Brain Mechanisms of Avoidance: Implications for Addiction and Anxiety

回避的大脑机制：对成瘾和焦虑的影响

• 批准号: 10197073
• 负责人: JOSEPH E LEDOUX
• 金额: $ 49.26万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197073
• 关键词: Amygdaloid structure; Anatomy; Anxiety; Anxiety Disorders; Area; Avoidance Learning; Axon; Behavior; Behavioral; Biochemistry; Biological; Brain; CNR1 gene; Compulsive Behavior; Conditioned Stimulus; Consumption; Data; Desire for food; Development; Distress; Drug abuse; Drug usage; Emotional; Endocannabinoids; Event; Extinction (Psychology); Fiber; Functional disorder; Funding; Goals; Grant; Impairment; Incentives; Interneurons; Learning; Lesion; Light; Mediating; Memory; Motivation; Negative Reinforcements; Negative Reinforcer; Neural Pathways; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Obsessive-Compulsive Disorder; Operant Conditioning; Pain; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Play; Positive Reinforcements; Process; Publishing; RNA Interference; Rattus; Reaction; Receptor Activation; Receptor Signaling; Research; Research Personnel; Rewards; Role; Shock; Signal Transduction; Specificity; Stimulus; Stress; Structure; Substance abuse problem; Techniques; Testing; Training; Viral; Withdrawal Symptom; Work; addiction; aversive conditioning; avoidance behavior; base; classical conditioning; compulsion; conditioned fear; conditioning; coping; disorder control; drug reward; drug withdrawal; dysphoria; effective therapy; endocannabinoid signaling; knock-down; learned behavior; neuromechanism; optogenetics; prevent; receptor; reinforced behavior; relating to nervous system; repetitive behavior; response; small hairpin RNA

Project Summary/Abstract In spite of massive amounts of work, the neural basis of compulsive behavior in anxiety and especially addiction remains poorly understood. Much progress has been made in recent years in understanding the motivational role of drugs as positive incentives and rewards. Although it has long been known that aversive motivation also plays a role in addiction, this is less clearly understood. External stimuli associated with environmental stress or drug withdrawal are negative reinforcers that contribute to instrumental drug seeking and consumption responses by strengthening behaviors that allow escape from and/or avoidance of the aversive states elicited by these stimuli. Because active avoidance conditioning is based on negative reinforcement and involves brain circuits that overlap with addiction, we argue that a detailed understanding of the neural basis of escape/avoidance behavior will provide important information that may allow a deeper understanding of the role of aversive states in substance abuse. While much research was conducted on the neural basis on avoidance in the 1950s and 60s, this work fell out of favor, in part because the results did not lead to a clear understanding of the circuitry. However, in the intervening years, the neural basis of the first phase of avoidance, Pavlovian fear conditioning, has been elucidated in detail. This information makes it possible to revisit the neural basis of avoidance in a new light. In particular, given that we now understand in detail the neural mechanisms through which a neutral environmental stimulus associated with an aversive unconditioned stimulus (US) becomes a Pavlovian conditioned stimulus (CS) that elicits aversive states, we can now build on this information to understand the neural basis of avoidance conditioning. This is especially true if the same stimuli used as CSs and USs (tone and shock) are used to reveal the neural mechanisms of Pavlovian conditioning are also used in avoidance conditioning. The previously funded grant examined the contribution of the amygdala, a key structure for Pavlovian aversive conditioning, to avoidance. In this proposal we continue to pursue the role of the amygdala, but in addition also begin to dissect the broader circuitry involved. Specifically, we examine the role of connections between the subareas of the amygdala and nucleus accumbens, in the transition from Pavlovian conditioned reactions to negatively reinforced avoidant actions. Optogenetic techniques will be used to relate activity in specific amygdalostriatal pathways to discrete stages of avoidance learning and behavior, including precise negative reinforcement events (i.e. CS-termination, US- omission or both). Lastly, because dysfunction in nucleus accumbens endocannabinoid signaling may promote negative reinforcement and compulsions, we will use biochemistry, pharmacology and receptor knockdowns to examine the contribution that endocannabinoid signaling makes to negatively-reinforced avoidance responses.

项目总结/摘要 尽管做了大量的工作，但焦虑症中强迫行为的神经基础， 人们对成瘾仍然知之甚少。近年来，在理解 药物作为积极激励和奖励的激励作用。尽管人们早就知道厌恶 动机也在成瘾中起作用，但这一点还不太清楚。外部刺激与 环境压力或药物戒断是导致工具性药物寻求的负性因素 和消费反应，通过加强行为，允许逃避和/或避免 由这些刺激引起的厌恶状态。因为主动回避条件反射是基于消极的 强化，并涉及与成瘾重叠的大脑回路，我们认为，详细了解 逃避/回避行为的神经基础将提供重要的信息， 了解厌恶状态在药物滥用中的作用。虽然有很多研究是关于 在20世纪50年代和60年代，这项工作失宠，部分原因是结果没有 从而对电路有一个清晰的了解。然而，在这期间的几年里，第一次的神经基础 回避阶段，巴甫洛夫恐惧条件反射，已被详细阐明。这些信息使得 我们有可能以新的视角重新审视回避的神经基础。特别是，鉴于我们现在了解到， 详细的神经机制，通过中性环境刺激与厌恶相关 无条件刺激（US）变成了巴甫洛夫条件刺激（CS）， 现在可以在此基础上了解回避条件反射的神经基础。这是特别 如果使用与CS和US（音调和电击）相同的刺激来揭示 巴甫洛夫条件反射也用于回避条件反射。以前资助的赠款审查了 杏仁核是巴甫洛夫厌恶性条件反射的关键结构，对回避的作用。本提案中 我们继续研究杏仁核的作用，但除此之外，我们也开始解剖更广泛的神经回路。 涉案具体来说，我们研究的作用，杏仁核和核的亚区之间的连接 巴甫洛夫条件反应向消极强化回避行为的转变。 光遗传学技术将被用来关联活动在特定的杏仁核纹状体通路的离散阶段 回避学习和行为，包括精确的负强化事件（即CS-终止，US- 省略或两者）。最后，由于延髓核内源性大麻素信号传导功能障碍， 负强化和强迫，我们将使用生物化学，药理学和受体敲除， 研究内源性大麻素信号对负强化回避反应的贡献。