The Role of the Paraventricular Thalamus in Incentive Salience Attribution

描述（由申请人提供）：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部分人上瘾。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，而且高复发倾向使其成为一个难以治疗的问题。使一些人更容易复发的一个因素是环境中的线索可以对行为施加过度控制的程度。例如，先前与吸毒行为有关的线索（即注射器、管子等）的呈现已被证明会引发人类成瘾者的药物渴望感，从而导致寻求药物的行为和复发。这种现象部分是由巴甫洛夫学习过程介导的。然而，事实证明，这些过程背后的神经生物学原理很难理解，因为它们是复杂情绪和动机状态的结果。最近，弗拉格尔博士及其同事开发了一种动物模型，该模型捕捉到了个体倾向于将激励动机价值归因于奖励线索的差异，从而使我们能够梳理出潜在的神经生物学机制。在这个模型中，将动机价值归因于提示的大鼠表现出了符号跟踪行为，这可以通过它们的方法和与提示的互动来证明。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器，在它的呈现后，这些动物会去目标或奖励传递的位置。先前的研究表明，对奖励相关线索表现出信号跟踪行为的大鼠在自我给药行为消失后更容易复发。研究还表明，多巴胺能系统的差异，以及其他通常不被认为是经典奖赏回路一部分的系统，是信号和目标跟踪行为的基础。在信号追踪者和目标追踪者对线索的反应中，有一个大脑区域显示出神经元活动的显著差异，那就是丘脑室旁核（PVT），这个区域最近在临床前成瘾文献中得到了关注。有趣的是，这个位置很好地充当了大脑边缘、运动和皮层区域之间的接口，使其成为与手势和目标跟踪行为相关的研究的一个引人注目的目标。目前的建议旨在揭示PVT和相关电路在符号和目标跟踪行为中的作用。逆行标记结合免疫组织化学将用于识别PVT回路中对线索呈现的神经元活性差异。此外,

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.