The Role of the Paraventricular Thalamus in Incentive Salience Attribution

描述(申请人提供)：许多人在他们的一生中尝试滥用药物，但只有相对较小的一小部分人会上瘾。尽管如此，吸毒成瘾是一个突出的健康问题，每年给美国造成超过6000亿美元的损失，而且吸毒成瘾的高复发率使其成为一个难以治疗的问题。让一些人更容易复发的一个因素是，环境中的暗示可以在多大程度上断言对行为的过度控制。例如，提示的呈现(例如，注射器、管子等)以前与吸毒行为有关的研究表明，在人类吸毒者中会触发对毒品的渴望，这会导致寻求毒品的行为和复发。这种现象在一定程度上是由巴甫洛夫式的学习过程所调节的。然而，事实证明，这些过程背后的神经生物学很难理解，因为它们是复杂的情绪和动机状态的结果。最近，弗拉格尔博士和他的同事开发了一种动物模型，该模型捕捉了将激励动机价值归因于奖励线索的倾向的个体差异，从而允许我们梳理潜在的神经生物学机制。在这个模型中，将激励价值归因于线索的大鼠表现出手势跟踪行为，这从它们的方法和与线索的互动中得到了证明。对于其他被称为目标追踪者的动物来说，线索只是作为奖励可用性的预测因子，当它呈现时，这些动物就会去目标或奖励交付的位置。先前的工作表明，在药物自我给药行为消失后，对奖赏相关线索做出反应而表现出符号跟踪行为的大鼠有更大的复发倾向。研究还表明，多巴胺能系统以及通常不被认为是经典奖赏回路一部分的其他系统的差异，是手势和目标跟踪行为的基础。手势跟踪者和目标追踪者对线索呈现的反应在神经元活动方面显示出显著差异的一个大脑区域是丘脑室旁核(PVT)，这一区域最近在临床前成瘾文献中得到了关注。有趣的是，这个站点的位置很好，可以作为大脑边缘、运动和皮质区域之间的接口，使其成为与手势和目标跟踪行为相关的引人注目的研究目标。目前的提案旨在揭示PVT及其相关电路在手势和目标跟踪行为中所起的作用。逆行标记结合免疫组织化学将被用来识别PVT回路中线索呈现时神经元活动的差异。此外, 将使用局部药物操作来评估PVT谷氨酸、多巴胺和食欲素传递在手势和目标跟踪行为中的作用。这些研究将促进我们对神经生物学过程的了解，这些神经生物学过程是将激励动机价值归因于奖励配对线索的基础，这种行为特征与复发和成瘾的易感性有关。

DESCRIPTION (provided by applicant): Many individuals experiment with drugs of abuse over their lifetime, but only a relatively small subset become addicted. Nonetheless, drug addiction is a prominent health concern, costing the United States over $600 billion annually, and the high propensity to relapse makes it an incredibly difficult problem to treat. One factor that makes some individuals more susceptible to relapse is the degree to which cues in the environment can assert inordinate control over behavior. For example, presentation of cues (i.e. syringes, pipes, etc.) previously associated with drug-taking behavior has been shown to trigger feelings of drug craving in human addicts, which leads to drug-seeking behavior and relapse. This phenomenon is mediated in part by Pavlovian-learning processes. However, the neurobiology underlying these processes has proven difficult to understand since they are a result of complex emotional and motivational states. Recently, an animal model has been developed by Dr. Flagel and colleagues that captures the individual variation in the propensity to attribute incentive motivational value to reward cues and thereby allows us to tease apart the underlying neurobiological mechanisms. In this model, rats that ascribe motivational value to a cue demonstrate sign-tracking behavior, as evidenced by their approach and interaction with the cue. For others, known as goal-trackers, the cue simply serves as a predictor for reward availability, and upon its presentation these animals go to the goal, or location of reward delivery. Previous work has shown that rats who demonstrate sign-tracking behavior in response to reward-associated cues have a greater tendency to relapse following extinction of drug self- administration behavior. It has also been shown that differences in the dopaminergic system, as well as other systems not normally considered part of the classic reward circuitry, underlie sign- and goal-tracking behaviors. One brain area that has shown robust differences in neuronal activity in response to cue-presentation between sign- and goal-trackers is the paraventricular nucleus of the thalamus (PVT), a region that has recently gained attention in the pre-clinical addiction literature. Interestingly, this site is well-positioned to act as an interfae between limbic, motor and cortical areas of the brain, making it a compelling target of investigation in relation to sign- and goal-tracking behaviors. The current proposal aims to uncover the role the PVT and associated circuitry plays in sign- and goal-tracking behavior. Retrograde labeling in combination with immunohistochemistry will be used to identify differences in neuronal activity in response to cue presentation in the PVT circuitry. In addition, local pharmacological manipulations will be used to assess the role of PVT glutamate, dopamine, and orexin transmission in sign- and goal-tracking behavior. These studies will advance our knowledge of the neurobiological processes that underlie the attribution of incentive motivational value to reward-paired cues, a behavioral trait that has been linked to susceptibility to relapse and addiction.