Psychostimulant Addiction and Nutrient-sensing Neurons (PANN)

滥用可卡因和甲基苯丙胺(冰毒)是一个紧迫的公共卫生问题。虽然上瘾涉及到 许多因素，更好地了解药物使用后的生物学变化将大大促进 开发新的治疗策略。最近，人们越来越有兴趣确定如何 与中脑边缘奖赏系统连接的回路调节精神刺激性成瘾。这样的一个 回路是起源于下丘脑外侧的黑色素浓缩激素(MCH)神经元。 虽然这些葡萄糖感觉神经元的研究主要集中在能量平衡、睡眠-清醒、酒精 和食物摄入量，有迹象表明，这些神经元也参与了可卡因和 类似冰毒的行为。我们目前对MCH在成瘾中的作用的研究一直受到以下因素的阻碍 缺乏神经元特异性，并且没有使用临床前自我给药方法， 在老鼠身上产生类似成瘾的行为。此外，人们还发现可卡因会改变大脑 行为相关时间尺度上的血糖水平，但可卡因如何改变MCH的活性 神经元或它们对中脑边缘系统的输入仍不清楚。该项目旨在确定 精神刺激后MCH神经元活性的变化及其与细胞外葡萄糖的关系 体内水平(目标1)。实验将确定促黄体生成素-促性腺激素神经元在调节Long中的功能作用 获得和间歇获得可卡因或冰毒自我给药，这两种方法产生 大鼠成瘾样行为(目标2)。该项目将使用最先进的神经科学工具，包括 基因编码的钙指示剂的光学记录，使用酶连接的体内血糖监测 生物传感器，以及基因靶向的设计师受体，专门由设计师药物激活。vbl.使用 这些方法将使我们能够确定可卡因和冰毒经历是否会改变对 精神刺激药物通过葡萄糖相关的机制，如果MCH神经元的活动调节 上瘾的症状。这将导致技术开发和关键的初步数据 随后的申请。未来的提案将集中在MCH神经元如何影响中心应力区， 有助于成瘾和复发，并确定MCH神经元及其特定投射如何 促进与奖励相关的基本流程，如激励显著归因通常受 中边缘系统。了解成瘾的生物学机制，是一个重要的 作为制定可在国家和地方两级实施的有效干预措施的组成部分。

Cocaine and methamphetamine (meth) abuse is an urgent public health problem. While addiction involves many factors, a better understanding of the biological changes after drug use would significantly advance the development of new therapeutic strategies. There is a recent increased interest in determining how circuits that interface with the mesolimbic reward system regulates psychostimulant addiction. One such circuit are Melanin Concentrating Hormone (MCH) neurons that originate from the lateral hypothalamus. While these glucose-sensing neurons are studied primarily in energy balance, sleep-wakefulness, alcohol and food intake, there are hints that these neurons also are involved in processes underlying cocaine and meth addiction-like behavior. Our current research into the role of MCH in addiction has been hampered by a lack of neuronal specificity, and has not used preclinical self-administration approaches that consistently produce addiction-like behaviors in rats. Moreover, it has been discovered that cocaine changes brain glucose levels at a behaviorally relevant timescale, but how cocaine can change the activity of MCH neurons or their input into the mesolimbic system remains unknown. This project seeks to determine the changes in MCH neuronal activity after psychostimulant experience and link it to extracellular glucose levels in vivo (Aim 1). Experiments will determine the functional role of LH MCH neurons in regulating long access and intermittent access cocaine or meth self-administration, two approaches that produce addiction-like behavior in rats (Aim 2). This project will use state of the art neuroscience tools including optical recording of genetically encoded calcium indicators, in vivo glucose monitoring using enzyme-linked biosensors, and genetically targeted designer receptors exclusively activated by designer drugs. Using these approaches will allow us to determine whether cocaine and meth experience alters the response to psychostimulant drugs via a glucose related mechanism, and if the activity of MCH neurons regulate addiction-like symptoms. This will result in technical development and critical preliminary data for subsequent applications. Future proposals will focus on how MCH neurons impact central stress areas, contributing to addiction and relapse and determining how MCH neurons and their specific projections contribute towards basic reward-related processes like incentive salience attribution normally regulated by the mesolimbic system. Understanding the biological mechanisms underlying addiction, is an important component to developing effective interventions that can be applied both at a national and local level.