Food intake control by leptin signaling in the hippocampus

描述(由申请人提供)：这份建议书描述了一个为期3年的培训计划，旨在为候选人(Scott E.Kanoski博士)提供所需的专业知识，以结合一系列面向职业的技能(例如，指导、实验室管理、拨款申请)，从而拓宽其以肥胖为重点的研究生涯的范围。拟议的培训计划将极大地提高候选人在南加州大学(USC)建立和维持一个富有成效的独立行为神经科学实验室的能力，该实验室从事专注于肥胖症治疗和预防的研究。这位候选人于2009年8月获得博士学位，并作为宾夕法尼亚大学心理学系的博士后研究员进行研究。他的南加州大学生物学助理教授职位将于2013年1月开始。南加州大学生物系有着深厚的研究传统，这将为应聘者提供理想的培训和研究环境。主要导师是南加州大学生物学教授艾伦·瓦茨博士，他是行为神经科学领域的知名研究员，也是控制能量平衡和新陈代谢的神经解剖学和神经化学系统方面的专家。为了促进拟议研究的新的跨学科方法，候选人还将由共同导师David McKemy博士(南加州大学)和Harvey Grill博士(宾夕法尼亚大学)指导，David McKemy博士是躯体感觉和伤害性感觉领域的著名神经生物学研究员，Harvey Grill博士是饮食和能量消耗的神经内分泌控制方面的著名专家。这项提案中的研究将检验一种新的假设，即脂肪细胞衍生的激素瘦素在腹侧海马区(VHPC)发出信号，以抑制与获得有回报的美味食物相关的动机行为。腹侧海马区是大脑中调节学习和动机过程的区域。该提案中描述的实验使用了大鼠模型，并结合了最先进的神经解剖学(免疫组织化学和神经学示踪剂)、分子(免疫印迹、qPCR)、遗传学(RNA干扰)、药理学(药物的中心传递)和行为技术(学习和记忆范式)。实验直接基于本提案中提出的初步数据，旨在：1)评估VHPC中的瘦素受体(LepRb)信号是否与针对食物采购的习得动机行为在生理上相关，2)确定与VHPC协调沟通的神经回路，通过瘦素信号减少食物摄入量，以及3)确定VHPC瘦素减少食物摄入量是否涉及脑源性神经营养因子(BDNF)信号。研究结果将有助于通过告知神经内分泌和细胞内/分子系统来控制食物摄入量和食物驱动的行为，从而促进药理学肥胖治疗的发展。

DESCRIPTION (provided by applicant):This proposal describes a 3-year training program designed to provide the candidate (Dr. Scott E. Kanoski) with the expertise needed to incorporate a range of neuroanatomical, molecular, and other career oriented skills (e.g., mentoring, lab management, grant writing) that will broaden the scope of his obesity-focused research career. The proposed training plan will substantially benefit the candidate's ability to establish and maintain a productive independent behavioral neuroscience laboratory at the University of Southern California (USC) conducting research focused on obesity treatment and prevention. The candidate received a Ph.D. in Aug. 2009 and conducted research as a postdoctoral fellow in the Department of Psychology at the University of Pennsylvania. His position as Assistant Professor of Biology at USC begins January 2013. The Department of Biology at USC has a strong research tradition that will provide an ideal training and research environment for the candidate. The primary mentor, Dr. Alan Watts, Professor of Biology at USC, is a well-established researcher in the field of behavioral neuroscience and an expert in the neuroanatomical and neurochemical systems that control energy balance and metabolism. To facilitate the novel interdisciplinary approaches of the proposed research, the candidate will also be guided by co-mentor, Dr. David McKemy (USC), a prominent neurobiological researcher in the fields of somatosensation and nociception, and by Dr. Harvey Grill (University of Pennsylvania), a renowned expert in the neuroendocrine controls of feeding and energy expenditure. The research in this proposal will examine the novel hypothesis that the adipose cell-derived hormone leptin signals in the ventral hippocampus (VHPC), a brain region that regulates learning and motivational processes, to suppress motivational behaviors related to obtaining rewarding, palatable foods. The experiments described in the proposal use a rat model and integrate state-of-the-art neuroanatomical (immunohistochemistry and neurological tracers), molecular (immunoblot, qPCR), genetic (RNA interference), pharmacological (central delivery of agents), and behavioral techniques (learning and memory paradigms). Building directly on preliminary data presented in this proposal, experiments are designed to: 1) assess whether leptin receptor (LepRb) signaling in the VHPC is physiologically relevant to learned motivated behaviors directed towards food procurement, 2) identify the neural circuits that communicate in concert with the VHPC to reduce food intake via leptin signaling, and 3) identify whether food intake reduction by VHPC leptin involves brain-derived neurotrophic factor (BDNF) signaling. Results will contribute to the development of pharmacological obesity treatment by informing about the neuroendocrine and intracellular/molecular systems that control food intake and food-motivated behavior.