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）：下丘脑弓状核中表达刺豚鼠相关肽（AgRP）的神经元是能量平衡的关键调节因子。 AgRP 神经元具有合成代谢作用：AgRP 神经元的光遗传学或药物遗传学刺激可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 神经元发挥的重要作用，人们对了解调节其活动的因素非常感兴趣。以前的大多数研究都是 研究人员致力于检查瘦素、胰岛素和生长素释放肽等循环因子对它们的直接调节作用。然而，它们通过大脑其他神经元释放的神经递质进行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递缺陷也可能导致饮食失调。此外，AgRP 神经元的激素调节（例如生长素释放肽）的作用机制很可能是传入突触传递的调节。通过Brad Lowell博士小组（贝斯以色列女执事医疗中心和哈佛医学院医学教授）最近的工作，该候选人发现谷氨酸突触传递在AgRP神经元中起着关键作用。特别是，他发现 AgRP 神经元（而不是相邻的 POMC 神经元）具有树突棘，即 1um3 的突起，大多数谷氨酸突触驻留在其中，并且谷氨酸 NMDA 受体在其中发挥作用来控制突触可塑性。此外，他发现禁食诱导的 AgRP 神经元激活及其相关的进食行为与棘数量的显着增加（即棘发生）是平行的（并且可能是由其引起的），而这依赖于突触后 NMDAR。因此，由突触后 NMDAR 调节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摄食行为中发挥着关键作用。这些研究结果最近发表在 Neuron 上，为候选人提供了一个独特的机会来询问喂养回路中的突触调节。然而，要进行此类研究，需要一些最先进的技术（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 BIDMC 不具备。为了实现这些目标，候选人现在接受 Bernardo Sabatini 博士（哈佛医学院神经生物学系、HHMI 神经生物学教授）的培训，使用此类先进技术来研究脊柱的结构和功能特性。在这个 K01 指导职业发展奖中，在 Sabatini 博士的指导和 Lowell 博士的共同指导下，候选人建议获得以下方面的科学知识和技术（电生理学与 2 光子显微镜成像相结合）：突触研究，并培养其他必要的技能以实现职业独立（近期目标）。该候选人现在是 BIDMC 和哈佛医学院的医学讲师。一旦完成Sabatini博士的培训，他将转任BIDMC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，并应用多学科方法来理解突触可塑性下丘脑神经元控制进食、能量消耗和燃料代谢（长期目标）。因此，K01奖项将为候选人提供受保护的时间，以便在他独立之前获得必要的培训。同时，本次奖项中提出的项目将极大地帮助候选人获得后续的R01拨款支持。