Metabolic status and cocaine-induced responses in hypocretin neurons

吸毒一直被认为是一种慢性病，也是许多其他疾病的风险因素 精神错乱。为了更好地治疗成瘾和防止今后滥用非法药物，必须了解 成瘾行为的潜在机制。临床和动物研究已经证实，新陈代谢 地位决定了人类和动物的奖赏阈值。食物限制 增加对滥用药物的敏感性，而过度营养则降低对药物的敏感性。然而，它 调节新陈代谢状态的大脑回路如何与奖赏回路相互作用仍然难以捉摸。这个 外侧下丘脑(LH)，一个整合了来自不同大脑区域的广泛输入的中央中枢 编码新陈代谢、行为和环境线索是大脑中调节这两种能量的关键区域 动态平衡和食物/药物奖励。特别是，一组选择性的神经元专门合成 神经肽下丘脑素(hcrt，又称增食欲素)影响食物的摄取，在食物奖励中起着重要作用。 和吸毒成瘾。目前还不完全清楚HCRT系统在电路层次结构中扮演什么角色 负责食物奖励和药物成瘾。其他人和我们最近的研究表明，HCRT系统 在暴露于可卡因的动物中经历经验依赖的突触可塑性，这导致我们的 HCRT细胞中经验依赖性突触可塑性的表达有助于 动物成瘾行为的发展。如果这是真的，在大脑中建立突触可塑性的能力 Hcrt神经元可能参与了动物对成瘾行为的易感性。基于我们之前的 研究，我们假设动物的新陈代谢状态可能有助于确定对 可卡因通过调节Hcrt神经元的突触可塑性。在此R21应用程序中，我们将开始 通过确定饮食诱导的肥胖(DIO)或慢性热量限制来解决这一假设 (Cr)改变可卡因触发Hcrt系统中分子(Hcrt-IRES-Cre小鼠)可塑性的能力 和DREADDS)、细胞(电生理和EM研究)和行为(可卡因条件作用部位 偏好)接近。两个具体目标是：1)确定DIO是否在HCRT中诱导适应 神经元，这阻碍了表达依赖活动(或经验)的突触可塑性。2)至 确定慢性CR是否诱导Hcrt神经元适应，从而促进活性的表达 (或经验)依赖的突触可塑性。在完成这些重要的概念验证之后 研究，我们将进行更全面的研究，以确定分子和细胞信号如何 Hcrt神经元中的通路参与不同环境下动物成瘾行为的发展 代谢状态。我们的长期目标是弥合我们目前对成瘾的理解上的知识鸿沟 并弥合临床研究和基础研究之间关于hcrt系统在成瘾中的作用的差距。 行为，这是一个到目前为止还没有被很好地探索的研究领域。

Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. To better treat addiction and prevent future abuse of illicit drugs, it is essential to understand the mechanisms underlying addictive behaviors. Clinical and animal studies have established that the metabolic status contributes to the determination of reward threshold in humans and animals. Food restriction increases the sensitivity to drugs of abuse, while over-nutrition decreases the sensitivity to drugs. However, it is still elusive how the brain circuitry regulating the metabolic status interacts with the reward circuitry. The lateral hypothalamus (LH), a central hub integrating a wide range of inputs from various brain regions encoding metabolic, behavioral and environmental cues, is a critical brain area to regulate both energy homeostasis and food/drug reward. Particularly, a selective group of neurons exclusively synthesizing the neuropeptide hypocretin (Hcrt, also called orexin) affect food intake and play a prominent role in food award and drug addiction. Currently it is not entirely clear what role the Hcrt system plays in the hierarchy of circuitry responsible for food reward and drug addiction. Recent studies by others and us indicate that the Hcrt system undergoes experience-dependent synaptic plasticity in animals exposed to cocaine, which leads to our overall hypothesis that the expression of experience-dependent synaptic plasticity in Hcrt cells contributes to the development of addictive behaviors in animals. If this is true, the ability to establish synaptic plasticity in Hcrt neurons may contribute to the susceptibility of animals to addictive behaviors. Based on our previous studies, we hypothesize that the metabolic status of animals may contribute to determination of sensitivity to cocaine through modulating synaptic plasticity in Hcrt neurons. In this R21 application we will begin to address this hypothesis by determining whether either diet-induced obesity (DIO) or chronic calorie restriction (CR) alters the ability of cocaine to trigger plasticity in the Hcrt system with molecular (Hcrt-IRES-Cre mice and DREADDs), cellular (electrophysiological and EM studies) and behavioral (cocaine conditioned place preference) approaches. Two specific aims are: 1) To determine whether DIO induces adaptation in Hcrt neurons, which impedes the expression of activity (or experience)-dependent synaptic plasticity. 2) To determine whether chronic CR induces adaptation in Hcrt neurons, which facilitates the expression of activity (or experience)-dependent synaptic plasticity. Following completion of these important proof-of-concept studies, we will conduct a more comprehensive study to determine how molecular and cellular signaling pathways in Hcrt neurons contribute to the development of addictive behaviors in animals under different metabolic status. Our long-term goal is to bridge the knowledge gap in our current understanding of addiction and to bridge the gap between clinical studies and basic research on the role of the Hcrt system in addictive behaviors, an area of study that has not been well explored thus far.