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: 9756638
• 负责人: Hannah Marian Baumgartner
• 金额: $ 3.67万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756638
• 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; 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.

项目摘要。这个建议的主要目标是调查激励的激励作用， 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神经回路是 大脑的主要压力制造者1. CRF神经元的激活传统上被认为产生厌恶 动机状态，包括成瘾者停止使用药物后的厌恶性戒断状态1，2，3。 具体地说，中央杏仁核（CeA）和纹状体床核中CRF神经元的兴奋 根据顺应性过程，推测终末肌（BNST）产生厌恶性退缩状态1，2，4 模型（也称为成瘾的享乐稳态、享乐失调和别稳态假说）。 然而，其他研究，包括我自己的初步研究，表明激活脑皮层中的CRF神经元， 以及NAc，也可能有助于强化奖励的积极激励动机，而不会诱导 任何厌恶的状态5，6，7.如果是这样的话，这将有助于解释为什么压力继续加速恢复复发 即使戒断症状消失后也会上瘾。我的初步证据表明BNST中只有CRF神经元 会引起传统的厌恶状态目前的提案旨在调查令人惊讶的 在CeA和NAc中CRF神经元的积极激励动机作用，使用选择性光遗传学工具， 通过Cre靶向光遗传通道视紫红质特异性激活CRH-Cre大鼠中表达CRF的神经元。 在NAc和CeA中CRF神经元刺激的预测正激励动机效应将是 与BNST中CRF-神经元刺激的预测负面厌恶效应形成对比。激励效应 也将在这些结构中检查抑制CRF神经元的作用。激励激励将放大 使用CRF神经元的激光自我刺激和获得感官奖励的操作性2选择任务进行测量， 这一模型狭隘地聚焦于强烈的追求，类似于成瘾8，9。在这个选择任务中，老鼠要么获得蔗糖， 奖励或静脉注射药物奖励：两种奖励选择之一总是获得激光伴随的奖励 调节CRF神经元活动，而另一种选择只获得奖励。最后，分布式神经 通过刺激CRF神经元募集的回路，介导CeA或NAc位点的激励动机，或 BNST网站的厌恶动机，将绘制和比较，通过测量遥远的Fos表达，在其他 大脑结构和特定的因果预测将使用光遗传学工具进行检查。通过拟议的 培训，我将学习新的技术，包括静脉药物自我管理程序和行为 CRF神经元所需的先进的光遗传学和免疫组织化学技术 成像和束跟踪，以及用于映射解剖激活模式。这次培训将帮助我发展 成为一个多产的独立研究科学家这些结果也可以为理解临床 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 CRF神经元的应激激活在成瘾和复吸中的作用。