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: 10272900
• 负责人: Shelly Beth Flagel
• 金额: $ 50.2万
• 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/10272900
• 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 (Psychology); Food; Functional disorder; Goals; Hypothalamic structure; Incentives; Individual; Individual Differences; Lateral; Lead; Learning; Lesion; Mediating; Microdialysis; Molecular Genetics; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Play; Predictive Value; 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; base; 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; motivated behavior; motivational processes; neural circuit; neurochemistry; novel; psychologic; receptor; relating to nervous system; 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.

项目摘要/摘要 与奖励相关的环境中的刺激（提示）可以激发正常行为，使一个人近距离 靠近宝贵的资源（例如食物）；但是他们也可以对行为过分控制， 有成瘾的情况。奖励提示动机行为的能力是通过帕夫洛夫学习发生的 过程。当反复将离散提示与奖励的呈现配对时，它可以获得能力 充当预测因子，但也可以获得激励动机。在成瘾的个人中，提示 以前曾与吸毒经验获得相关联 即使有强烈的停止使用渴望，行为并煽动继电器。神经生物学过程 事实证明，奖励提示对行为的过度控制很难辨别，因为提示可以 类似地获得“预测”和“激励”特性，在大多数研究中，这两个心理 过程混淆。在拟议的研究中，我们将探讨提示回报学习的自然变化 确定专门负责激励动机价值属性（激励）的神经回路 显着性）奖励提示。当大鼠暴露于帕夫洛维亚条件的方法范式时，有些 被称为“目标追踪者”，将预测价值归因于离散食品相关的提示；而其他人称为 “签名轨迹”将激励性显着性归因于提示。相对于目标跟踪器，签名轨道越来越多 通过离散的食品和药物提示易受行为控制，并且具有更大的提示倾向 诱发恢复或缓解。使用这种动物模型，我们发现 丘脑（PVT）在激励学习过程和控制个体差异中起着至关重要的作用 救济承诺。 PVT似乎是将“自上而下”和“自下而上”输入到的节点 调节提示驱动的行为，但是皮层下电路固定激励显着属性仍然存在 可以确定。这里要测试的中心假设是对Pvt的输入和输出均为 必要且足够促进多巴胺依赖的激励学习。我们将使用分子遗传学 与病毒矢量的方法，可以选择性地表达工程人工受体（例如Dreadd）以确定 精选PVT电路中神经元的瞬时活动如何影响归因激励措施的承诺 奖励提示的显着性。具体而言，我们将从下丘脑（LH）靶向输入到PVT，并且 从PVT到伏隔核的输出（NACSH）。我们将确定PVT-NACSH是否 途径可以调节与腹侧对段区域无关的提示驱动行为，以及如何操纵 这些皮层下回路会影响NACSH的神经化学活性。此外，我们将确定LH-是否是否 PVT和PVT-NACSH途径媒体在提示引起的恢复原状的承诺中的个体差异 寻求毒品的行为。这项工作将确定有助于神经元电路的关键组成部分 成瘾责任。