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），但也可以对行为产生过分控制 有成瘾的情况。 过程。 充当预测指标，但也可以在个人中获得侵略性的动机。 以前曾与吸毒的皇帝相关联 行为和促进复发，即使如此强烈地渴望停止使用神经生物学过程 奖励提示获得对行为的过度控制已证明是辨别的，因为提示可以 同时获得“预测”和“激励”特性，在大多数研究中 在支撑研究中，过程是混淆的。 确定专门负责激励动机价值（激励）的神经回路 薪金）奖励提示。 被称为“目标追踪者”，将预测价值归因于迪斯科食品相关的提示； “签名追踪者”属性激励量相对于目标跟踪。 通过离散的食物和药物提示易受行为控制，并且具有更大的提示倾向 诱发了使用此动物模型的恢复或复发。 丘脑（PVT）在激励学习过程和调节个体差异中起着至关重要的作用 在复发倾向中。 调节提示驱动的行为，但是皮层亚电路降低激励奖励激励吸引力仍然存在 确定要测试的中心假设是 促进多巴胺的必要和足够的必要和足够的奖励触发触发触发触发奖励触发奖励触发爆发爆发奖励奖励奖励。 使用向量的方法，以选择性表达发动机人造受体（例如Dreadd）来确定 在某些PVT电路中，神经元的不断变化的活动如何影响属性刺激 提示提示。 从PVT到核的输出构成壳（NACSH）。 途径可以独立于狭tement段的行为以及如何处理 这些亚皮质会影响NACSH中的神经化学活性。 PVT和PVT-NACSH途径介导了提示诱导的恢复倾向的个体差异 这项工作的毒品行为将确定促成神经回路的基督成分。 成瘾责任。