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

通过室旁丘脑核动态控制提示驱动行为

• 批准号: 9021633
• 负责人: Shelly Beth Flagel
• 金额: $ 52.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021633
• 关键词: Affect; Afferent Neurons; Animal Model; Attention; Attenuated; Behavior; Behavior Control; Brain; Brain region; Cocaine; Corpus striatum structure; Coupled; Cues; Disease; Dopamine; Drug Receptors; Engineering; Environment; Excision; Exhibits; Exposure to; FOS gene; Food; Food Patterns; Functional disorder; GTP-Binding Proteins; Goals; Health; Hyperphagia; Incentives; Individual; Individual Differences; Lead; Learning; Lesion; Literature; Location; Mediating; Messenger RNA; Methodology; Molecular Genetics; Motor; Neurobiology; Neurons; Partner in relationship; Pathological Gambling; Pharmaceutical Preparations; Play; Population; Population Heterogeneity; Positioning Attribute; Predictive Value; Procedures; Process; Property; Psychopathology; Rattus; Relapse; Resources; Rewards; Role; Site; Stimulus; Structure; Structure of paraventricular nucleus of thalamus; Substance abuse problem; System; Techniques; Testing; Thalamic structure; Variant; Ventral Tegmental Area; Viral Vector; Water; Work; addiction; classical conditioning; combinatorial; designer receptors exclusively activated by designer drugs; driving behavior; drug seeking behavior; experience; genetic approach; incentive salience; motivated behavior; neural circuit; neuromechanism; new therapeutic target; novel; novel therapeutic intervention; psychologic; receptor; reinforcer; response; selective expression

 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.

 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，使人接近有价值的资源（即食物、水、伴侣），但他们也可以获得对行为的过度控制，例如奖励线索激发正常行为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，当离散线索与奖励的呈现重复配对时，它可以获得行动的能力。作为预测因素，但也可以诱导获得动机特性，例如，对于成瘾者来说，先前与吸毒经历相关的线索获得了维持吸毒行为并引发复发的能力，即使有强烈的欲望。我们最近发现，在老鼠中，食物线索与巴甫洛夫激励动机价值（“激励显着性”）的关联程度存在相当大的个体差异，这种差异可以预测它们随后会多么热衷于寻求药物和药物。使用巴甫洛夫条件反射范式，大鼠可以被分类为信号追踪者（将激励显着性归因于奖励线索）或目标追踪者（仅将预测价值赋予奖励线索）。从与奖励相关的线索的预测特性中解析激励，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，我们将利用归因于激励的倾向的这种自然变化。此外，我们将使用一种新颖的分子遗传学方法，利用病毒载体表达工程人工受体（称为 DREADD 受体），以研究如何瞬时调节特定大脑回路的活动。会改变倾向 具体来说，拟议的研究重点是丘脑室旁核（PVT）的传入系统，该部位在成瘾文献中受到越来越多的关注，并且最近被证明在成瘾中发挥着作用。我们将检验这样的假设：信号跟踪行为是多巴胺依赖性的，是通过皮层下过程介导的，包括来自腹侧被盖区（VTA）的多巴胺能投射。与多巴胺无关的目标跟踪行为是通过皮质“自上而下”传入 PVT 来调节的，我们还将研究改变这些特定回路的活动将如何影响食物和药物的模式。 -信号追踪器与目标追踪器中提示引起的整个大脑的神经活动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，并有可能带来新的治疗方法。干预措施。