Ventral pallidal circuitry in alcohol seeking and reinstatement by stress

寻找酒精和压力恢复的腹侧苍白球回路

• 批准号: 9385558
• 负责人: Jocelyn M Richard
• 金额: $ 13.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385558
• 关键词: Abstinence; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anatomy; Area; Automobile Driving; Award; Behavior; Behavioral; Brain; Calcium; Cells; Characteristics; Chronic; Chronic stress; Cocaine; Collection; Cues; Data; Dependence; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Environment; Exhibits; Extinction (Psychology); Fiber; Fluorescence; Future; Globus Pallidus; Grant; Histologic; Image; Implant; Injection of therapeutic agent; Laboratories; Learning; Length; Measurement; Measures; Medial; Methods; Modeling; Neurons; Nucleus Accumbens; Opsin; Optics; Organ; Pathway interactions; Pattern; Pharmacology; Phase; Photometry; Play; Population; Prefrontal Cortex; Rattus; Relapse; Resolution; Rewards; Role; Solvents; Specificity; Stress; System; Testing; Three-Dimensional Imaging; Training; Transgenic Organisms; Viral; Virus; Withdrawal; Yohimbine; acute stress; alcohol availability; alcohol cue; alcohol exposure; alcohol relapse; alcohol response; alcohol seeking behavior; awake; base; behavioral response; calcium indicator; dependence relapse; experimental study; interest; neural circuit; neural correlate; novel; optical fiber; optogenetics; relating to nervous system; response; selective expression; sensor; skills; stressor; three dimensional structure; vapor

Project Summary Acute or chronic stress contributes to both escalation of alcohol use and relapse to alcohol seeking after abstinence. Stressors are hypothesized to contribute to relapse in part by promoting responses to cues in the environment that have been previously associated with alcohol availability, yet the brain mechanisms of this interaction between cues and stress are poorly understood. An area of the brain implicated in both stress- and cue-induced reward seeking is the ventral pallidum (VP). I have previously found that VP neurons encode the vigor of cue-elicited reward seeking, and my preliminary results suggest that VP neurons encode reinstatement of reward seeking by the pharmacological stressor, yohimbine. In the current proposal, I aim to confirm and expand my findings regarding VP encoding of reinstatement by stress, using a behavioral stressor, and to further dissect the neural circuit mechanisms by which VP neurons contribute to alcohol seeking. Here, in the K99 phase, I will examine VP encoding of cued alcohol seeking and reinstatement induced by stress in dependent versus non-dependent alcohol seeking rats. This aim will provide me with new training in models of alcohol dependence and stress reinstatement. I will then examine encoding of alcohol seeking behavior in inputs to VP from the prefrontal cortex (PFC) and basolateral amygdala (BLA), using a novel method for projection specific measurement of activity. This method, fiber photometry, uses viral-based expression of a fluorescent calcium indicator paired with optical measurement of fluorescence. Training in this skill will allow me to measure projection-specific neural activity in the proposed aims and future projects. Further, this aim will provide critical information regarding the timing of activity in BLA and PFC inputs during alcohol seeking, to be tested in the R00 phase. I will also assess the collateralization of these neurons, comparing two methods: traditional sectioning and immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO). This method provides unprecedented access to the three-dimensional structure of immunolabeled cells, and the opportunity to obtain both large-scale and high resolution information simultaneously, crucial for planned experiments in my future laboratory. In the R00 phase I will test the functional role of temporally precise activity in BLA and PFC inputs to VP during cued alcohol seeking and reinstatement of alcohol seeking, using optogenetics. I will also measure activity in genetically-defined populations of neurons projecting from the nucleus accumbens (NAc), which include both D1- and D2-dopamine receptor dominant neurons. Using transgenic rats I will selectively express calcium indicators in either D1- or D2-dominant neurons projecting to VP. These experiments will provide novel data regarding the differential activity of D1 and D2 neurons projecting to VP and will provide an important framework for future experiments and grants. These experiments will characterize the neural circuit mechanisms by which VP neurons drive alcohol seeking, and how they differ across different states of dependence and following stress.

项目摘要 急性或慢性压力既有助于饮酒的升级，又有助于寻求酒精的复发 节制。假设压力源是通过促进对线索的反应的部分原因 以前与酒精可用性相关的环境，但大脑机制 提示与压力之间的相互作用知之甚少。大脑的区域与压力和 提示引起的奖励寻求是腹侧粒子（VP）。我以前已经发现VP神经元编码 提示吸引的奖励的活力，而我的初步结果表明副总裁神经元编码恢复原状 由药理学压力源Yohimbine寻求奖励。在当前的建议中，我的目标是确认和 扩展我关于使用压力，使用行为压力源对恢复恢复的VP编码的发现，并进一步 解剖VP神经元有助于饮酒的神经回路机制。 在这里，在K99阶段，我将研究提出的酒精寻求和恢复原状的副总裁 通过依赖与非依赖性酒精寻求大鼠的压力。这个目标将为我提供新的培训 酒精依赖和恢复应力的模型。然后，我将检查寻求酒精的编码 使用一种新方法 用于投影特定的活性测量。该方法（纤维光度法）使用基于病毒的表达 荧光钙指示剂与荧光的光学测量配对。训练这一技能将使我 在拟议的目标和未来项目中衡量投影特定的神经活动。此外，这个目标将 提供有关在寻求酒精期间BLA和PFC输入中活动时机的关键信息， 在R00阶段进行测试。我还将评估这些神经元的抵押品，并比较两种方法： 传统的分区和免疫标签的三维器官的三维成像 （IDISCO）。该方法提供了对免疫标记的三维结构的前所未有的访问 细胞，以及同时获得大规模和高分辨率信息的机会，至关重要 我将来的实验室计划实验。 在R00期中 在提取酒精期间，使用光遗传学寻求和恢复酒精。我还将测量活动 在八核（NAC）投射的神经元的遗传定义群体中，其中包括 D1和D2-多巴胺受体显性神经元。使用转基因大鼠我将有选择地表达钙 投射到VP的D1或D2占主导性神经元中的指标。这些实验将提供新的数据 关于投射到VP的D1和D2神经元的差异活动，并将提供一个重要的框架 用于将来的实验和赠款。这些实验将表征神经回路机制 副总裁神经元驱动酒精，以及它们如何在不同状态的依赖状态和压力下如何差异。