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它的持久性，尽管有潜在的严重不良后果。为了进一步了解为什么瘾君子不能从负面结果中学习，我们建议探索一个新发现的大脑区域，即被盖旋转内侧核(RMTg)的作用，我们和其他人最近发现，它编码负向奖励预测错误，并与各种厌恶行为密切相关。 行为。我们假设，这种结构的损伤会导致一种成瘾表型，在这种表型中，动物总是寻求结果，尽管结果令人厌恶。我们提出了两个目标，第一个目标是更好地理解RMTG帮助学习负面结果的基本机制。我们的第二个目标是更具翻译性，探索RMTG在惩罚下的可卡因寻找中的作用，以及它对个体发展成瘾行为倾向的差异的贡献。 与公共健康相关：上瘾行为的一个特点是，尽管有大量的负面后果，但它仍然存在，这可以采取各种形式，包括身体上令人厌恶的结果(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，我们将探索我们最近发现的机制，即旋转内侧被盖核(RMTg)的损伤使动物在从厌恶结果中学习方面存在显著缺陷。这将有助于更好地治疗行为 个人寻求药物奖励的障碍，尽管它们招致了巨大的成本。

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.