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

基本信息

批准号：
10434844
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434844
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 Coping Skills 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 antagonist aversive conditioning avoidance behavior base classical conditioning compulsion conditioned fear conditioning 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

项目摘要

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.

项目摘要/摘要尽管有大量工作，但焦虑症中强迫行为的神经基础，尤其是成瘾仍然很少了解。近年来，在理解药物作为积极的激励和奖励的动机作用。虽然长期以来已经知道这种反感动机在成瘾中也起着作用，这是不清楚的。外部刺激环境压力或戒断药物是负面的增强剂，有助于寻求工具性药物通过加强允许逃脱和/或避免的行为来进行消费反应这些刺激引起的厌恶状态。因为主动回避条件基于负面加强并涉及与成瘾重叠的大脑电路，我们认为对逃避/回避行为的神经基础将提供重要的信息，从而可以更深入地了解厌恶状态在滥用药物中的作用。虽然对在1950年代和60年代回避的神经基础，这项工作不受欢迎，部分原因是结果没有导致对电路的清晰了解。但是，在随后的几年中，第一个的神经基础避免的阶段，详细阐明了巴夫洛夫恐惧调节。这个信息使它成为可以重新审视新的避免神经基础。特别是，鉴于我们现在了解详细介绍与厌恶相关的中性环境刺激的神经机制无条件的刺激（US）成为一种可以引起厌恶状态的刺激性刺激（CS），我们现在可以基于此信息来了解回避条件的神经基础。尤其是如果使用与CSS和USS（音调和冲击）相同的刺激来揭示神经机制帕夫洛夫调节也用于回避条件。先前资助的赠款检查了杏仁核的贡献，杏仁核是避免帕夫洛维亚厌恶条件的关键结构。在此提案中我们继续扮演杏仁核的角色，但此外还开始剖析更广泛的电路涉及。具体而言，我们检查了杏仁核和核的亚地区之间的连接作用伏尊徒在从帕夫洛维亚的条件反应过渡到负强化的回避行动中。光遗传学技术将用于将特定杏仁核途径中的活性与离散阶段联系起来回避学习和行为，包括精确的负面强化事件（即CS终止，美国遗漏或两者兼而有之。最后，因为伏隔核内源性大麻素信号传导的功能障碍可能会促进负强化和强迫，我们将使用生物化学，药理学和受体敲低检查内源性大麻素信号对否定反应反应的贡献。