Glutamatergic Neurons in the Arcuate Nucleus (ARC) and Regulation of Satiety

弓状核 (ARC) 中的谷氨酸能神经元与饱腹感的调节

• 批准号: 9353418
• 负责人: BRADFORD B LOWELL
• 金额: $ 43.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353418
• 关键词: Acute; Affect; Agonist; CNR1 gene; Cannabinoids; Development; Drops; Eating; Employee Strikes; Excitatory Synapse; Fasting; Feedback; GLP-I receptor; Genetic; Genetic study; Glutamates; Hour; Human; Hunger; Hyperphagia; Lead; Link; Mediating; Modeling; Mus; Neurons; Obesity; Oxytocin; Oxytocin Receptor; Prosencephalon; RNA; Rabies; Regulation; Role; Satiation; Site; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Yin-Yang; base; feeding; gamma-Aminobutyric Acid; improved; increased appetite; inhibitory neuron; interest; loss of function; novel; novel therapeutic intervention; optogenetics; postsynaptic; receptor; relating to nervous system; transcriptome sequencing; transmission process

Glutamatergic Neurons in the Arcuate Nucleus (ARC) and Regulation of Satiety ARCAgRP neurons are activated by fasting and inhibited by feeding. When turned on, they rapidly and potently drive hunger. ARCPOMC neurons, on the other hand, are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and their activity leads to opposite effects - decreased hunger. The antagonistic “yin-yang” functions of these two neurons is a constant feature of essentially all proposed models of homeostatic hunger/satiety regulation. At odds with this widely held view, however, is the finding that opto- and chemo-genetic activation of ARCPOMC neurons fails to decrease food intake over a period of less than 8-12 hours of stimulation. Contrast this with the potent effect on hunger observed just minutes following ARCAgRP neuron stimulation. This striking lack of effect strongly suggests that ARCPOMC neurons, by themselves, are not the full counterpoint to ARCAgRP neurons. Based on this, we hypothesize the following: A) A functionally important, presently unknown neural component of the ARC-based homeostatic satiety system is missing from current models. B) Excitatory ARCVGLUT2 neurons not expressing POMC provide this missing component and when stimulated / inhibited, they rapidly increase / decrease satiety. C) Reconciling the known important roles of αMSH and MC4Rs as evidenced by genetic studies, with the inability of acute selective stimulation of ARCPOMC neurons to rapidly affect hunger, we hypothesize that ARCPOMC neurons do not work in isolation but instead decrease hunger by increasing the strength of excitatory synaptic transmission across the ARCVGLUT2 neuron à PVH satiety neuron synapse. We postulate that this occurs via αMSH/MC4R-mediated effects on synaptic plasticity. The following 3 aims are proposed: Aim 1: ARCVGLUT2 satiety neurons – their function, identity and Cre/Flp drivers providing “access”. Aim 2: The interaction between ARCVGLUT2 neurons and the melanocortin system – convergence on PVH satiety neurons and an important role for αMSH/MC4R-driven excitatory synaptic plasticity. Aim 3: ARCVGLUT2 satiety neurons – their regulation and the responsible afferent circuits / mechanisms. As these ARCVGLUT2 neurons exert hitherto unknown strong, bidirectional control over hunger / satiety, it is important to explore their regulation, features and functions as they could provide mechanisms for previously observed phenomenon for which the basis is either unknown or incompletely understood. Examples include, but are not limited to, αMSH/MC4R regulation of hunger (as discussed above), a forebrain site of action for NTS “satiety” neurons, and regulation of hunger by GLP-1R agonists, oxytocin and cannabinoids (via cognate receptors expressed by ARCVGLUT2 neurons). These studies should improve understanding of hunger / satiety.

弧形核（ARC）中的谷氨酸能神经元和饱腹感调节 Arcagrp神经元被禁食激活，并通过喂养抑制。打开时，它们迅速而可能 开车饥饿。另一方面，ARCPOMC神经元被视为与Arcagrp神经元的对立。他们 以相反的方式进行调节，其活动会导致相反的影响 - 发达的饥饿。这 这两个神经元的拮抗“阳阳”功能是所有提出模型的恒定特征 稳态饥饿/饱腹感。然而，与这种广泛持有的观点相反，发现选择 ARCPOMC神经元的化学遗传激活在小于8-12的时间内无法降低食物摄入量 小时的刺激。将其与对饥饿的潜在影响进行对比，仅在Arcagrp之后几分钟 神经元刺激。这种引人注目的缺乏效果强烈表明ARCPOMC神经元本身不是 Arcagrp神经元的完整对立。基于此，我们假设以下内容： a）基于ARC的稳态的功能上重要的，目前未知的神经成分 当前型号缺少饱腹感系统。 b）未表达pomc的兴奋性arcVglut2神经元提供了这种缺失的成分，何时 受刺激 /抑制作用，它们迅速增加 /减少饱腹感。 c）与遗传研究证明了αMSH和MC4R的已知重要作用， 急性选择性刺激ARCPOMC神经元无法快速影响饥饿，我们假设 ARCPOMC神经元不能孤立起作用，而是通过增加兴奋性的强度来减少饥饿 穿过ArcVglut2NeuronàPVH饱腹神经元突触的突触传播。我们假设这个 通过αMSH/MC4R介导的对合成可塑性的影响发生。提出了以下3个目标： AIM 1：ARCVGLUT2饱腹神经元 - 其功能，身份和Cre/FLP驱动程序提供“访问”。 AIM 2：ArcVglut2神经元与黑色素质素系统之间的相互作用 - PVH收敛 饱腹神经元和αMSH/MC4R驱动的令人兴奋的合成可塑性的重要作用。 AIM 3：Arcvglut2饱腹神经元 - 其调节和负责的传入电路 /机制。 由于这些ArcVglut2神经元迄今未知强，双向控制饥饿 /饱腹 探索其调节，功能和功能很重要，因为它们可以提供以前的机制 观察到的现象是基础未知或未完全理解的现象。示例包括， 但不限于饥饿的αMSH/MC4R调节（如上所述），这是一个前脑作用部位 NTS“饱腹感”神经元，以及GLP-1R激动剂，氧气和大麻素的饥饿调节（通过Cognate） ArcVglut2神经元表达的受体）。这些研究应提高对饥饿 /饱腹感的理解。