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; 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.

项目摘要 越来越多的证据表明，成瘾的部分原因是药物配对提示对行为的主导地位。 也就是说，当试图戒酒时，具有物质使用障碍的人（SUD）努力专注于 当存在吸毒的提醒时，与吸毒无关的任何事物都会加剧渴望和 产生复发。我们最近发现了一个新颖的神经基因座，似乎偏向学习和行为 迈向与奖励直接相关的提示。具体而言，我们发现GABA能神经元 下丘脑（LH）驱动与奖励有关的信息的学习和行为，而 积极反对对环境中其他关系的学习，这些关系与 奖励。这是第一次发现一个地区有助于这种解离。我们可以看到如何 LH介导的学习和行为平衡的变化可能导致成瘾； LH的增加 在药物暴露后看到的功能可以增强提示引诱的药物寻求，同时试图避免戒酒， 劫持LH的适应性功能，专注于有助于预测可能促进生存下生存的奖励的提示 正常情况。这项工作将洞悉成瘾的病理生理状态如何 即使在自愿戒酒期间也有助于复发，并提出一个可能驱动临床前的神经目标 努力开发泡沫的治疗方法。 该建议将测试一个新颖的理论框架，以说明LH对学习的影响。 具体而言，我们假设LH GABA能神经元偏向于靠近奖励的线索，并且 远离那些更远端到奖励的人。为了测试这一点，我们已经开发了一项创新的任务 基于人类参与者的认知神经科学文献，使我们能够隔离行为和神经活动 在同一动物中奖励的近端和远端预测指标中。此外，我们将发现 了解LH功能支持的近端提示。根据初步数据，我们假设 将涉及奖励的特定感官表示，这允许LH影响灵活的行为 特定方式。最后，我们的初步工作也表明甲基苯丙胺自我管理 增强控制距离奖励具有过度行为的控制，这也取决于 具体的奖励表示。这扩大了我们对苏德造成的行为改变的了解， 与许多成瘾理论相对应，这些理论专注于习惯行为的重点和增强， 这是没有自愿控制的，没有奖励表示。根据初步工作，我们 假设药物暴露后LH GABA能神经元功能的增强会产生这种作用。 因此，我们将直接检验我们的理论，即LH GABA神经元促进了对近端提示的偏见 特定的方式，并且随着药物的暴露而增强了此功能。