Dendritic Spines on AgRP Neurons as Communication Hubs Controlling Feeding

AgRP 神经元上的树突棘作为控制进食的通讯中心

• 批准号: 8786984
• 负责人: Dong Kong
• 金额: $ 6.56万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786984
• 关键词: Dendritic; Spines; AgRP; Neurons; Communication

DESCRIPTION (provided by applicant): Hypothalamic neurons, among which include AgRP and POMC neurons in the arcuate nucleus, detect changes in nutritional status and relay signals to downstream targets to regulate food intake and energy expenditure. Dysfunction of these neurons is believed to cause obesity and anorexia nervosa. The mechanism, however, is still poorly understood. Attention has been primarily focused on the regulation of these neurons by humoral factors, like insulin, leptin, and ghrelin. The synaptic regulation of these neurons, on the other hand, which is likely to be important, has been largely overlooked. Our preliminary studies have revealed a critical role for NMDA receptors and dendritic spines on AgRP neurons. Left unknown, however, are the mechanisms behind this regulation. Thus, the goal of this project is to determine the role of NMDA receptors and the synapses that form on individual dendritic spines of AgRP neurons, and to identify the specific signaling mechanisms that operate within the spines. However, technical challenges to observing and stimulating localized activity at single synapses have prevented the achievement of this goal. Advanced approaches like 2-photon laser scanning microscopy (2PLSM) and 2-photon uncaging of glutamate (2PLU) need to be employed. These powerful technologies occupy a unique niche in understating synaptic functions. With mentoring by Dr. Brad Lowell, an expert in mouse genetics and the hypothalamus, and co- mentoring by Dr. Bernardo Sabatini, a leading expert in synaptic plasticity and dendritic spines, a combination of approaches will be used to assess synaptic regulation of AgRP neurons. Specifically, 2PLU/2PLSM, in combination with electrophysiology and calcium imaging will be used to determine how the synaptic plasticity of excitatory neurotransmission to AgRP neurons is regulated by feeding-related signals. These studies should provide mechanistic insight into the regulation of AgRP neuron activity, and consequently, a better understanding of how feeding behavior is controlled. The applicant is now an Instructor of Medicine in the Division of Endocrinology, Dept. of Medicine, at Beth Israel Deaconess Medical Center and Harvard Medical School. The proposed studies will be performed at BIDMC as the primary location and Dept. of Neurobiology of Harvard Medical School as the second location. With the support of the Mentored Research Scientist Development Award, the applicant will be trained both technically and intellectually. The training to be supported by this award will greatly facilitate the applicant becoming a successful independent investigator in employing unique skill sets to address key questions in the neuroscience of feeding.

描述（由申请人提供）：下丘脑神经元，其中包括弧形核中的AGRP和POMC神经元，检测营养状况的变化以及对下游靶标的继电器信号以调节食物摄入和能量的摄入量和能量费用。这些神经元的功能障碍被认为会引起肥胖和神经性厌食症。但是，该机制仍然很少了解。注意力主要集中在通过胰岛素，瘦素和生长素等体液因素来调节这些神经元。这些神经元的突触调节 另一方面，这很可能很重要，在很大程度上被忽略了。我们的初步研究揭示了NMDA受体和树突状刺在AGRP神经元上的关键作用。但是，未知是该法规背后的机制。因此，该项目的目的是确定NMDA受体的作用以及在AGRP神经元的单个树突状刺上形成的突触，并确定在棘中运行的特定信号机制。但是，观察和刺激单个突触中局部活动的技术挑战阻止了实现这一目标。需要采用高级方法，例如2光子激光扫描显微镜（2PLSM）和谷氨酸（2PLU）的2光片剂。这些强大的技术在低估​​的突触功能方面占据了独特的利基市场。在小鼠遗传学和下丘脑专家Brad Lowell博士的指导下，并由突触可塑性和树突状刺领域的领先专家Bernardo Sabatini博士进行指导，方法将用于评估AGRP的突触调节神经元。具体而言，将使用2PLU/2PLSM结合电生理学和钙成像来确定如何通过喂养相关信号调节对AGRP神经元的兴奋性神经传递的突触可塑性。这些研究应提供对AGRP神经元活性调节的机械洞察力，因此可以更好地了解如何控制喂养行为。现在，申请人是贝丝以​​色列执事医学中心和哈佛医学院内分泌学系的医学教练。拟议的研究将在BIDMC作为哈佛医学院神经生物学的主要地点和部门进行。在指导研究科学家发展奖的支持下，申请人将在技术上和智力上接受培训。该奖项的培训将极大地促进申请人成为成功的独立研究者，以采用独特的技能来解决喂养神经科学的关键问题。