The role of hypocretin neurons in cocaine reinforcement

求职者：我的职业目标是成为一名研究科学家，研究生理和病理条件下人类和动物复杂行为的潜在机制。我有相当多的成就记录来证明我对这个目标的追求。在耶鲁大学博士后培训期间，我关于神经递质、神经肽和神经营养因子在调节发育和成熟的下丘脑神经元活动中的作用的工作，导致在高质量期刊上发表了同行评议的论文(包括7篇第一作者论文和9篇二次作者论文)。我获得了美国心脏协会和美国国立卫生研究院颁发的职业发展奖助金。在过去的七年里，我建立了自己的独立研究项目，并获得了美国国立卫生研究院的R01拨款，用于研究下丘脑摄食调节的细胞机制。我们已经证明了下丘脑神经元神经元的可塑性是能量平衡和睡眠调节的基础，这已经发表在高影响力的同行评议期刊上。在此申请中，我建议通过这里概述的一段时间的严格研究训练，我在基础行为科学方面的研究能力将得到大幅提高，我将能够在我的研究中追求新的方向(毒瘾)。环境：我是耶鲁大学医学院比较医学系的副教授。在我追求成为一名独立调查员的过程中，耶鲁大学为我的职业发展提供了一个出色的环境。我觉得我将能够充分利用这里的环境和资源来实现我在这份申请中列出的目标。研究：吸毒一直被认为是一种慢性病，也是许多其他疾病和障碍的风险因素。有令人信服的证据表明，吸毒是一种后天习得的行为。正常大脑中潜在的学习和记忆机制(经验依赖型神经可塑性)被成瘾物质“劫持”，从而产生持久而令人信服的吸食非法药物的冲动。长期以来，下丘脑外侧核一直被认为参与动物奖赏相关行为的调节。现在清楚的是，下丘脑系统参与了与药物奖励相关的行为。目前尚不清楚下丘脑神经元的经验依赖性神经可塑性是否对药物滥用的发展是必要的。在这个提议中，我们的主要假设是，下丘脑神经元内经验依赖性的可塑性对于可卡因强化相关行为的表达是必不可少的。其具体目的是确定可卡因自身给药是否导致下丘脑谷氨酸能输入突触强度的持久变化，以及确定取消下丘脑神经元突触可塑性的操作是否改变了动物体内可卡因的强化。相关性：我们的长期目标是弥合关于中枢神经系统在可卡因成瘾中的作用的临床研究和基础研究之间的差距。本申请中提出的研究培训与NIH和OppNet的任务高度相关。 公共卫生相关性：吸毒一直被认为是一种慢性病，也是许多其他疾病和障碍的风险因素。目前约有1970万美国人使用非法药物，这给美国的医疗保健系统、经济和社会带来了沉重的负担。这项提议的长期目标是弥合临床研究和基础研究之间的差距，这些研究是关于下丘脑泌素系统在可卡因成瘾相关行为中的作用。

DESCRIPTION (provided by applicant): Candidate: My career goal is to be a research scientist addressing mechanisms underlying complicated behaviors in humans and animals under physiological and pathological conditions. I have a substantial record of accomplishment to demonstrate my pursuit of this goal. During my postdoctoral training at Yale, my work on the role of neurotransmitters, neuropeptides and neurotrophic factors in the modulation of neuronal activity in developing and mature hypothalamic neurons, led to peer-reviewed publications (including seven first-author papers and nine secondary author papers) in high quality journals. I was awarded career development grants/awards from the American Heart Association and the NIH. During the last seven years, I established my own independent research program and was awarded a R01 grant from the NIH to address cellular mechanisms underlying feeding regulation in the hypothalamus. We have demonstrated that neuronal plasticity in hypocretin neurons underlies energy homeostasis and sleep regulation, which has been published in high- impact peer-reviewed journals. In this application, I propose that through a period of rigorous research training outlined here, my research ability in basic behavioral science will be substantially enhanced and I will be capable to pursue a new direction (drug addiction) in my research. Environment: I am an Associate Professor in the Section of Comparative Medicine at Yale University School of Medicine. Yale University has provided an outstanding environment for career development during my pursuit to be an independent investigator. I feel that I will be able to take full advantage of the environment and resources here to achieve my goals outlined in this application. Research: Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. There is compelling evidence that drug addiction is a learned behavior. Mechanisms underlying learning and memory (experience-dependent neuroplasticity) in the normal brain are "hijacked" by addictive substances to produce an enduring and compelling urge to consume illicit drugs. The lateral hypothalamus (LH) has long been recognized to participate in the regulation of reward-related behaviors in animals. It is now clear that the hypocretin system participates in behaviors related to drug reward. It is not clear whether the experience-dependent neuroplasticity in hypocretin neurons is essential for the development of drug abuse. In this proposal, our chief hypothesis is that the experience-dependent plasticity in hypocretin neurons is essential for the expression of behaviors related to cocaine reinforcement. The specific aim is to determine whether cocaine self-administration results in enduring changes in synaptic strength of hypocretin glutamatergic inputs and to determine whether manipulations that abolish synaptic plasticity in hypocretin neurons alter cocaine reinforcement in animals. Relevance: Our long-term goal is to bridge the gap between clinical studies and basic research on the role of the CNS in cocaine addiction. The research training proposed in this application is highly relevant to the mission of the NIH and the OppNet. PUBLIC HEALTH RELEVANCE: Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. About 19.7 million Americans are current users of illicit drugs, which has posed a significant burden on the health care system, economy and society in the country. The long-term goal of this proposal is to bridge the gap between clinical studies and basic research on the role of the hypocretin system in cocaine addiction-related behaviors.