Food intake control by leptin signaling in the hippocampus

描述（由申请人提供）：本提案描述了一个为期3年的培训计划，旨在为候选人（斯科特E博士）。Kanoski），具有整合一系列神经解剖学、分子学和其他职业技能（例如，指导，实验室管理，赠款写作），这将扩大他的肥胖为重点的研究生涯的范围。拟议的培训计划将大大有利于候选人的能力，以建立和维护一个富有成效的独立行为神经科学实验室在南加州大学（USC）进行研究，重点是肥胖的治疗和预防。候选人获得了博士学位。2009年8月，在宾夕法尼亚大学心理学系担任博士后研究员。他在南加州大学生物学助理教授的位置开始于2013年1月。南加州大学生物系有着悠久的研究传统，将为候选人提供理想的培训和研究环境。主要导师，南加州大学生物学教授Alan Watts博士是行为神经科学领域的知名研究人员，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的专家。为了促进拟议研究的新颖跨学科方法，候选人还将由共同导师大卫麦克米博士（南加州大学）指导，他是躯体感觉和伤害感受领域的杰出神经生物学研究员，并由哈维·格里尔博士（宾夕法尼亚大学）指导，他是摄食和能量消耗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个新的假设，即脂肪细胞衍生的激素瘦素在腹侧海马体（VHPC）中发出信号，这是一个调节学习和动机过程的大脑区域，以抑制与获得奖励，可口食物有关的动机行为。该提案中描述的实验使用大鼠模型，并整合了最先进的神经解剖学（免疫组织化学和神经示踪剂），分子（免疫印迹，qPCR），遗传学（RNA干扰），药理学（药物的中心递送）和行为技术（学习和记忆范式）。直接建立在本提案中提出的初步数据基础上，实验旨在：1）评估VHPC中的瘦素受体（LepRb）信号传导是否与针对食物获取的习得动机行为生理相关，2）鉴定与VHPC协同通信以通过瘦素信号传导减少食物摄入的神经回路，和3）鉴定VHPC瘦素引起的食物摄入减少是否涉及脑源性神经营养因子（BDNF）信号传导。结果将有助于药物肥胖治疗的发展，通过了解控制食物摄入和食物动机行为的神经内分泌和细胞内/分子系统。

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.