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

基本信息

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
项目类别：
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

项目摘要

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。该提案的主要目标是调查激发的动机作用释放脑边缘结构中皮质激素释放因子（CRF）的神经元。 CRF神经电路是大脑的主压力触发1。传统上认为CRF神经元的激活会引起厌恶在瘾君子中停止使用毒品后，包括厌恶戒断状态，包括厌恶戒断状态。1,2,3。具体而言，中央杏仁核（CEA）和Stria的床核中CRF神经元的激发假设末端（BNST）根据对手制处，以产生厌恶性撤回状态1,2,4 模型（也称为Hedonic稳态，享乐主义失调和成瘾的同性恋假设）。但是，其他研究，包括我自己的试点研究，表明CRF神经元在CEA中的激活，以及NAC，也可能有助于加强积极的奖励动机，而无需诱导任何厌恶状态5,6,7。如果是这样，这将有助于解释为什么压力在恢复时继续沉淀复发瘾君子即使戒断症状消失了。我的飞行员证据表明，只有BNST中的CRF神经元激活时会导致传统的厌恶状态。目前的提议旨在调查令人惊讶的 CRF神经元在CEA和NAC中的积极激励动机作用，使用选择性光遗传学工具来特异性地通过CRE靶向的光遗传学通道Ropopsin来特异性激活CRH-CRE大鼠中表达CRF的神经元。 NAC和CEA中CRF神经元刺激的预测的积极激励动机效应将是与BNST中CRF-Neuron刺激的预测负面厌恶作用相比。动机效应在这些结构中也将检查抑制CRF神经元的抑制。激励动机放大将是使用CRF神经元的激光自刺激和操作员2选择任务获得感官奖励的测量，哪些模型狭义地集中了强烈的追求，类似于成瘾8,9。在此选择任务中，老鼠赚了一个蔗糖奖励或静脉毒品奖励：两种奖励选择之一总是会获得激光伴随的奖励这可以调节CRF神经元活动，而另一种选择仅会获得奖励。最后，分布式神经通过刺激CRF神经元介导的CEA或NAC位点激励动机或通过测量其他遥远的FOS表达，将对BNST站点的厌恶动机进行映射和比较将使用光遗传学工具检查大脑结构和特定因果预测。通过拟议的培训，我将学习新技术，包括静脉药自我管理程序和行为经济学分析以及CRF神经元所需的高级光遗传学和免疫组织化学技术成像和道追踪，用于映射解剖激活模式。这项培训将帮助我发展成为一名富有成效的独立研究科学家。结果还可能提供了解临床的见解 CEA，NAC和BNST的CRF神经元电路在激励动机中与厌恶动机，相关的角色 CRF神经元在成瘾和复发中的应力激活的作用。