信息中发挥作用 乙醇。与mPFC一样，在AIC中也观察到了慢性 酒精暴露目前的建议是为了调查是否依赖诱导的改变， AIC-RMTg电路也通过一组神经元参与了对乙醇厌恶性质的耐受性。 与父母补助金中提出的实验平行的实验。目的1将使用体内纤维光度法测量 在耐受性发展过程中，RMTg投射AIC输入中钙信号的变化。目标2将使用 全细胞膜片钳切片电生理学鉴定依赖性诱导的多巴胺能神经元的变化 表明对乙醇的厌恶特性的潜在耐受性。其他研究将使用病毒介导的 交叉方法，以确定耐受后发生的生理水平变化是否 也与树突棘密度和形态的变化有关。这些研究的结果将 增加了在母公司赠款中产生的发现，并对可能发挥的协同作用提出了新的看法 通过AIC和mPFC在慢性耐受乙醇的厌恶性质的机制。在 此外，该奖项为少数民族候选人提供了一个机会，以获得尖端的新培训， 在一个非常成功的导师的指导下，在丰富的科学环境中， NIAAA资助的PI在酒精研究中心的表观遗传学。在以下方面的支持下得出的结论： 该奖项将作为候选人开发国家研究服务奖申请的基础 作为一名酒精研究员，她将继续接受培训，并获得职业发展。

PROJECT SUMMARY Chronic alcohol exposure is associated with the development of tolerance to alcohol’s aversive properties, which serve to limit drinking. 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 aims of the parent grant are designed to test the hypothesis that dependence-induced plasticity in RMTg-projecting neurons in discrete subregions of the medial prefrontal cortex (mPFC) facilitates chronic tolerance to ethanol’s aversive properties. This hypothesis is supported by the presence of dense connectivity and significant functional overlap between the mPFC and RMTg. However, the RMTg also receives input from the anterior insular cortex (AIC). The AIC is critically involved in processing interoceptive information to guide behavioral responding to environmental stimuli including those associated with reward and aversion. In particular, loss of AIC function results in behavioral deficits in response to aversive stimuli. While the function of this neural circuit is not yet known, data from our lab suggests that both the AIC and RMTg play a role in signaling information regarding the aversive properties of ethanol. Like the mPFC, significant neuroadaptive changes are also observed in the AIC following chronic ethanol exposure. The current proposal is designed to investigate whether dependence-induced alterations in AIC-RMTg circuitry are also mechanistically involved in tolerance to ethanol’s aversive properties via a set of experiments that parallel those proposed in the parent grant. Aim 1 will use in vivo fiber photometry to measure changes in calcium signal in RMTg-projecting AIC inputs during the development of tolerance. Aim 2 will use whole-cell patch-clamp slice electrophysiology to identify dependence-induced changes in glutamatergic signaling underlying tolerance to ethanol’s aversive properties. Additional studies will use a virally-mediated intersectional approach to determine whether changes at the physiological level that occur after tolerance are also associated with changes in dendritic spine density and morphology. The results of these studies will augment the findings generated in the parent grant and shed new light on the possible synergistic role played by the AIC and mPFC in the mechanisms underlying chronic tolerance to the aversive properties of ethanol. In addition, this award provides an opportunity for the minority candidate to gain new training in cutting-edge approaches in addiction neuroscience in a rich scientific environment under the mentorship of a highly successful NIAAA-funded PI within the Center for Alcohol Research in Epigenetics. Findings generated with the support of this award will serve as a foundation for the candidate to develop a National Research Service Award application to further her training and career development as an alcohol researcher.