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(申请人提供)：下丘脑神经元，包括弓状核中的AgRP和POMC神经元，检测营养状态的变化，并将信号传递到下游目标，以调节食物摄入量和能量消耗。这些神经元的功能障碍被认为是导致肥胖和神经性厌食症的原因。然而，人们对其机制仍知之甚少。人们的注意力主要集中在体液因素对这些神经元的调节上，如胰岛素、瘦素和Ghrelin。这些神经元的突触调节，在 另一方面，这很可能是重要的，但在很大程度上被忽视了。我们的初步研究揭示了NMDA受体和树突棘在AgRP神经元上的关键作用。然而，这一规定背后的机制是未知的。因此，本项目的目标是确定NMDA受体和在单个AgRP神经元树突棘上形成的突触的作用，并确定在这些树突棘内工作的特定信号机制。然而，观察和刺激单个突触局部活动的技术挑战阻碍了这一目标的实现。需要采用先进的方法，如双光子激光扫描显微镜(2PLSM)和谷氨酸双光子去化(2PLU)。这些强大的技术在低估突触功能方面占据了一个独特的利基市场。在小鼠遗传学和下丘脑专家布拉德·洛厄尔博士的指导下，以及突触可塑性和树突棘方面的领先专家贝尔纳多·萨巴蒂尼博士的共同指导下，将使用多种方法组合来评估AgRP神经元的突触调节。具体地说，2PLU/2PLSM结合电生理学和钙成像将被用来确定兴奋性神经传递到AgRP神经元的突触可塑性如何受到与摄食相关的信号的调节。这些研究应该为AgRP神经元活动的调节提供机械性的见解，从而更好地理解摄食行为是如何被控制的。申请人现为内分泌科内分泌科讲师。贝丝以色列女执事医学中心和哈佛医学院的医学博士。拟议的研究将在BIDMC作为主要地点和部门进行。哈佛医学院的神经生物学作为第二个地点。在导师研究科学家发展奖的支持下，申请者将接受技术和智力方面的培训。该奖项支持的培训将极大地促进申请者成为一名成功的独立调查者，利用独特的技能集来解决喂养神经科学中的关键问题。