Probing the role of a hypothalamic-thalamic-striatal circuit in cue-driven behaviors

探讨下丘脑-丘脑-纹状体回路在线索驱动行为中的作用

• 批准号: 10669235
• 负责人: Shelly Beth Flagel
• 金额: $ 52.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669235
• 关键词: Abstinence; Affect; Animal Model; Attenuated; Behavior; Behavior Control; Corpus striatum structure; Cues; Disease; Dopamine; Drug Addiction; Drug user; Engineering; Environment; Equilibrium; Exposure to; Extinction; Food; Functional disorder; Goals; Hypothalamic structure; Incentives; Individual; Individual Differences; Lateral; Learning; Lesion; Mediating; Microdialysis; Molecular Genetics; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Play; Predictive Value; Predisposition; Process; Property; Psychopathology; Rattus; Relapse; Resources; Rewards; Role; Signal Transduction; Stimulus; Structure of paraventricular nucleus of thalamus; Substance abuse problem; Testing; Thalamic structure; Variant; Ventral Tegmental Area; Viral Vector; Work; addiction; addiction liability; cocaine self-administration; designer receptors exclusively activated by designer drugs; drug seeking behavior; experience; experimental study; genetic approach; hypocretin; in vivo; incentive salience; individual variation; interest; maladaptive behavior; motivated behavior; motivational processes; neural; neural circuit; neurochemistry; novel; psychologic; receptor; response; selective expression; vector

PROJECT SUMMARY/ABSTRACT Stimuli (cues) in the environment associated with reward can motivate normal behavior, bringing one in close proximity to valuable resources (e.g. food); but they can also gain inordinate control over behavior, as is the case with addiction. The ability of reward cues to motivate behavior occurs through Pavlovian learning processes. 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. In individuals with addiction, 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. The neurobiological processes by which reward cues gain inordinate control over behavior have proven difficult to discern because cues can simultaneously acquire “predictive” and “incentive” properties, and in most studies these two psychological processes are confounded. In the proposed studies we will exploit natural variation in cue-reward learning to identify the neural circuitry specifically responsible for the attribution of incentive motivational value (incentive salience) to reward cues. When rats are exposed to a Pavlovian conditioned approach paradigm, some, termed “goal-trackers”, attribute predictive value to a discrete food-associated cue; whereas others, termed “sign-trackers” attribute incentive salience to the cue. Relative to goal-trackers, sign-trackers are more susceptible to behavioral control by discrete food- and drug-paired cues and have a greater propensity for cue- induced reinstatement or relapse. Using this animal model, we have found that the paraventricular nucleus of the thalamus (PVT) plays a critical role in incentive learning processes and in regulating individual differences in relapse propensity. The PVT appears to act as a node that integrates “top-down” and “bottom-up” input to regulate cue-driven behaviors, but the subcortical circuitry subserving incentive salience attribution remains to be determined. The central hypothesis to be tested here is that both input to and output from the PVT are necessary and sufficient to promote dopamine-dependent incentive learning. We will use a molecular-genetic approach with viral vectors to selectively express engineered artificial receptors (e.g. DREADD) to determine how transiently altering activity of neurons in select PVT circuits affects the propensity to attribute incentive salience to reward cues. Specifically, we will target inputs to the PVT from the lateral hypothalamus (LH), and outputs from the PVT to the nucleus accumbens shell (NAcSh). We will determine whether the PVT-NAcSh pathway can regulate cue-driven behavior independent of the ventral tegmental area, and how manipulating these subcortical circuits affects neurochemical activity in the NAcSh. In addition, we will determine if the LH- PVT and PVT-NAcSh pathways mediate individual differences in the propensity for cue-induced reinstatement of drug-seeking behavior. This work will identify critical components of the neural circuitry that contribute to addiction liability.

项目概要/摘要 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 接近有价值的资源（例如食物）；但他们也可以获得对行为的过度控制，就像 奖励线索激发行为的能力是通过巴甫洛夫学习发生的。 当离散提示与奖励的呈现重复配对时，它可以获得以下能力： 作为预测因素，但也可以诱导成瘾者获得动机特性。 以前曾与吸毒经历有关 获得维持吸毒的能力 行为并引发复发，即使有强烈的愿望停止使用神经生物学过程。 事实证明，奖励线索通过这种方式获得对行为的过度控制是很难辨别的，因为线索可以 同时获得“预测”和“激励”属性，并且在大多数研究中这两种心理 在拟议的研究中，我们将利用提示奖励学习的自然变化来实现。 识别专门负责激励动机价值（incentive 当老鼠暴露于巴甫洛夫条件方法范式时，一些， 被称为“目标追踪器”，将预测价值归因于与食物相关的离散线索；而其他则被称为“目标追踪器”。 与目标追踪者相比，“符号追踪者”将激励显着性归因于提示。 对离散食物和药物配对线索的行为控制敏感，并且更倾向于线索- 使用该动物模型，我们发现室旁核诱导恢复或复发。 丘脑 (PVT) 在激励学习过程和调节个体差异方面发挥着关键作用 在复发倾向中，PVT 似乎充当了一个整合“自上而下”和“自下而上”输入的节点。 调节线索驱动的行为，但维持激励显着性归因的皮层下电路仍然是 这里要测试的中心假设是 PVT 的输入和输出都是 促进多巴胺依赖性激励学习是必要且充分的，我们将使用分子遗传学。 使用病毒载体选择性表达工程人工受体（例如 DREADD）以确定 短暂改变选定 PVT 回路中神经元的活动如何影响归因激励的倾向 具体来说，我们将针对来自外侧下丘脑 (LH) 的 PVT 输入，以及 从 PVT 到伏隔核壳 (NAcSh) 的输出 我们将确定 PVT-NAcSh 是否存在。 通路可以独立于腹侧被盖区调节线索驱动的行为，以及如何操纵 这些皮层下回路会影响 NAcSh 中的神经化学活动。此外，我们将确定 LH- 是否存在。 PVT 和 PVT-NAcSh 通路介导线索诱导恢复倾向的个体差异 这项工作将确定有助于寻药行为的神经回路的关键组成部分。 责任成瘾。