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治疗策略的发展。最近有越来越多的兴趣，以确定如何接口电路与中脑边缘奖励系统调节精神兴奋剂成瘾。一个这样的回路是源自外侧下丘脑的黑色素浓集激素（MCH）神经元。虽然这些葡萄糖感知神经元主要在能量平衡，睡眠-觉醒，酒精和食物摄入方面进行研究，但有迹象表明这些神经元也参与了可卡因和甲基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受到缺乏神经元特异性的阻碍，并且没有使用临床前自我给药方法，这些方法在大鼠中持续产生成瘾样行为。此外，已经发现可卡因在行为相关的时间尺度上改变大脑葡萄糖水平，但可卡因如何改变MCH神经元的活性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验后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神经元在调节长期访问和间歇访问可卡因或冰毒自我管理中的功能作用，这两种方法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，包括遗传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，以及由设计药物专门激活的遗传靶向设计受体。使用这些方法将使我们能够确定可卡因和冰毒的经验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。这将导致技术发展和关键的初步数据，用于随后的应用。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，并确定MCH神经元及其特定的预测如何促进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性归因。了解成瘾的生物学机制是制定可在国家和地方一级实施的有效干预措施的重要组成部分。

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.