Defining the differential roles of Glutamatergic and GABAergic projections from the Lateral Preoptic Area to the Lateral Habenula in Reward, Aversion, and Drug-Seeking Behavior.

定义从外侧视前区到外侧缰核的谷氨酸能和 GABA 能投射在奖励、厌恶和药物寻求行为中的不同作用。

• 批准号: 9926602
• 负责人: David J Barker
• 金额: $ 24.9万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926602
• 关键词: Abstinence; Anatomy; Architecture; Aversive Stimulus; Award; Axon; Behavioral; Brain; Calcium; Cells; Cocaine; Cocaine Dependence; Complex; Cues; Data; Dendrites; Drug Addiction; Drug abuse; Electron Microscopy; Electrophysiology (science); Environment; Female; Fiber; Fiber Optics; GABA Receptor; Gender; Glutamate Receptor; Glutamates; Goals; Grant; Habenula; Human; Image; Immunoelectron Microscopy; Individual Differences; Intervention; Label; Lateral; Lead; Location; Measures; Mental Depression; Mental disorders; Mentors; Mentorship; Modeling; Morale; Mus; Neurons; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phase; Photometry; Play; Preoptic Areas; Presynaptic Terminals; Procedures; Process; Public Health; Publishing; Punishment; Research; Rewards; Role; Running; Self Administration; Sick Role; Signal Transduction; Stimulus; Structure; Sucrose; Synapses; Syndrome; Techniques; Testing; Tracer; Training; United States; Viral; Work; addiction; animal tissue; basal forebrain; calcium indicator; conditioned fear; density; drug relapse; drug seeking behavior; dual diagnosis; experimental study; gamma-Aminobutyric Acid; gender difference; in vivo; in vivo calcium imaging; insight; interest; male; motivated behavior; nervous system disorder; neuronal cell body; novel; postsynaptic; preference; presynaptic; programs; receptor; response; reward processing; tool

Project Summary/Abstract Drug addiction is a complex neurological disorder which produces aberrant function in limbic circuits and limbic-associated structures. One specific portion of the basal forebrain—the lateral preoptic area—serves as an important relay between limbic structures and the lateral habenula, a region that has been implicated in addiction and depression. Under the primary mentorship of Drs. Marisela Morales and Geoffrey Schoenbaum, the present Pathway to Independence award will allow me to obtain training in electron microscopy and in vivo calcium imaging in order to elucidate the role of the preopto-habenular projection in the processing of rewarding and aversive stimuli, and eventually the role that this circuitry plays in cocaine addiction. In the mentored phase of this grant, I will use a combination of viral tracers and immuno-electron microscopy in order to determine the targets of the lateral preoptic area glutamatergic and GABAergic axons that establish synapses on lateral habenula neurons and to determine how individual differences in postsynaptic receptors contribute to individual differences in the processing of rewarding and aversive stimuli. Subsequently, fiber photometry calcium imaging will be used in order to determine how the terminals of lateral preoptic glutamatergic and GABAergic neurons in the lateral habenula process rewarding or aversive outcomes and their associated cues. In the independent phase, I will combine these cutting-edge techniques with my prior training in order to simultaneously record the axon terminals of lateral preoptic neurons in the lateral habenula using fiber photometry and the responses of the postsynaptic cells in the lateral habenula using single-unit electrophysiological recordings in order to establish a role for the preopto-habenular pathway in cocaine self-administration, punishment-imposed abstinence, and cued reinstatement. In summary, the research proposed in this Pathway to Independence Award will elucidate the ultrastructural architecture and functional mechanisms of a novel circuit that participates in cocaine self-administration while simultaneously providing me with the tools to establish an independent research program capable of producing high impact studies that bridge anatomical data with cutting-edge techniques for examining circuit function.

项目总结/摘要 药物成瘾是一种复杂的神经系统疾病，它在边缘回路中产生异常功能， 边缘相关结构。基底前脑的一个特定部分--外侧视前区--起着 边缘结构和外侧缰之间的重要中继，这一区域与 成瘾和抑郁在Marisela Morales和Geoffrey Schoenbaum博士的主要指导下， 目前的独立之路奖将使我能够获得电子显微镜和体内 钙成像，以阐明前视缰投射在处理的作用， 奖励和厌恶刺激，以及最终这个回路在可卡因成瘾中所起的作用。在 在这个资助的指导阶段，我将使用病毒示踪剂和免疫电子显微镜的组合， 为了确定外侧视前区神经元和GABA能轴突的目标， 外侧缰核神经元上的突触，并确定突触后受体的个体差异 有助于个体差异的奖励和厌恶刺激的处理。随后，纤维 将使用光度钙成像以确定外侧视前区的末端如何 外侧缰突中的多巴胺能和GABA能神经元对奖赏或厌恶结果的影响， 他们的相关线索在独立阶段，我将联合收割机这些尖端技术与我的先前 训练以同时记录外侧视前神经元的轴突终末 用纤维光度法测定缰核内突触后细胞的反应， 单单位电生理记录，以确定前视缰通路在 可卡因自我管理，惩罚施加的禁欲，和暗示恢复。总而言之， 在这个独立之路奖提出的研究将阐明超微结构的架构， 参与可卡因自我给药同时 为我提供了建立一个能够产生高影响力的独立研究项目的工具 将解剖学数据与检查电路功能的尖端技术相结合的研究。