Neural Mechanism by which Punishment Modulates Drug-Seeking

描述（由申请人提供）：成瘾行为的定义特征之一是其持续性，尽管可能会产生严重的不良后果。为了进一步理解为什么成瘾者无法从负面结果中学习，我们建议探索一个新发现的大脑区域的作用，即吻内侧被盖核（RMTg），我们和其他人最近已经证明它编码负面奖励预测错误，并在各种厌恶性行为中发挥重要作用。 行为。我们假设，这种结构的损伤导致成瘾表型，其中动物持续寻求结果，尽管令人厌恶的结果。我们提出了两个目标，其中第一个是为了更好地了解RMTg有助于学习负面结果的基本机制。我们的第二个目标是更多的翻译，探索RMTg在惩罚下寻求可卡因的作用，以及它对成瘾行为倾向的个体差异的贡献。 公共卫生相关性：成瘾行为的一个标志是，尽管会产生巨大的负面后果，但它仍会持续存在，这些后果可以采取多种形式，包括身体上的厌恶性后果（戒断、毒性）或社会、认知和经济损失。为了更好地理解这些行为背后的病理学，我们将探讨我们最近发现的机制，即头内侧被盖核（RMTg）的病变使动物在学习厌恶结果方面明显不足。这将有助于更好地治疗行为 尽管花费巨大，但个体仍寻求药物奖励的疾病。

DESCRIPTION (provided by applicant): One of the defining features of addictive behavior is its persistence despite potentially severe adverse outcomes. To further understand why addicts fail to learn from negative outcomes, we propose to explore the role of a newly identified brain region, the rostromedial tegmental nucleus (RMTg), which we and others have recently shown to encode negative reward prediction errors, and to be critically involved in a variety of aversive behaviors. We hypothesize that impairment of this structure leads to an addiction phenotype in which animals persistently seek outcomes despite aversive outcomes. We propose two aims, the first of which is designed to better understand the basic mechanisms by which the RMTg contributes to learning about negative outcomes. Our second aim is more translational, exploring the role of the RMTg in cocaine-seeking under punishment, as well as its contribution to individual variation in propensity to develop addictive behaviors. PUBLIC HEALTH RELEVANCE: One hallmark of an addictive behavior is its persistence despite large negative outcomes, which can take a variety of forms, include physically aversive outcomes (withdrawal, toxicity) or social, cognitive, and financial losses. To better understand the pathology underlying these behaviors, we will explore the mechanisms underlying our recent findings that lesions of the rostromedial tegmental nucleus (RMTg) render animals strikingly deficient in learning from aversive outcomes. This will facilitate better treatments for behavioral disorders in which individuals seek drug rewards despite the large costs they incur.