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

前边缘输入到嘴内侧被盖核在编码对乙醇厌恶特性的敏感性中的作用

• 批准号: 10749662
• 负责人: Kathryn Przybysz
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-15 至 2024-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10749662
• 关键词: Acute; Address; Adult; Alcohol consumption; Alcohols; Area; Automobile Driving; Aversive Stimulus; Behavioral; Behavioral Assay; Biological Assay; Brain; Calcium Signaling; Cell Nucleus; Cells; Classification; Clinical; Data; Electrophysiology (science); Environment; Ethanol; Exhibits; Exposure to; Female; Fiber; Fright; Functional disorder; Gene Expression; Goals; Heavy Drinking; Individual; Individual Differences; Lead; Learning; Literature; Measures; Medial; Mediating; Molecular; Nature; Neurobiology; Neurons; Neurosciences Research; Pharmaceutical Preparations; Phenotype; Photometry; Physiological; Physiology; Population; Prefrontal Cortex; Procedures; Property; Public Health; Rattus; Research Personnel; Resistance; Rewards; RiboTag; Risk; Role; Signal Transduction; Source; Taste aversion; Techniques; Testing; Training; Viral; Work; alcohol exposure; alcohol response; alcohol reward; alcohol risk; alcohol sensitivity; alcohol use disorder; behavioral response; cost; disorder risk; drinking; experimental study; in vivo; individual variation; innovation; insight; male; neural; neural circuit; neurobiological mechanism; neuromechanism; patch clamp; pre-clinical; response; training opportunity; transcriptome sequencing; whole genome

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.

项目摘要 个人对酒精的奖励和厌恶属性的主观反应有助于他们的风险， 酒精使用障碍（AUD）例如，那些对厌恶属性不太敏感的人 通常限制饮酒的酒精含量更有可能大量饮酒并发展为AUD。条件性味觉 厌恶（CTA）是一种检测方法，允许临床前研究人员探测对 毒品使用这种检测方法，我们的初步数据显示存在显着的个体差异的敏感性 与临床人群中观察到的相似的乙醇厌恶性质。具体来说，一些 个体表现出强烈的乙醇诱导的CTA（CTA敏感），而其他个体对乙醇表现出最小的CTA （CTA抗性）。尽管有强有力的证据表明，对乙醇的主观反应与 AUD，编码对乙醇厌恶特性敏感性的神经生物学底物， 明白我们实验室最近的工作表明，嘴内侧被盖核（RMTg）信号， 乙醇的令人厌恶的特性。驱动RMTg参与信号乙醇厌恶的神经回路 是未知的，但我们实验室的数据指向内侧前额叶皮层的前边缘（PL）细分， 潜在的来源。PL和RMTg都与对厌恶刺激的行为反应有关， 发现PL向RMTg发送密集的投影。我们还发现这种投射被激活 在暴露于厌恶性刺激时，这个回路的刺激会驱动回避。我们一起， 假设投射RMTg的PL神经元编码对乙醇厌恶性质的敏感性， 回路活动的差异导致对乙醇的主观反应的个体差异。我们将测试 这一假设涉及三个具体目标。在目标1中，我们将联合收割机CTA与体内纤维光度法相结合， CTA敏感和耐药个体中的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RMTg投射PL神经元在CTA中的生理学差异 表型在目标3中，我们将在RMTg投射的PL神经元中进行全基因组RNA测序，以评估 CTA敏感和耐药个体的翻译差异。这些实验将提供 新的机制洞察神经生物学潜在的敏感性，乙醇的厌恶性质，同时也 为申请人提供神经科学概念创新和尖端方法的新培训 research.