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: 8509162
• 负责人: Dong Kong
• 金额: $ 8.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509162
• 关键词: Ablation; Achievement; Adult; Affinity Chromatography; Anorexia; Anorexia Nervosa; Area; Arts; Attenuated; Award; Behavior; Binding; Brain; Communication; Data; Dendritic Spines; Desire for food; Eating; Eating Disorders; Electrophysiology (science); Energy Metabolism; Fasting; Feeding behaviors; Food; Gene Expression; Genetic; Glutamates; Goals; Grant; Hypothalamic structure; Image; Insulin; Israel; K-Series Research Career Programs; Knockout Mice; Knowledge; Laboratories; Laser Scanning Microscopy; Lasers; Leptin; Light; Medical center; Medicine; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metabolism; Methodology; Microscope; Microscopy; Mitochondria; Molecular; Molecular Profiling; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Neurosciences Research; Obesity; Pathologic Processes; Pathway interactions; Peptides; Photons; Physiological; Physiological Processes; Play; Property; Publications; Publishing; Regulation; Reporting; Research; Research Personnel; Ribosomes; Role; SK potassium channel; Science; Starvation; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Transmission; Synaptic plasticity; Technology; Testing; Time; Training; Translating; UCP2 protein; Work; base; career; effective therapy; energy balance; feeding; ghrelin; ghrelin receptor; hormone regulation; instructor; interest; medical schools; molecular site; neurotransmitter release; novel; nutrition; optogenetics; postsynaptic; professor; public health relevance; research study; response; skills; synaptogenesis; tomography; transmission process

DESCRIPTION (provided by applicant): Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus are critical regulators of energy balance. AgRP neurons are anabolic: optogenetic or pharmaco-genetic stimulation of AgRP neurons drives intense feeding behavior and promotes obesity; disruption of these neurons in adult mice causes severe anorexia. Given the important roles played by AgRP neurons, there is great interest in understanding the factors that regulate their activity. Most previous studies have been placed on examining their direct regulation by circulating factors, such as leptin, insulin, and ghrelin. Their synaptic regulation by neurotransmitters released from other neurons in the brain, however, has been greatly overlooked. This is unfortunate because defective synaptic transmission on these neurons could also contribute to eating disorders. Furthermore, it is likely that the mechanism-of-action for hormonal regulation of AgRP neurons, for example by ghrelin, is modulation of afferent synaptic transmission. Through the recent work at Dr. Brad Lowell group (Prof of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School), the candidate has found that glutamatergic synaptic transmission plays a key role in AgRP neurons. In particular, he discovered that AgRP neurons but not the adjacent POMC neurons have dendritic spines, 1um3 protrusions where majority of glutamatergic synapses reside and within which glutamate NMDA receptors operate to control synaptic plasticity. In addition, he found that the fasting- induced activation of AgRP neurons and its related feeding behavior are paralleled (and likely caused) by a marked increase in the number of spines (i.e. spinogenesis), and this is dependent on postsynaptic NMDARs. Thus, glutamatergic transmission and its plasticity, as modulated by postsynaptic NMDARs, play critical roles in controlling AgRP neuron activity and their related feeding behaviors. These findings, which are recently published on Neuron, provide the candidate a unique opportunity to interrogate synaptic regulations in the feeding circuits. However, to pursue such studies, some state-of-art technologies (such as electrophysiology combined with 2-photon microscope imaging), which are beyond the scope of Dr. Lowell's lab and not available at BIDMC, are required. Toward these ends, the candidate is now trained by Dr. Bernardo Sabatini (Prof of Neurobiology, HHMI, Dept. of Neurobiology, Harvard Medical School), to use such advanced technologies to study structural and functional properties of spines. In this K01 mentored career development award, under the mentorship of Dr. Sabatini, and co- mentorship of Dr. Lowell, the candidate proposes to obtain acquisition in both scientific knowledge and in technologies (electrophysiology combined with 2-photon microscope imaging) related to synapse studies, and develop other necessary skills toward his career independence (immediate goal). The candidate is now Instructor in Medicine at BIDMC and Harvard Medical School. Once he finishes training with Dr. Sabatini, he will be transitioned to Assistant Professor at BIDMC and establish his own laboratory, become an independent investigator in the area of nutrition, obesity and neuroscience research, and apply multi- disciplinary methodology to understand synaptic plasticity in hypothalamic neurons controlling feeding, energy expenditure, and fuel metabolisms (long-term goal). Therefore, the K01 award will provide the candidate protected time to obtain necessary training before he becomes independent. At the same time, the proposed project in this award will greatly help the candidate to obtain subsequent R01 grant support.

描述（由申请人提供）：下丘脑的弓形核中与Agouti相关的肽（AGRP）表达神经元是能量平衡的关键调节剂。 AGRP神经元是合成代谢的：AGRP神经元的光遗传学或药物基因刺激驱动强烈的喂养行为并促进肥胖症；这些神经元在成年小鼠中的破坏会引起严重的厌食症。鉴于AGRP神经元所扮演的重要角色，人们对了解调节其活动的因素有很大的兴趣。以前的大多数研究是 通过循环因子（例如瘦素，胰岛素和生长素释放蛋白）检查其直接调节。然而，它们对从大脑其他神经元释放的神经递质的突触调节被极大地忽略了。这是不幸的，因为这些神经元上的突触传播缺陷也可能导致饮食失调。此外，例如，Ghrelin的激素调节激素调节的作用机理可能是对传入突触传播的调节。通过Brad Lowell Group博士的最新工作（医学教授，贝丝以色列执事医学中心和哈佛医学院），候选人发现谷氨酸能突触传播在AGRP神经元中起关键作用。特别是，他发现AGRP神经元而不是相邻的POMC神经元具有树突状棘，1UM3突起，其中大多数谷氨酸能突触均位于其中，谷氨酸NMDA受体在其中工作以控制突触可变。此外，他发现禁食诱导的AGRP神经元的激活及其相关的喂养行为是由于棘突数的明显增加（即旋转生成）并行的（并可能引起的），这取决于突触后NMDAR。因此，通过突触后NMDAR调节的谷氨酸能传播及其可塑性在控制AGRP神经元活性及其相关喂养行为方面起着关键作用。这些最近发表在神经元上的发现为候选人提供了一个独特的机会，可以在喂养电路中询问突触法规。但是，为了进行此类研究，需要某些最先进的技术（例如电生理学与2光子显微镜成像相结合），这些技术超出了Lowell博士实验室的范围，并且不需要BIDMC。在这些目的方面，候选人现在由Bernardo Sabatini博士（神经生物学教授，HHMI，HHMI，HHMI，HHMI，哈佛医学院）培训，使用此类先进的技术来研究刺的结构和功能性能。在Sabatini博士的指导下以及洛厄尔博士的共同指导下的K01指导职业发展奖中，候选人提议获得与科学知识和技术（电生理学与2光孔显微镜成像）相关的收购突触研究，并发展其他必要的技能，以实现其职业独立性（直接目标）。该候选人现在是BIDMC和哈佛医学院医学教练。一旦他与Sabatini博士结束培训，他将被过渡到BIDMC的助理教授，并建立自己的实验室，成为营养，肥胖和神经科学研究领域的独立研究者，并采用多学科方法来了解多学科的方法论控制喂养，能量消耗和燃料代谢（长期目标）的下丘脑神经元。因此，K01奖将为候选人提供受保护的时间，以便在独立之前获得必要的培训。同时，本奖项中的拟议项目将极大地帮助候选人获得随后的R01赠款支持。