Dynamic control of cue-driven behavior via the paraventricular thalamic nucleus

 描述(由申请者提供)：与奖励相关的环境中的刺激(线索)可以激发正常的行为，使一个人更接近有价值的资源(即食物、水、配偶)；但它们也可能获得对行为的过度控制，就像上瘾一样。奖励线索激发正常和不适应行为的能力是通过巴甫洛夫式的学习过程实现的。因此，当一个离散的线索与奖励的呈现反复配对时，它可以获得作为预测的能力，但也可以获得激励动机属性。例如，在成瘾者中，以前与吸毒经历有关的线索获得了维持吸毒行为和煽动复发的能力，即使有强烈的戒毒愿望。我们最近发现，在老鼠身上，食物线索被归因于巴甫洛夫激励激励价值(“激励突显”)的程度存在相当大的个体差异，这种差异预测了它们以后寻求药物的热情和复发的倾向。使用巴甫洛夫条件反射范式，老鼠可以被归类为符号追踪者--那些将激励的显著程度归因于奖励线索的老鼠，或目标追踪者--那些只为奖励线索赋予预测值的老鼠。因此，这个动物模型允许我们从与奖励相关的线索的预测性属性中解析动机，并阐明这些不同形式的线索-奖励学习背后的神经电路。在拟议的研究中，我们将利用一个独特的不同种类的老鼠种群，利用这种将激励显著归因于奖励线索的倾向的自然变化。此外，我们将使用一种新的分子遗传学方法，使用病毒载体来表达工程化的人工受体(称为DREADD受体)，以检查特定大脑回路的瞬时调节活动将如何改变 标志跟踪或目标跟踪。具体地说，拟议的研究重点是丘脑室旁核(PVT)的传入系统，这是一个在成瘾文献中得到越来越多关注的地方，最近被证明在手势与目标跟踪行为中发挥作用。我们将验证这样一种假设，即依赖于多巴胺的手势跟踪行为是通过皮质下过程介导的，包括从腹侧被盖区(VTA)到PVT的多巴胺能投射；而目标跟踪行为是通过PVT的皮质“自上而下”传入调节的，这种行为不依赖于多巴胺。我们还将研究在信号跟踪者和目标跟踪者中，这些特定回路中活动的改变将如何影响食物和药物线索诱导的整个大脑的神经元活动模式。这项工作将有助于更好地理解在成瘾等精神病理中出错的神经机制，并有可能导致新的治疗干预措施。

 DESCRIPTION (provided by applicant): Stimuli (cues) in the environment associated with reward can motivate normal behavior, bringing one in close proximity to valuable resources (i.e. food, water, mates); but they can also gain inordinate control over behavior, as is the case with addiction. The ability of reward cues to motivate both normal and maladaptive behavior occurs through Pavlovian learning processes. Thus, when a discrete cue is repeatedly paired with presentation of a reward, it can acquire the ability to act as a predictor, but can also acquire incentive motivational properties. For example, in addicts, cues that have been previously associated with the drug- taking experience acquire the ability to maintain drug-seeking behavior and instigate relapse, even when there is a strong desire to stop use. We have recently discovered that in rats there is considerable individual variation in the extent to which food cues are attributed with Pavlovian incentive motivational value ("incentive salience") and this variation predicts how avidly they will later seek drugs and the propensity to relapse. Using a Pavlovian conditioning paradigm, rats can be classified as sign-trackers-those that attribute incentive salience to reward cues, or goal-trackers-those that assign only predictive value to reward cues. Thus, this animal model allows us to parse the incentive from the predictive properties of reward-associated cues and to elucidate the neural circuitry underlying these distinct forms of cue-reward learning. In the proposed studies we will exploit this natural variation in the propensity to attribute incentive salience to reward cues, using a uniquely heterogeneous population of rats. Further, we will use a novel molecular-genetic approach that uses viral vectors to express engineered artificial receptors (known as DREADD receptors), to examine how transiently modulating activity of specific brain circuits will alter the propensity to sign-track or goal-track. Specifically, the proposed studies focus on afferent systems to the paraventricular nucleus of the thalamus (PVT), a site that has gained increasing attention in the addiction literature, and has recently been shown to play a role in sign- vs. goal-tracking behavior. We will test the hypothesis that sign-tracking behavior, which is dopamine dependent, is mediated via subcortical processes including dopaminergic projections from the ventral tegmental area (VTA) to the PVT; and that goal-tracking behavior, which is dopamine-independent, is mediated via cortical "top-down" afferents to the PVT. We will also examine how altering activity in these specific circuits will affect patterns of food- and drug-cue-induced neuronal activity throughout the brain in sign- trackers vs. goal-trackers. This work will lead to better understanding of the neural mechanisms that go awry in psychopathologies like addiction, and has the potential to lead to novel therapeutic interventions.