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: 8846106
• 负责人: Dong Kong
• 金额: $ 15.26万
• 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/8846106
• 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; Health; 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; 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; research study; response; skills; synaptogenesis; tomography; transmission process; two-photon

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(申请人提供)：下丘脑弓状核中表达刺鼠相关肽(AgRP)的神经元是能量平衡的关键调节者。AgRP神经元是合成代谢的：AgRP神经元的光遗传或药物遗传刺激驱动强烈的摄食行为并促进肥胖；成年小鼠这些神经元的破坏会导致严重的厌食症。鉴于AgRP神经元的重要作用，人们对了解调节其活动的因素非常感兴趣。之前的大多数研究都是 重点研究它们受循环因子的直接调节，如瘦素、胰岛素和胃促生长素。然而，大脑中其他神经元释放的神经递质对它们的突触调节却被大大忽视了。这是不幸的，因为这些神经元上的突触传输缺陷也可能导致进食障碍。此外，激素调节AgRP神经元的作用机制，例如Ghrelin，很可能是调节传入突触传递。通过布拉德·洛厄尔博士(医学教授、贝丝以色列女执事医学中心和哈佛医学院)最近的研究，这位候选人发现谷氨酸能突触传递在AgRP神经元中扮演着关键角色。特别是，他发现AgRP神经元而不是邻近的POMC神经元有树突棘，1um3突起是大多数谷氨酸能突触的居住地，谷氨酸NMDA受体在其中发挥作用来控制突触的可塑性。此外，他发现，禁食诱导的AgRP神经元的激活及其相关的摄食行为与脊柱数量的显著增加(即棘突形成)平行(并且可能是由这种行为引起的)，而这依赖于突触后的NMDAR。因此，受突触后NMDAR调控的谷氨酸能传递及其可塑性在控制AgRP神经元活动及其相关的摄食行为中起着至关重要的作用。最近发表在《神经元》杂志上的这些发现，为候选人提供了一个独特的机会来询问馈电回路中的突触调节。然而，为了进行这样的研究，需要一些最先进的技术(如电生理学和双光子显微镜成像相结合)，这些技术超出了洛厄尔博士的实验室的范围，BIDMC没有。为了达到这些目的，候选人现在接受贝尔纳多·萨巴蒂尼博士(HHMI系神经生物学教授)的培训。哈佛医学院神经生物学教授)利用这种先进技术来研究脊椎的结构和功能特性。在萨巴蒂尼博士的指导和洛厄尔博士的共同指导下，在这项K01指导职业发展奖中，候选人提议获得与突触研究相关的科学知识和技术(电生理学与双光子显微镜成像相结合)，并发展其他必要的技能，以实现职业独立(直接目标)。这位候选人现在是BIDMC和哈佛医学院的医学讲师。完成萨巴蒂尼博士的培训后，他将过渡到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员，并应用多学科方法了解控制摄食、能量消耗和燃料代谢的下丘脑神经元的突触可塑性(长期目标)。因此，K01奖将为考生提供受保护的时间，以便在他独立之前获得必要的培训。同时，该奖项中建议的项目将极大地帮助候选人获得后续的R01拨款支持。