Dendritic Spines on AgRP Neurons as Communication Hubs Controlling Feeding

描述（由申请人提供）：下丘脑弓状核中表达Agouti相关肽（AgRP）的神经元是能量平衡的关键调节因子。AgRP神经元是合成代谢的：AgRP神经元的光遗传学或药物遗传学刺激驱动强烈的进食行为并促进肥胖;成年小鼠中这些神经元的破坏引起严重的厌食症。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 放在检查他们的直接调节循环因子，如瘦素，胰岛素，和ghrelin。然而，它们通过大脑中其他神经元释放的神经递质进行的突触调节却被极大地忽视了。这是不幸的，因为这些神经元上有缺陷的突触传递也可能导致饮食失调。此外，可能的是，AgRP神经元的激素调节的作用机制，例如通过生长激素释放肽，是传入突触传递的调制。通过布拉德洛厄尔博士（医学教授，贝斯以色列女执事医学中心和哈佛医学院）最近的工作，候选人发现，神经元突触传递在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，1 μ m 3突起，其中大多数谷氨酸能突触位于其中，谷氨酸NMDA受体控制突触可塑性。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是由棘数量的显著增加（即棘发生）引起的（并且可能是由其引起的），并且这依赖于突触后NMDAR。因此，突触后NMDARs调控的突触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起着关键作用。这些发现最近发表在Neuron上，为候选人提供了一个独特的机会来询问喂食回路中的突触调节。然而，为了进行这些研究，需要一些最先进的技术（如电生理学与双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，BIDMC也无法提供。为此，该候选人现在接受Bernardo Sabatini博士（HHMI神经生物学教授）的培训。of Neurobiology，哈佛医学院），使用这种先进的技术来研究脊柱的结构和功能特性。在K 01指导职业发展奖中，在Sabatini博士的指导下，以及Lowell博士的共同指导下，候选人建议获得与突触研究相关的科学知识和技术（电生理学结合双光子显微镜成像），并发展其他必要的技能，以实现职业独立（近期目标）。候选人现在是BIDMC和哈佛医学院的医学讲师。一旦他完成与Sabatini博士的培训，他将被转换为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，并应用多学科方法来了解控制进食，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，K 01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，本次获奖的拟立项项目将极大地帮助候选人获得后续R 01的资助支持。

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.