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

• 批准号: 10814113
• 负责人: Melissa Sharpe
• 金额: $ 28.59万
• 依托单位: UNIVERSITY OF SYDNEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814113
• 关键词: Abstinence; Animals; Automobile Driving; Behavior; Behavioral; Books; Calcium; Cognitive; Complex; Computer Models; Cues; Data; Dedications; Dissociation; Distal; Drug Exposure; Drug usage; Environment; Equilibrium; Fiber; Food; Friends; Functional disorder; Genetic; Goals; Hippocampus; Human; Hypersensitivity; Hypothalamic structure; Impairment; Individual; Knowledge; Lateral; Learning; Link; Literature; Maps; Mediating; Methamphetamine; Modeling; Nature; Neurons; Neurosciences; Outcome; Pain; Participant; Pattern; Performance; Persons; Pharmaceutical Preparations; Photometry; Psychological reinforcement; Punishment; Rattus; Relapse; Research; Restaurants; Rewards; Role; Route; Self Administration; Sensory; Stimulus; Substance Use Disorder; System; Testing; Time; Vision; With laterality; Work; addiction; behavior influence; cell type; cognitive neuroscience; computer framework; craving; flexibility; gamma-Aminobutyric Acid; innovation; insight; learning strategy; neural; neural correlate; novel; optogenetics; outcome prediction; pre-clinical; response; sensor; substance use treatment; theories

PROJECT SUMMARY Growing evidence suggests addiction results in part from a dominance that drug-paired cues exert over behavior. That is, when trying to remain abstinent, people with substance-use disorders (SUDs) struggle to focus on anything that is not related to drug use when reminders of drug use are present, exacerbating craving and producing relapse. We have recently uncovered a novel neural locus that appears to bias learning and behavior towards cues that are immediately related to rewards. Specifically, we have found that GABAergic neurons in the lateral hypothalamus (LH) drive learning and behavior directed to information related to rewards, while actively opposing learning about other relationships in the environment that are not immediately relevant to rewards. This is the first time one region has been found to contribute to this dissociation. We can see how a change in this balance in learning and behavior mediated by LH could contribute to addiction; increases in LH function seen following drug exposure could potentiate cue-elicited drug seeking 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. This work will provide insight into how the pathophysiological state of addiction can contribute to relapse even during voluntary abstinence, and suggest a neural target that could drive pre-clinical work to develop treatments for SUDs. This proposal will test a novel theoretical framework to account for the influence LH has over learning. Specifically, we hypothesize that LH GABAergic neurons bias learning towards cues proximal to rewards, and away from those more distal to rewards. To test this, we have developed an innovative task taken from the cognitive neuroscience literature based on human participants, allowing us to isolate behavior and neural activity during both proximal and distal predictors of rewards in the same animal. Further, we will uncover the nature of learning about proximal cues supported by LH function. On the basis of preliminary data, we hypothesize this will involve a sensory-specific representation of reward, which allows LH to influence behavior in flexible and specific ways. Finally, our preliminary work also demonstrates that methamphetamine self-administration enhances the control that cues proximal to rewards have over behavior, and that this is also dependent on a specific reward representation. This expands our knowledge of the behavioral change that results from SUDs, standing as a counterpoint to many theories of addiction that focus on and enhancement of habitual behavior, which is without voluntary control and devoid of reward representations. On the basis of preliminary work, we hypothesize that enhancements of LH GABAergic neuronal function after drug exposure produces this effect. Accordingly, we will directly test our theory that LH GABA neurons promote a bias towards proximal cues in a specific manner, and that this function is enhanced in following drug exposure.

项目总结 越来越多的证据表明，成瘾的部分原因是与药物配对的线索对行为施加的主导作用。 也就是说，当试图保持禁欲时，患有物质使用障碍(SOD)的人很难专注于 当出现吸毒提醒时，任何与吸毒无关的东西，都会加剧渴望和 导致旧病复发。我们最近发现了一个新的神经轨迹，它似乎对学习和行为产生了偏见 指向与奖励直接相关的暗示。具体地说，我们发现大脑中的GABA能神经元 外侧下丘脑(LH)驱动与奖励相关的信息的学习和行为，而 积极反对学习环境中与其他关系不直接相关的关系 奖励。这是第一次发现一个区域对这种解离有贡献。我们可以看到一个 由黄体生成素调节的学习和行为的这种平衡的改变可能导致成瘾； 接触药物后出现的功能可能会加强线索诱导的药物寻找，同时试图保持戒酒， 劫持促黄体生成素的适应功能，以专注于有助于预测奖励的线索，这些线索可能会在 正常情况下。这项工作将提供对成瘾的病理生理状态如何 即使在自愿禁欲的过程中也会导致复发，并提出一个可以推动临床前研究的神经靶点 致力于开发肥皂泡的治疗方法。 这一建议将测试一种新的理论框架，以解释学习能力对学习的影响。 具体地说，我们假设LHGABA能神经元将学习偏向于奖励近端的线索，并且 远离那些更遥远的奖励。为了测试这一点，我们开发了一个创新的任务，取自 认知神经科学文献以人类参与者为基础，使我们能够分离行为和神经活动 在同一动物的近端和远端的奖赏预测中。此外，我们还将揭开 学习由黄体生成素功能支持的近端线索。根据初步数据，我们假设 将涉及一种特定于感官的奖赏表征，这允许黄体生成素以灵活和 具体的方式。最后，我们的初步工作也证明了甲基苯丙胺的自我给药 增强了对奖励附近提示对行为的控制，这也依赖于 具体的奖励表示法。这扩大了我们对肥皂水引起的行为变化的了解， 作为许多关注和加强习惯行为的成瘾理论的对立面， 它没有自愿控制，也没有奖励表示。在前期工作的基础上，我们 假设药物暴露后LHGABA能神经元功能的增强会产生这种效应。 因此，我们将直接测试我们的理论，即LGBA神经元在大脑中促进对近端线索的偏向 这一功能在药物暴露后得到加强。