Surprising roles of corticotropin releasing factor (CRF) neurons in reward motivation

促肾上腺皮质激素释放因子（CRF）神经元在奖励动机中的惊人作用

• 批准号: 9912629
• 负责人: Hannah Marian Baumgartner
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912629
• 关键词: Amygdaloid structure; Anatomy; Area; Behavior; Behavioral; Brain; CRF receptor type 1; CRH gene; Clinical; Cocaine; Consumption; Corticotropin-Releasing Hormone; Data; Disease; Distant; Drug Addiction; Drug usage; Goals; Homeostasis; Hypothalamic structure; Image; Immunohistochemistry; Incentives; Intravenous; Lasers; Lateral; Lead; Learning; Maps; Measures; Mediating; Modeling; Mood Disorders; Motivation; Neurons; Nucleus Accumbens; Opioid; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Pilot Projects; Population; Procedures; Process; Rattus; Relapse; Research; Rewards; Role; Scientist; Self Administration; Self Medication; Self Stimulation; Sensory; Site; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Sucrose; System; Techniques; Testing; Training; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; Work; addiction; allostasis; behavioral economics; brain circuitry; craving; drug reward; drug withdrawal; economic evaluation; hedonic; incentive salience; insight; midbrain central gray substance; neural circuit; neurobiological mechanism; neuronal circuitry; neurotransmitter release; opioid abuse; optogenetics; paraventricular nucleus; positive emotional state; psychostimulant; recruit; relating to nervous system; release factor; remifentanil; response; reward circuitry; stress state; theories; therapeutic target; tool

PROJECT SUMMARY. The primary goal of this proposal is to investigate the motivational role of excitation of neurons that release corticotropin releasing factor (CRF) in brain limbic structures. CRF neural circuitry is the brain's master stress trigger1. The activation of CRF neurons is traditionally believed to generate aversive motivational states including aversive withdrawal states after discontinuation of drug use in addicts1,2,3. Specifically, excitation of CRF neurons in both the central amygdala (CeA) and in the bed nucleus of the stria terminalis (BNST) are hypothesized to generate aversive withdrawal states1,2,4 according to opponent-process models (also called hedonic homeostasis, hedonic dysregulation and allostasis hypotheses of addiction). However, other research, including my own pilot studies, demonstrates that activation of CRF neurons in CeA, as well as NAc, may also contribute to intensifying positive incentive motivation for rewards, without inducing any aversive states5,6,7. If so, this would help explain why stress continues to precipitate relapse in recovering addicts even after withdrawal symptoms are gone. My pilot evidence suggests that only CRF neurons in BNST cause a traditional aversive state when activated. The current proposal aims to investigate the surprising positive incentive motivation roles of CRF neurons in CeA and NAc, using selective optogenetic tools to specifically activate CRF-expressing neurons in CRH-Cre rats, via Cre-targeted optogenetic channelrhodopsin. The predicted positive incentive motivation effects of CRF-neuron stimulation in NAc and CeA will be contrasted to predicted negative aversive effects of CRF-neuron stimulation in BNST. Motivation effects of inhibiting CRF neurons will also be examined in these structures. Incentive motivation amplification will be measured using laser self-stimulation of CRF neurons and an operant 2-choice task earning sensory rewards, which models narrowly focused intense pursuit, similar to addiction8,9. In this choice task, rats earn either sucrose rewards or intravenous drug rewards: one of the two reward choices always earn a reward accompanied by laser that modulates CRF neuronal activity, while the other choice earns the reward alone. Finally, distributed neural circuitry recruited by stimulation of CRF neurons that mediate incentive motivation for CeA or NAc sites, or aversive motivation for BNST sites, will be mapped and compared by measuring distant Fos expression in other brain structures, and specific causal projections will be examined using optogenetic tools. Through the proposed training, I will learn new techniques including intravenous drug self-administration procedures and behavioral economics analysis, and advanced optogenetic and immunohistochemistry techniques needed for CRF neuron imaging and tract tracing, and for mapping anatomical activation patterns. This training will help me to develop into a productive, independent research scientist. The results may also provide insights for understanding clinical roles of CRF neuronal circuitry of CeA, NAc, and BNST in incentive motivation vs. aversive motivation, relevant to the roles of stress activation of CRF neurons in addiction and relapse.

项目总结。这项建议的主要目的是调查激励的动机作用 在大脑边缘结构中释放促肾上腺皮质激素释放因子(CRF)的神经元。CRF神经电路是 大脑的主要压力触发1。CRF神经元的激活传统上被认为会产生厌恶情绪 动机状态包括戒毒后的厌恶戒断状态1、2、3。 具体地说，杏仁中央核(CEA)和纹状体床核CRF神经元的兴奋 终结者(BNST)被假设为根据对手过程产生厌恶退出状态1、2、4 模型(也称为成瘾的享乐性稳态、享乐性失调和异质性假说)。 然而，包括我自己的试点研究在内的其他研究表明，CEA中CRF神经元的激活， 与NAC一样，也可能有助于强化奖励的正向激励动机，而不是诱导 任何令人厌恶的状态5、6、7.如果是这样的话，这将有助于解释为什么在康复过程中压力会继续促使复发 成瘾者即使在戒断症状消失后也是如此。我的初步证据表明，只有BNST中的CRF神经元 当被激活时，会导致传统的厌恶状态。目前的提案旨在调查令人惊讶的 CRF神经元在CEA和NAC中的正向激励动机作用，使用选择性光遗传学工具 通过CRE靶向的光遗传通道视紫红质，特异性激活CRH-CRE大鼠CRF表达的神经元。 刺激NAC和CEA的CRF神经元的正向激励动机效应将被预测为 与刺激BNST中CRF神经元的负性厌恶效应形成对比。激励效应 抑制CRF神经元的作用也将在这些结构中进行检测。激励激励将被放大 通过激光对CRF神经元的自我刺激和获得感官奖励的可操作性的双选择任务进行测量， 哪个模型狭隘地专注于强烈的追求，类似于上瘾8，9。在这个选择任务中，大鼠要么获得蔗糖 奖励或静脉注射毒品奖励：两种奖励选择中的一种总是获得伴随激光的奖励 这调节了CRF神经元的活动，而另一种选择只获得了回报。最后，分布式神经网络 通过刺激CRF神经元而招募的回路，介导CEA或NAC部位的激励动机，或 BNST站点的厌恶动机，将通过测量其他站点中远距离Fos的表达来进行映射和比较 大脑结构和特定的因果投射将使用光遗传工具进行检查。通过建议的 在培训中，我将学习新的技术，包括静脉注射药物自我给药程序和行为 经济学分析，以及CRF神经元所需的先进光遗传学和免疫组织化学技术 成像和轨迹跟踪，并用于绘制解剖激活模式。这次培训将帮助我发展 成为一名多产的独立研究科学家。这一结果也可能为理解临床提供一些见解。 CEA、NAC和BNST的CRF神经元回路在激励动机与厌恶动机中的作用，相关 应激激活的CRF神经元在成瘾和复发中的作用。