Brain Mechanisms of Avoidance: Implications for Addiction and Anxiety

项目摘要/摘要 尽管有大量的工作，但焦虑中强迫行为的神经基础，尤其是 对上瘾的了解仍然很少。近几年来，在理解 药物的激励作用是积极的激励和奖励。尽管人们很早就知道，厌恶 动机在上瘾中也起到了作用，但这一点还不太清楚。与以下因素相关的外部刺激 环境压力或戒毒是促进工具性药物寻求的负面强化因素 和消费反应，通过加强允许逃避和/或避免 由这些刺激引起的厌恶状态。因为主动回避训练是建立在消极的基础上 强化和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，可能允许更深层次的 对厌恶状态在物质滥用中的作用的理解。虽然许多研究都是关于 神经基础上的回避在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 使您对电路有一个清晰的了解。然而，在其间的几年里，第一个 回避阶段，巴甫洛夫恐惧条件作用，已被详细阐明。这些信息使它 有可能从新的角度重新审视回避的神经基础。特别是，鉴于我们现在理解在 详细说明中性环境刺激与厌恶情绪相关的神经机制 无条件刺激(US)变成了巴甫洛夫条件刺激(CS)，它会引起厌恶状态，我们 现在可以在这些信息的基础上理解回避条件反射的神经基础。这是特别的 如果使用与CSS和USS相同的刺激(音调和电击)来揭示 巴甫洛夫条件反射也用于回避条件反射。先前资助的赠款审查了 巴甫洛夫厌恶条件反射的关键结构--杏仁核对回避的贡献。在本建议书中 我们继续追求杏仁核的作用，但也开始解剖更广泛的回路 牵涉其中。具体地说，我们研究了杏仁核子区域和核之间的联系所起的作用。 在从巴甫洛夫条件性反应到负强化的回避作用的过渡过程中。 光遗传技术将用于将特定杏仁纹状体通路中的活动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，US- 遗漏或两者兼而有之)。最后，由于伏核功能障碍，内源性大麻素信号可能促进 负强化和强迫，我们将使用生物化学、药理学和受体击倒来 研究内源性大麻素信号对负面强化的回避反应的贡献。

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.