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才能在缺乏能量的状态下寻找和食用食物。虽然这种能量稳态协调表明大脑起源，但中央黑皮质素 4 受体 (Mc4r) 系统是否直接通过运动回路调节运动尚不清楚。在这里，我们报告斑马鱼和小鼠的下丘脑 Pomc 神经元对含有Mc4r的脊髓区域有长程投射。-表达 V2a 中间神经元，前运动网络的关键组成部分。此外，在斑马鱼中，Mc4r 激活降低了脊髓 V2a 神经元的兴奋性以及游泳和觅食，而 Mc4r 的全身性或 V2a 神经元特异性阻断促进了运动。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 激发，并且对 Mc4r 信号传导的急性抑制会降低运动活动。此外，我们发现脊髓层 X 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。总的来说，我们的研究将脊髓 V2a 中间神经元确定为中枢 Mc4r 系统的进化保守二级神经元，在能量稳态和运动控制系统之间提供直接的解剖和功能联系。这种调节系统对运动活动的净影响可能在不同脊椎动物物种之间变化，甚至可能在一个物种内变化。我们根据运动对能量平衡的模糊性和不同物种的不同生活条件来讨论这种现象的生物学意义。