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

弓状核内的谷氨酸能神经元与饱腹感的调节 ARCAgRP神经元在禁食时被激活，在进食时被抑制。打开后，它们会迅速而有力地 驱赶饥饿。另一方面，ARCPOMC神经元被视为ARCAgRP神经元的对应物。他们 以相反的方式受到监管，它们的活动会产生相反的效果--减少饥饿。这个 这两个神经元的相互拮抗的“阴阳”功能基本上是所有提出的模型的一个恒定特征。 动态平衡饥饿/饱腹感调节。然而，与这一普遍持有的观点不同的是，发现光学- 而ARCPOMC神经元的化学遗传激活在8-12小时内并不能减少食物摄入量 数小时的刺激。这与ARCAgRP几分钟后观察到的对饥饿的强大影响形成了对比 神经元刺激。这种惊人的缺乏作用强烈地表明，ARCPOMC神经元本身并不是 ARCAgRP神经元的完整对应物。在此基础上，我们假设如下： A)以ARC为基础的内稳态的一个功能上重要的、目前未知的神经成分 目前的车型缺少饱腹感系统。 B)不表达POMC的兴奋性ARCVGLUT2神经元提供这种缺失的成分，以及何时 刺激/抑制，它们迅速增加/减少饱腹感。 C)将遗传学研究证明的α、MSH和MC4Rs的已知重要作用与 急性选择性刺激ARCPOMC神经元不能迅速影响饥饿，我们假设 ARCPOMC神经元不是孤立工作的，而是通过增加兴奋性强度来减少饥饿 通过ARCVGLUT2神经元的突触传递类似于PVH饱和神经元突触。我们假定这一点 通过α、msh/mc4r对突触可塑性的影响而发生。提出了以下三个目标： 目的1：ARCVGLUT2饱腹感神经元--它们的功能、身份和CRE/FLP驱动因子提供“通路”。 目的2：ARCVGLUT2神经元与黑素皮质素系统的相互作用--PVH上的聚集性 饱腹感神经元在α刺激的兴奋性突触可塑性中起重要作用。 目的3：ARCVGLUT2饱和神经元--它们的调节和负责的传入回路/机制。 当这些ARCVGLUT2神经元对饥饿/饱腹感施加迄今未知的强大双向控制时， 重要的是要探索它们的监管、特点和功能，因为它们可以为以前的 观察到的现象，其基础不是未知就是不完全了解。例如， 但不限于，αmsh/mc4r对饥饿的调节(如上所述)，一个前脑作用部位 NTS“饱腹感”神经元和GLP-1R激动剂、催产素和大麻素对饥饿的调节(通过同源 ARCVGLUT2神经元表达的受体)。这些研究应该会提高对饥饿/饱腹感的理解。

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.