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

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线索对行为的支配作用。 也就是说，当试图保持禁欲时，物质使用障碍（SUD）患者很难专注于 任何与药物使用无关的东西，当药物使用的提醒存在时，加剧了渴望， 导致复发我们最近发现了一个新的神经位点，似乎偏向学习和行为 与奖励直接相关的线索。具体地说，我们已经发现， 外侧下丘脑（LH）驱动与奖励相关的信息的学习和行为， 积极反对学习环境中与环境不直接相关的其他关系， 奖励这是第一次发现一个区域有助于这种解离。我们可以看到， 这种由LH介导的学习和行为平衡的变化可能导致成瘾; LH增加 在药物暴露后观察到的功能可以在试图保持禁欲的同时增强线索诱导的药物寻求， 劫持LH的适应功能，专注于帮助预测奖励的线索，这些奖励可能促进在 正常情况这项工作将提供深入了解如何成瘾的病理生理状态， 甚至在自愿禁欲期间也会导致复发，并提出了一个可以驱动临床前的神经靶点。 致力于开发SUD的治疗方法。 这项建议将测试一个新的理论框架，以解释LH对学习的影响。 具体来说，我们假设LH GABA能神经元偏向于接近奖励的线索， 远离那些远离奖励的人。为了测试这一点，我们开发了一个创新的任务， 基于人类参与者的认知神经科学文献，使我们能够分离行为和神经活动 在近端和远端预测奖励在同一动物。此外，我们还将揭示 学习由LH功能支持的近端线索。根据初步数据，我们假设 将涉及奖励的感官特异性表示，这使得LH能够以灵活的方式影响行为， 具体方式。最后，我们的初步工作还表明，甲基苯丙胺自我管理， 增强了接近奖励的线索对行为的控制，这也取决于 具体奖励。这扩展了我们对SUD导致的行为变化的认识， 与许多关注和增强习惯行为的成瘾理论相反， 它没有自愿控制，也没有报酬表示。在前期工作的基础上， 假设药物暴露后LH GABA能神经元功能增强产生这种效应。 因此，我们将直接测试我们的理论，LH GABA神经元促进偏向近端线索在一个神经元。 具体的方式，并且这种功能在药物暴露后增强。

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.