Establishing a link between habits and punishment resistance

项目摘要 成瘾的定义特征是一种无法控制的使用药物的冲动，尽管有负面影响。 序列（即，惩罚）。吸毒成瘾的人发现很难遏制寻求毒品的行为，即使他们 导致有害后果，表明这些行为是抗拒惩罚的。类似类型的 在最近的成瘾动物模型中观察到了惩罚抵抗， 在受到脚震的情况下自行注射可卡因该领域的一个流行观点是， 是由于未能对习惯进行目标导向的控制。然而，这个账户的一个主要差距是， 缺乏经验证据支持这一观点。虽然目标导向行为和习惯行为被认为是中介的， 背内侧纹状体和背外侧纹状体的独立神经系统， 关于惩罚如何影响由这些系统引导的既定行为。没有一个明确的认识 是什么驱使成瘾者抗拒惩罚，成功的治疗策略的发展将继续下去。 被阻碍。这个项目的总体目标是建立习惯性反应和双关语之间的联系， 大鼠自我给药模型中的耐受性。核心假设是，惩罚抵抗源于 由于皮质神经元的募集减少， 和丘脑向背内侧纹状体的输入。该项目的具体目标是：确定习惯性的作用， 在惩罚抵抗中的反应，识别参与惩罚抵抗和感觉的纹状体成分， 性，并确定输入纹状体介导的反应，惩罚。这些目标将被调查 使用系统水平的方法，涉及成瘾的预防性相关动物模型，光遗传学 工具，以及一种新的结果贬值程序，开发用于评估可卡因的习惯性反应。 这些研究将为该领域常用的理论框架提供重要的新证据， 提供关键的洞察力的行为过程和神经生物学机制的强迫性药物使用 尽管有负面后果。

PROJECT SUMMARY The defining characteristic of addiction is an uncontrollable urge to use drugs despite negative conse- quences (i.e., punishment). Addicted individuals find it difficult to curb drug-seeking behaviors even when they lead to harmful consequences, indicating that these behaviors are resistant to punishment. A similar type of punishment resistance has been observed in recent animal models of addiction, with a subset of rats continuing to self-administer cocaine despite receiving footshock. A prevailing view in the field is that punishment resistance arises from failure to exert goal-directed control over habits. However, a major gap in this account is that there is a lack of empirical evidence to support it. While goal-directed and habitual behaviors are known to be mediated by separate neural systems in dorsomedial striatum and dorsolateral striatum, respectively, much less is known about how punishment affects well-established behavior guided by these systems. Without a clear understanding of what drives punishment resistance in addiction, development of successful treatment strategies will continue to be hindered. The overall objective of this project is to establish a link between habitual responding and pun- ishment resistance in a rat self-administration model. The central hypothesis is that punishment resistance stems from a failure to switch from habitual responding to goal-directed control, due to reduced recruitment of cortical and thalamic inputs to dorsomedial striatum. The specific aims of this project are to: determine the role of habitual responding in punishment resistance, identify striatal components involved in punishment resistance and sensi- tivity, and identify inputs to striatum that mediate the response to punishment. These aims will be investigated using a systems-level approach that involves translationally-relevant animal models of addiction, optogenetic tools, and a novel outcome devaluation procedure that was developed to assess habitual responding for cocaine. These studies will provide critical new evidence for the theoretical framework commonly used by the field, and provide key insights into the behavioral processes and neurobiological mechanisms of compulsive drug use despite negative consequences.