Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol

对乙醇厌恶特性长期耐受的神经生物学机制

• 批准号: 10616956
• 负责人: Elizabeth J Glover
• 金额: $ 7.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616956
• 关键词: Alcohols; Anterior; Automobile Driving; Aversive Stimulus; Award; Behavioral; Brain; Calcium Signaling; Cell Nucleus; Cells; Chronic; Consumption; Data; Dendritic Spines; Dependence; Development; Electrophysiology (science); Environment; Epigenetic Process; Ethanol; Fiber; Foundations; Funding; Impairment; Light; Measures; Medial; Mediating; Mentorship; Minority; Morphology; National Institute on Alcohol Abuse and Alcoholism; National Research Service Awards; Neurons; Neurophysiology - biologic function; Neurosciences; Photometry; Physiological; Play; Prefrontal Cortex; Property; Research Personnel; Rewards; Role; Signal Transduction; Slice; Stimulus; Testing; Training; Viral; addiction; alcohol exposure; alcohol research; career development; density; design; drinking; experimental study; glutamatergic signaling; in vivo; neural circuit; neurobiological mechanism; neuromechanism; parent grant; patch clamp; response

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.

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。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。电路中的信号受损 编码厌恶可能是一种候选机制。被盖旋转内侧核(RMTg)的特点是 因为它参与了厌恶，包括发出乙醇厌恶特性的信号。父母助学金的目的 被设计用来检验这样的假设，即依赖在离散的RMTg投射神经元中诱导可塑性 内侧前额叶皮质(MPFC)的亚区有助于对乙醇的厌恶特性的慢性耐受。 这一假设得到了以下事实的支持：存在密集的连通性和显著的功能重叠 MPFC和RMTG。然而，RMTG也接受来自前岛叶皮质(AIC)的输入。AIC是 关键参与处理内感信息以指导对环境刺激的行为反应 包括那些与奖励和厌恶有关的东西。特别是，AIC功能的丧失会导致行为 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，但来自我们的数据 实验室认为，AIC和RMTg在发送有关厌恶属性的信息方面都发挥了作用 乙醇。与mPFC一样，慢性阻塞性肺疾病后的AIC也观察到了显著的神经适应性变化。 酒精暴露。目前的建议旨在调查依赖诱导的改变是否 AIC-RMTg电路还通过一系列机制参与了对乙醇厌恶特性的耐受 与父母拨款中建议的实验平行的实验。目标一号将使用体内纤维光度法来测量 耐力形成过程中RMTg-投射AIC输入细胞钙信号的变化AIM 2将使用 全细胞膜片钳切片电生理学检测依赖诱导的谷氨酸能改变 表明对乙醇令人厌恶的特性的潜在耐受性。其他研究将使用病毒介导的 确定耐受后发生的生理水平的变化是否 也与树突棘密度和形态的变化有关。这些研究的结果将 扩大在父母赠款中产生的调查结果，并阐明可能发挥的协同作用 AIC和mPFC在慢性耐受乙醇厌恶特性的机制中的作用。在……里面 此外，该奖项为少数族裔候选人提供了一个在尖端技术方面获得新培训的机会 在成瘾神经科学的指导下在丰富的科学环境下取得极大成功 NIAAA资助的表观遗传学酒精研究中心内的PI。在以下项目的支持下产生的结果 该奖项将作为候选人开发国家研究服务奖申请的基础 以促进她作为酒精研究人员的培训和职业发展。