Effect of chronic ethanol exposure on synaptic organization in the rostromedial tegmental nucleus

慢性乙醇暴露对吻内侧被盖核突触组织的影响

• 批准号: 10809364
• 负责人: Kevin Michael Boergens
• 金额: $ 22.24万
• 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: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809364
• 关键词: 3-Dimensional; Address; Affect; Applications Grants; Automobile Driving; Aversive Stimulus; Behavior; Behavioral; Brain region; Cell Nucleus; Cellular Morphology; Cellular Structures; Characteristics; Chronic; Complex; Data; Data Set; Dependence; Development; Drug Exposure; Electron Microscope; Ethanol; Exhibits; Extinction; Foundations; Future; Genetic Transcription; Heterogeneity; Interneurons; Investigation; Label; Laboratories; Maps; Medial; Mediating; Midbrain structure; Morphology; Neurobiology; Neurons; Neurosciences Research; Nucleus Accumbens; Pattern; Phenotype; Physiology; Play; Prefrontal Cortex; Prevalence; Psychological reinforcement; Rattus; Regulation; Research; Rewards; Role; Signal Transduction; Subcellular Anatomy; Synapses; Synaptic plasticity; Techniques; Ventral Tegmental Area; Work; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol use disorder; cell type; comparison group; connectome; cost; density; design; dopaminergic neuron; experimental study; insight; interest; motivated behavior; nanometer resolution; neurobiological mechanism; neurochemistry; neuromechanism; novel; response; synaptic function

PROJECT SUMMARY In 2009 two laboratories independently discovered the rostromedial tegmental nucleus (RMTg) – a small GABAergic nucleus that encodes negative reward prediction error via the inhibitory control it exerts over midbrain dopamine neurons. Together with subsequent studies demonstrating a role for the RMTg in responding to aversive stimuli, this work sparked new research investigating involvement of this region in the neurobiological mechanisms underlying alcohol use disorder. The medial prefrontal cortex (mPFC) plays a key role in regulating alcohol seeking and taking behavior. Interestingly, our recent work revealed the presence of dense input from the mPFC to the RMTg that spans both the prelimbic (PL) and infralimbic (IL) subregions. Studies manipulating PL and IL activity at the subregional level suggest that these two regions exert opposing control over alcohol seeking. However, the application of circuit-specific approaches is beginning to suggest a more complex picture with differing roles across discrete cortico-subcortical projections. Combined with only a very superficial understanding of the heterogeneity / uniformity of RMTg neurons, these conflicting data make it difficult to develop hypotheses regarding circuit motifs in RMTg and the potential synergistic or dichotomous functions of RMTg-projecting PL and IL mPFC neurons. Given the impact that recent data demonstrating the previously unappreciated heterogeneity of the ventral tegmental area has had on functional understanding of this region, a rigorous investigation of the RMTg is warranted. The aims described in the current proposal will combine circuit- specific labeling with state-of-the-art connectomics approaches to characterize the effects of chronic ethanol exposure on the RMTg and its cortical afferents at nanometer resolution. Acquisition of an RMTg connectome will provide crucial insight into cell structure and synaptic patterns as well as a precise neuronal map of dense cortical input to RMTg thought to play a critical role in top-down control over alcohol seeking. The resulting circuit data will provide a foundation for future studies investigating the functional consequences of dependence- induced synaptic reorganization by integrating subcellular anatomical findings with physiology and behavior.

项目摘要 2009年，两个实验室独立发现了杆状技术核（RMTG） - 一个小的 通过抑制性控制编码负奖励预测误差的GABA能核IT在中脑上出口 多巴胺神经元。随后的研究表明，RMTG在响应中的作用 厌恶刺激，这项工作引发了新的研究，调查了该地区参与神经生物学 酒精使用障碍的机制。媒体前额叶皮层（MPFC）在调节中起关键作用 寻求和采取行为的酒精。有趣的是，我们最近的工作揭示了来自 MPFC到RMTG，既跨越前BIC（PL）和Infralimbic（IL）子区域。研究操纵 次区域的PL和IL活性表明，这两个区域对酒精的控制产生了相反的控制 寻求。但是，特定电路方法的应用开始提出更复杂的图片 在离散的皮质增生项目中具有不同的角色。仅与非常肤浅的 了解RMTG神经元的异质性 /均匀性，这些相互矛盾的数据使得很难 开发有关RMTG中电路基序的假设以及潜在的协同或二分法功能 RMTG投射PL和IL MPFC神经元。鉴于最近的数据证明了先前的数据 腹侧盖区域的未接受异质性在对该区域的功能理解方面具有 有必要对RMTG进行严格的投资。当前提案中描述的目的将结合电路 - 采用最新连接方法的特定标签来表征慢性乙醇的影响 在纳米分辨率下，RMTG及其皮质传入的暴露。收购RMTG Connectome 将提供对细胞结构和突触模式的关键见解，以及密集的精确神经元图 RMTG的皮质输入认为在对酒精寻求酒精的自上而下的控制中起着至关重要的作用。最终的电路 数据将为未来研究的基础研究依赖的功能后果 - 通过将亚细胞解剖学发现与生理学和行为相结合，引起突触重组。