The Role of the Paraventricular Thalamus in Incentive Salience Attribution

描述（由申请人提供）：许多人在一生中尝试滥用药物，但只有相对较小的子集成瘾。尽管如此，药物成瘾仍然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，而且复发的高倾向性使其成为一个非常难以治疗的问题。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进行过度控制的程度。例如，提示（即注射器、管道等）的呈现先前与吸毒行为相关的药物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，这些过程背后的神经生物学已经被证明是难以理解的，因为它们是复杂的情绪和动机状态的结果。最近，Flagel博士及其同事开发了一种动物模型，该模型捕捉了个体将激励价值归因于奖励线索的倾向的差异，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，大鼠归因于动机价值的线索表现出迹象跟踪行为，证明了他们的方法和互动的线索。对于另一些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，一旦出现，这些动物就会前往目标或奖励交付的位置。先前的工作已经表明，响应于奖励相关线索而表现出符号追踪行为的大鼠在药物自我给药行为消失后具有更大的复发倾向。研究还表明，多巴胺能系统以及其他通常不被认为是经典奖励回路一部分的系统的差异，是标志追踪和目标追踪行为的基础。一个大脑区域已经显示出强烈的神经元活动差异，以响应信号和目标追踪器之间的线索呈现，这是丘脑室旁核（PVT），最近在临床前成瘾文献中获得了关注。有趣的是，这个位置很好地充当了大脑边缘系统、运动和皮质区域之间的接口，使其成为与符号和目标跟踪行为有关的引人注目的研究目标。目前的建议旨在揭示PVT和相关电路在标志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神经元活动的差异，以响应PVT电路中的线索呈现。此外，本发明还提供了一种方法， 局部药理学操作将用于评估PVT谷氨酸盐、多巴胺和食欲素传递在信号和目标追踪行为中的作用。这些研究将推进我们对神经生物学过程的认识，这些神经生物学过程是将激励价值归因于奖励配对线索的基础，奖励配对线索是一种与复发和成瘾易感性有关的行为特征。

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.