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.

弓状核谷氨酸能神经元与饱腹感的调节 ARCAgRP神经元被禁食激活，被进食抑制。当它们被打开时， 驱使饥饿。另一方面，ARCPOMC神经元被视为ARCAgRP神经元的对应物。他们 以相反的方式调节，它们的活动导致相反的效果-减少饥饿感。的 这两个神经元的拮抗性“阴阳”功能是基本上所有提出的模型的恒定特征 饥饿/饱足调节的平衡。然而，与这一广泛持有的观点不一致的是， 并且ARCPOMC神经元的化学遗传激活在少于8-12周的时间内不能减少食物摄入。 小时的刺激。将此与ARCAgRP后几分钟观察到的对饥饿的强效作用形成鲜明对比 神经元刺激这种明显的缺乏效应强烈表明，ARCPOMC神经元本身并不 与ARCAgRP神经元完全对应。基于此，我们假设如下： A）ARC为基础的自我平衡的一个功能重要的，目前未知的神经成分 目前的模型缺少饱腹感系统。 B）不表达POMC的兴奋性ARCVGLUT 2神经元提供这种缺失的组分，并且当 刺激/抑制，它们迅速增加/减少饱腹感。 C）证实了遗传研究所证实的αMSH和MC 4 R的已知重要作用， 急性选择性刺激ARCPOMC神经元不能迅速影响饥饿，我们假设， ARCPOMC神经元不单独工作，而是通过增加兴奋性神经元的强度来减少饥饿感。 通过ARCVGLUT 2神经元至PVH饱腹感神经元突触的突触传递。我们假设， 通过αMSH/MC 4 R介导的对突触可塑性的影响发生。提出了以下三个目标： 目的1：ARCVGLUT 2饱腹感神经元-它们的功能、身份和Cre/Flp驱动程序提供“访问”。 目的2：ARCVGLUT 2神经元和黑皮质素系统之间的相互作用-PVH上的会聚 饱腹感神经元和αMSH/MC 4 R驱动的兴奋性突触可塑性的重要作用。 目的3：ARCVGLUT 2饱腹感神经元-它们的调节和负责的传入回路/机制。 由于这些ARCVGLUT 2神经元对饥饿/饱腹感发挥迄今未知的强双向控制， 探索它们的调节、特征和功能很重要，因为它们可以为以前的行为提供机制 观察到的现象，其基础是未知的或不完全理解。例子包括， 但不限于，αMSH/MC 4 R对饥饿的调节（如上所述）， NTS“饱腹感”神经元，以及GLP-1 R激动剂、催产素和大麻素对饥饿的调节（通过同源 ARCVGLUT 2神经元表达的受体）。这些研究应该提高对饥饿/饱腹感的理解。