Metabolic status and cocaine-induced responses in hypocretin neurons

下丘脑分泌素神经元的代谢状态和可卡因诱导的反应

• 批准号: 9293280
• 负责人: XIAO-BING GAO
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293280
• 关键词: Acute; Addictive Behavior; Address; Affect; American; Animal Feed; Animals; Area; Attenuated; Award; Basic Science; Behavior; Behavioral; Brain; Brain region; Caloric Restriction; Cells; Chronic; Chronic Disease; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Country; Cues; DRD2 gene; Data; Development; Diet; Disease; Dopamine D2 Receptor; Drug Addiction; Drug abuse; Eating; Electrophysiology (science); Exposure to; Food; Future; Goals; Healthcare Systems; Homeostasis; Human; Hypothalamic structure; Illicit Drugs; Impairment; Internal Ribosome Entry Site; Investigation; Knowledge; Lateral; LoxP-flanked allele; Mediating; Metabolic; Molecular; Mus; Neuronal Plasticity; Neurons; Neuropeptides; Obese Mice; Obesity; Overnutrition; Pharmaceutical Preparations; Play; Predisposition; Rewards; Risk Factors; Role; Signal Pathway; Societies; Synapses; Synaptic plasticity; System; addiction; base; brain circuitry; cocaine exposure; designer receptors exclusively activated by designer drugs; drug development; drug of abuse; drug reward; drug seeking behavior; experience; feeding; food restriction; hypocretin; interdisciplinary approach; neural circuit; preference; prevent; receptor; reinforcer; response; reward circuitry

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.

吸毒成瘾被认为是一种慢性疾病，也是许多其他疾病的危险因素， 紊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， 地位有助于确定人类和动物的奖赏阈值。食物限制性 增加对滥用药物的敏感性，而营养过剩则降低对药物的敏感性。但 大脑中调节代谢状态的回路是如何与奖赏回路相互作用的，这仍然是一个谜。的 外侧下丘脑（LH），一个整合来自不同大脑区域的广泛输入的中枢枢纽 编码代谢，行为和环境线索，是一个关键的大脑区域，以调节能量， 稳态和食物/药物奖励。特别是，一组选择性的神经元专门合成 神经肽下丘脑分泌素（Hcrt，也称为食欲素）影响食物摄入，并在食物奖励中发挥重要作用 和毒瘾目前还不完全清楚Hcrt系统在电路层次中扮演什么角色 负责食物奖励和药物成瘾。我们和其他人最近的研究表明，Hcrt系统 在接触可卡因的动物中经历了经验依赖性突触可塑性，这导致了我们的 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，那么在大脑中建立突触可塑性的能力， Hcrt神经元可能与动物成瘾行为的易感性有关。基于我们之前 研究中，我们假设动物的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）或慢性热量限制是否 (CR)改变可卡因在Hcrt系统中触发可塑性的能力（Hcrt-IRES-Cre小鼠 和DREADDs）、细胞（电生理学和EM研究）和行为（可卡因条件位置 偏好）的方法。两个具体目标是：1）确定DIO是否诱导Hcrt适应 神经元，这阻碍了活动（或经验）依赖性突触可塑性的表达。2)到 确定慢性CR是否诱导Hcrt神经元的适应，这有助于活性的表达。 (or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，以确定如何分子和细胞信号 Hcrt神经元中的通路有助于不同条件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中的知识差距 并弥合临床研究和基础研究之间的差距，在Hcrt系统在成瘾中的作用。 行为，这是一个迄今为止尚未得到很好探索的研究领域。