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

 描述（由申请人提供）：与奖励相关的环境中的刺激（线索）可以激发正常行为，使一个人接近有价值的资源（即食物，水，配偶）;但它们也可以获得对行为的过度控制，就像成瘾一样。奖励线索激发正常和适应不良行为的能力是通过巴甫洛夫学习过程发生的。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器的能力，但也可以获得激励动机的属性。例如，在成瘾者中，先前与吸毒经历相关的线索获得了维持寻求药物行为和煽动复吸的能力，即使有强烈的停止使用的愿望。我们最近发现，在大鼠中，食物线索与巴甫洛夫激励激励价值（“激励显著性”）的关系在多大程度上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渴望程度和复发倾向。使用巴甫洛夫条件反射范式，大鼠可以被归类为符号追踪者-那些将激励显着性归因于奖励线索的人，或目标追踪者-那些只为奖励线索分配预测值的人。因此，这种动物模型使我们能够从奖励相关线索的预测特性中解析出激励，并阐明这些不同形式的线索奖励学习背后的神经回路。在拟议的研究中，我们将利用这种自然变化的倾向，属性激励显着性奖励线索，使用一个独特的异质种群的大鼠。此外，我们将使用一种新的分子遗传学方法，该方法使用病毒载体来表达工程化的人工受体（称为DREADD受体），以研究如何瞬时调节特定脑回路的活动将改变 信号跟踪或目标跟踪。具体来说，拟议的研究集中在丘脑室旁核（PVT）的传入系统，该部位在成瘾文献中获得了越来越多的关注，最近已被证明在符号与目标跟踪行为中发挥作用。我们将检验这一假设，即标记追踪行为，这是多巴胺依赖性的，是通过皮层下过程介导的，包括从腹侧被盖区（VTA）到PVT的多巴胺能投射;而这种目标追踪行为，不依赖于多巴胺，是通过皮层“自上而下”传入到室旁核。我们还将研究如何改变这些特定回路的活动将影响食物和药物的模式，在符号追踪者和目标追踪者中，线索诱导的神经元活动贯穿整个大脑。这项工作将有助于更好地理解成瘾等精神病理学中出错的神经机制，并有可能导致新的治疗干预。

 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.