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

项目摘要 复发是治疗物质使用障碍（SUD）的主要障碍。复发的部分原因是药物配对 对寻求毒品的行为施加强烈控制的线索。事实上，对药物配对线索的反应是预测性的， 随后复发的可能性，这种脆弱性不会随着时间的推移而消失;药物配对的影响 自药物暴露以来，行为线索随着时间的推移而逐渐增加。重要的是，这并不是针对 药物配对线索对奖励配对线索的行为和生理反应也与 复发，甚至与啮齿动物模型中发生SUD的倾向相关。这表明， 学习和行为的变化，以奖励配对线索，这可能会加剧药物暴露，使 SUD患者特别容易受到药物配对线索对行为的影响。 我们最近发现，外侧下丘脑（LHGABA）神经元中的GABA能神经元是 对学习奖励配对线索很重要。更重要的是，该地区似乎积极反对 学习与奖励无关的信息。这表明LHGABA神经元偏向于线索学习 与奖励直接相关的信息（近端线索），远离与奖励不直接相关的信息。 奖励（远端线索）。在正常情况下，这是好事。我们应该多注意信息 这与我们现在的需求直接相关。然而，先前的研究表明， 增强LH回路的功能。很容易看出这是如何产生对奖励配对线索的脆弱性的 在SUD中看到药物暴露后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），即使试图保持禁欲，劫持适应性 LH的功能集中在有助于预测奖励的线索上，这些奖励在正常情况下可能促进生存。 我们将测试一种新的LH功能的学习理论，以及如何加强这种功能 通过药物暴露来产生对奖励配对线索的脆弱性。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。与光遗传学和光纤 基因编码的钙传感器的光度测定，这将使我们能够隔离行为和神经活动 在同一动物的近端或远端预测期间。我们还将揭示学习近端 LH功能支持的线索。我们的初步数据显示，这涉及到一种感官特异性的表现， 奖励，它允许LH以灵活和特定的方式影响行为。最后，我们发现， 甲基苯丙胺自我管理增强行为控制的方式，近端线索，需要 一个特定的奖励表示。我们将记录暴露后LHGABA神经元在学习过程中的钙活性 药物来测试这是否与增强对近端线索的控制有关。然后，我们将从化学遗传学角度 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。这 将揭示LHGABA神经元作为关键的奖励配对线索的行为在SUD的增强效果。

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.