Psychostimulant Addiction and Nutrient-sensing Neurons (PANN)

可卡因和甲基苯丙胺（冰毒）滥用是一个紧迫的公共卫生问题。虽然成瘾涉及许多因素，但更好地了解药物使用后的生物学变化将大大促进新的治疗策略的发展。最近，人们对确定与中脑边缘奖赏系统相连接的神经回路如何调节精神兴奋剂成瘾越来越感兴趣。其中一个回路是黑色素集中激素（MCH）神经元，它起源于外侧下丘脑。虽然这些葡萄糖感应神经元主要与能量平衡、睡眠觉醒、酒精和食物摄入有关，但有迹象表明，这些神经元也参与了可卡因和冰毒成瘾行为的潜在过程。我们目前对MCH在成瘾中的作用的研究由于缺乏神经元特异性而受到阻碍，并且没有使用临床前自我给药方法来持续地在大鼠中产生成瘾样行为。此外，已经发现可卡因在行为相关的时间尺度上改变脑葡萄糖水平，但可卡因如何改变MCH神经元的活动或它们对中脑边缘系统的输入仍然未知。该项目旨在确定精神兴奋剂经历后MCH神经元活动的变化，并将其与体内细胞外葡萄糖水平联系起来（目的1）。实验将确定LH MCH神经元在调节可卡因或冰毒长期获取和间歇性获取自我给药中的功能作用，这两种方法会在大鼠中产生成瘾样行为（目的2）。该项目将使用最先进的神经科学工具，包括基因编码钙指标的光学记录，使用酶联生物传感器的体内葡萄糖监测，以及由设计药物激活的基因靶向设计受体。使用这些方法将使我们能够确定可卡因和冰毒是否通过葡萄糖相关机制改变对精神兴奋剂药物的反应，以及MCH神经元的活动是否调节成瘾样症状。这将为后续应用带来技术发展和关键的初步数据。未来的建议将集中在MCH神经元如何影响中枢应激区，促进成瘾和复发，以及确定MCH神经元及其特定投影如何参与基本的奖励相关过程，如通常由中脑边缘系统调节的激励显着归因。了解成瘾的生物学机制是制定有效干预措施的重要组成部分，可以在国家和地方一级应用。

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.