The role of the lateral hypothalamus in the balance of learning and behavior towards relevant stimuli

下丘脑外侧在平衡学习和针对相关刺激的行为中的作用

基本信息

批准号：
10522247
负责人：
Melissa Sharpe
金额：
$ 41.24万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10522247
关键词：
Animals Attention Behavior Behavior Control Behavioral Calcium Cell Nucleus Chemosensitization Computer Models Cues Data Distal Drug Addiction Drug Exposure Drug Modelings Equilibrium Exposure to Fiber Goals Human Hypersensitivity Hypothalamic structure Individual Knowledge Lateral Learning Lesion Link Literature Memory Methamphetamine Modeling Modernization Motivation Nature Neurons Participant Pathologic Performance Persons Pharmaceutical Preparations Photometry Physiological Psychological reinforcement Rattus Relapse Research Retrieval Rewards Rodent Model Role Self Administration Sensory Starvation Stimulus Substance Use Disorder Techniques Testing Time Vulnerable Populations addiction base behavior influence cell type cognitive neuroscience computer framework drug reward drug seeking behavior feeding flexibility innovation learned behavior memory encoding neural correlate novel optogenetics relating to nervous system response sensor substance use treatment theories

项目摘要

PROJECT SUMMARY Relapse is a major hurdle for treating substance use disorder (SUD). Relapse results in part from drug-paired cues exerting strong control over drug-seeking behavior. Indeed, the reactivity to drug-paired cues is predictive of subsequent likelihood of relapse, and this vulnerability does not go away with time; the effects of drug-paired cues over behavior increases progressively with time since drug exposure. Importantly, this is not specific to drug-paired cues. Behavioral and physiological responses to reward-paired cues is also related to likelihood of relapse, and is even correlated with a propensity to develop SUDs in rodent models. This points to an underlying change in learning and behavior to reward-paired cues, which may be exacerbated by drug exposure, to make individuals with SUDs particularly vulnerable to the effect of drug-paired cues over behavior. We have recently discovered that GABAergic neurons in the lateral hypothalamus (LHGABA) neurons are important for learning about reward-paired cues. What’s more is that this region appears to actively oppose learning about non-reward related information. This suggests that LHGABA neurons bias learning towards cues that are directly related to rewards (proximal cues) and away from information that is not directly related to rewards (distal cues). Under normal circumstances this is good. We should pay more attention to information that is directly relevant to what we need right now. However, prior research has shown that drug exposure strengthens function in LH circuits. It is easy to see how this could produce a vulnerability to reward-paired cues seen in SUDs. Increases in LH function seen following drug exposure could potentiate learning and behavior directed to proximal cues (e.g. drug-paired cues), even while trying to remain abstinent, hijacking the adaptive function of LH to focus on cues that help predict rewards that likely promote survival under normal circumstances. We will test a novel reinforcement-learning theory of LH function, and how this function might be strengthened by drug exposure to produce a vulnerability to reward-paired cues. We have developed an innovative task taken from the cognitive neuroscience literature based on human participants. In tandem with optogenetics and fiber photometry of a genetically-encoded calcium sensor, this will allow us to isolate behavior and neural activity during proximal or distal predictors in the same animal. We will also uncover the nature of learning about proximal cues supported by LH function. Our preliminary data shows this involves a sensory-specific representation of reward, which allows LH to influence behavior in flexible and specific ways. Finally, we have found that methamphetamine self-administration enhances behavioral control by proximal cues in a manner that requires a specific reward representation. We will record calcium activity in LHGABA neurons during learning after exposure to drugs to test if this is correlated with enhanced control of proximal cues. Then, we will chemogenetically stimulate LHGABA neurons during these tasks to see if we can mimic the effects of the drug on learning. This would reveal LHGABA neurons as critical to the enhanced effects of reward-paired cues over behavior in SUDs.

项目概要复发是治疗物质使用障碍 (SUD) 的主要障碍复发部分是由药物配对造成的。事实上，对药物配对线索的反应是有预测性的。随后复发的可能性，并且这种脆弱性不会随着药物配对的影响而消失；自药物暴露以来，对行为的暗示随着时间的推移而逐渐增加。重要的是，这并不是特定于药物暴露的。对奖励配对线索的行为和生理反应也与药物配对线索的可能性有关。复发，甚至与啮齿动物模型中发生 SUD 的倾向相关，这表明了一个潜在的问题。学习和行为发生变化以适应奖励配对线索，这种变化可能会因药物暴露而加剧，从而使患有 SUD 的个体特别容易受到药物配对线索对行为的影响。我们最近发现下丘脑外侧 (LHGABA) 神经元中的 GABA 能神经元对于了解奖励配对线索很重要，而且该区域似乎积极反对。学习非奖励相关信息这表明 LHGABA 神经元偏向于线索学习。与奖励（近端线索）直接相关并且远离与奖励不直接相关的信息奖励（远端提示）一般情况下我们应该多关注信息。这与我们现在的需要直接相关，但是，先前的研究表明药物暴露。增强 LH 回路的功能很容易看出这会如何产生对奖励配对线索的脆弱性。在 SUD 中观察到，药物暴露后 LH 功能的增加可能会增强学习和行为。指向近端线索（例如药物配对线索），即使在试图保持禁欲的同时，劫持了适应性 LH 的功能是专注于有助于预测可能促进正常情况下生存的奖励的线索。我们将测试一种新的 LH 功能强化学习理论，以及如何加强该功能我们开发了一项创新任务，通过药物暴露来产生对奖励配对线索的脆弱性。来自基于人类参与者的认知神经科学文献与光遗传学和纤维的结合。基因编码钙传感器的光度测定，这将使我们能够分离行为和神经活动在同一动物的近端或远端预测因子期间，我们还将揭示学习近端预测的本质。我们的初步数据显示，这涉及到 LH 功能的特定感官表征。奖励，这使得 LH 能够以灵活且特定的方式影响行为。最后，我们发现了这一点。甲基苯丙胺自我给药通过近端线索增强行为控制，其方式需要我们将记录暴露后学习过程中 LHGABA 神经元的钙活动。为了测试这是否与近端线索的增强控制相关，然后，我们将从化学遗传学角度进行测试。在这些任务中刺激 LHGABA 神经元，看看我们是否可以模仿药物对学习的影响。将揭示 LHGABA 神经元对于奖励配对线索对 SUD 行为的增强作用至关重要。