Institute for Zoology, University of Cologne, Zülpicher Straße 47b, Cologne 50674, Germany.
Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Straße 50, Cologne 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Straße 26, Cologne 50924, Germany.
Curr Biol. 2020 Dec 7;30(23):4579-4593.e7. doi: 10.1016/j.cub.2020.08.103. Epub 2020 Sep 24.
Locomotion requires energy, yet animals need to increase locomotion in order to find and consume food in energy-deprived states. While such energy homeostatic coordination suggests brain origin, whether the central melanocortin 4 receptor (Mc4r) system directly modulates locomotion through motor circuits is unknown. Here, we report that hypothalamic Pomc neurons in zebrafish and mice have long-range projections into spinal cord regions harboring Mc4r-expressing V2a interneurons, crucial components of the premotor networks. Furthermore, in zebrafish, Mc4r activation decreases the excitability of spinal V2a neurons as well as swimming and foraging, while systemic or V2a neuron-specific blockage of Mc4r promotes locomotion. In contrast, in mice, electrophysiological recordings revealed that two-thirds of V2a neurons in lamina X are excited by the Mc4r agonist α-MSH, and acute inhibition of Mc4r signaling reduces locomotor activity. In addition, we found other Mc4r neurons in spinal lamina X that are inhibited by α-MSH, which is in line with previous studies in rodents where Mc4r agonists reduced locomotor activity. Collectively, our studies identify spinal V2a interneurons as evolutionary conserved second-order neurons of the central Mc4r system, providing a direct anatomical and functional link between energy homeostasis and locomotor control systems. The net effects of this modulatory system on locomotor activity can vary between different vertebrate species and, possibly, even within one species. We discuss the biological sense of this phenomenon in light of the ambiguity of locomotion on energy balance and the different living conditions of the different species.
运动需要能量，但动物需要增加运动来寻找和消耗处于能量匮乏状态下的食物。尽管这种能量稳态协调表明其起源于大脑，但中央黑皮质素 4 受体 (Mc4r) 系统是否通过运动回路直接调节运动仍不清楚。在这里，我们报告称，斑马鱼和小鼠的下丘脑 Pomc 神经元具有长程投射到脊髓区域，这些区域含有 Mc4r 表达的 V2a 中间神经元，这是运动前网络的关键组成部分。此外，在斑马鱼中，Mc4r 的激活会降低脊髓 V2a 神经元的兴奋性以及游泳和觅食行为，而全身性或 V2a 神经元特异性的 Mc4r 阻断则会促进运动。相比之下，在小鼠中，电生理记录显示，X 层中三分之二的 V2a 神经元被 Mc4r 激动剂 α-MSH 兴奋，而急性抑制 Mc4r 信号会降低运动活性。此外，我们还发现了 X 层中的其他 Mc4r 神经元被 α-MSH 抑制，这与之前在啮齿动物中的研究一致，其中 Mc4r 激动剂会降低运动活性。总之，我们的研究将脊髓 V2a 中间神经元确定为中央 Mc4r 系统的进化保守的二阶神经元，为能量稳态和运动控制系统之间提供了直接的解剖学和功能联系。这种调节系统对运动活性的净效应在不同的脊椎动物物种之间可能会有所不同，甚至在同一物种中也可能有所不同。我们根据运动对能量平衡的模糊性以及不同物种的不同生活条件来讨论这种现象的生物学意义。
