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.

项目总结/摘要 环境中与奖励相关的刺激（线索）可以激发正常行为，使人接近 接近有价值的资源（如食物）;但他们也可以获得对行为的过度控制，就像 成瘾的案例奖励线索激励行为的能力通过巴甫洛夫学习发生 流程.当一个离散的线索与奖励的呈现反复配对时，它可以获得这样的能力： 作为一个预测器，但也可以获得激励激励属性。对于成瘾者来说，暗示 有过吸毒经历的人获得维持觅药的能力 行为和煽动复吸，即使有强烈的愿望停止使用。神经生物学过程 奖励线索对行为的过度控制已经被证明是难以辨别的，因为线索可以 同时获得“预测”和“激励”属性，在大多数研究中，这两种心理学属性 过程是混乱的。在拟议的研究中，我们将利用线索奖励学习中的自然变化， 确定专门负责激励价值（激励）归属的神经回路 奖励线索（reward cues）。当大鼠暴露于巴甫洛夫条件接近范式时， 被称为“目标追踪者”，将预测值归因于离散的食物相关线索;而其他人，被称为“目标追踪者”， “符号追踪者”将激励显著性归因于线索。相对于目标追踪者，符号追踪者 易受离散的食物和药物配对线索的行为控制，并有更大的线索倾向， 诱发复发或复发。利用这种动物模型，我们发现，室旁核， 丘脑（PVT）在激励学习过程和调节个体差异中起着关键作用 在复发倾向上。PVT看起来像一个节点，它集成了“自上而下”和“自下而上”的输入， 调节线索驱动的行为，但皮层下回路subserving激励显着归因仍然是， 被确定。这里要检验的中心假设是，PVT的输入和输出都是 必要和充分的促进多巴胺依赖性激励学习。我们将使用分子遗传学 用病毒载体选择性表达工程化人工受体（例如DREADD）的方法， 在特定的PVT回路中，神经元活动的瞬时改变如何影响归因激励的倾向 奖励线索的显著性。具体来说，我们将目标输入到PVT从外侧下丘脑（LH）， 从PVT输出到核壳层（NAcSh）。我们将确定PVT-NAcSh是否 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 这些皮层下回路影响NAcSh中的神经化学活性。此外，我们将确定是否LH- PVT和PVT-NAcSh通路介导线索诱导恢复倾向的个体差异 寻求毒品的行为。这项工作将确定神经回路的关键组成部分，有助于 成瘾倾向