美国哈佛医学院Mark L. Andermann和Stephen X. Zhang共同合作，近期取得重要工作进展。他们研究提出，随机神经肽信号竞相校准饱腹率。相关研究成果2024年11月6日在线发表于《自然》杂志上。

据介绍，神经肽在神经可塑性、尖峰和行为中起着重要作用。然而，关于它们在清醒大脑中的时空传递、整合和功能，仍存在许多基本问题。

研究人员探讨了下丘脑室旁核（PVH^MC4R）中表达MC4R的神经元如何整合神经肽信号，以调节与进食相关的快速突触传递，并控制向饱腹感的转变。研究人员发现，饥饿促进的AgRP轴突释放神经肽NPY以降低PVH^MC4R神经元中的第二信使cAMP，而饱腹促进的POMC轴突释放神经肽αMSH以增加cAMP。

每个释放事件都是随机的，可以影响直径约为100µm的区域内的多个神经元。释放后，NPY和αMSH肽竞争控制cAMP，在进食状态下，高αMSH会减弱NPY信号传导的幅度和持续性，而在禁食状态下，αMSH信号传导会被高NPY减弱。喂食通过同时提高α-MSH的释放和抑制NPY的释放来解决这种竞争，从而在整个用餐过程中维持PVH^MC4R神经元中cAMP的升高。反过来，升高的cAMP有助于增强每次进食时与进食相关的兴奋性输入，从而在几分钟内逐渐促进饱腹感。

总之，这一研究结果强调了肽信号整合和信息积累的生化模式，以指导行为状态的转变。

附：英文原文

Title: Stochastic neuropeptide signals compete to calibrate the rate of satiation

Author: Zhang, Stephen X., Kim, Angela, Madara, Joseph C., Zhu, Paula K., Christenson, Lauren F., Lutas, Andrew, Kalugin, Peter N., Sunkavalli, Praneel S., Jin, Yihan, Pal, Akash, Tian, Lin, Lowell, Bradford B., Andermann, Mark L.

Issue&Volume: 2024-11-06

Abstract: Neuropeptides have important roles in neural plasticity, spiking and behaviour1. Yet, many fundamental questions remain regarding their spatiotemporal transmission, integration and functions in the awake brain. Here we examined how MC4R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVHMC4R) integrate neuropeptide signals to modulate feeding-related fast synaptic transmission and titrate the transition to satiety2,3,4,5,6. We show that hunger-promoting AgRP axons release the neuropeptide NPY to decrease the second messenger cAMP in PVHMC4R neurons, while satiety-promoting POMC axons release the neuropeptide αMSH to increase cAMP. Each release event is all-or-none, stochastic and can impact multiple neurons within an approximately 100-μm-diameter region. After release, NPY and αMSH peptides compete to control cAMP—the amplitude and persistence of NPY signalling is blunted by high αMSH in the fed state, while αMSH signalling is blunted by high NPY in the fasted state. Feeding resolves this competition by simultaneously elevating αMSH release and suppressing NPY release7,8, thereby sustaining elevated cAMP in PVHMC4R neurons throughout a meal. In turn, elevated cAMP facilitates potentiation of feeding-related excitatory inputs with each bite to gradually promote satiation across many minutes. Our findings highlight biochemical modes of peptide signal integration and information accumulation to guide behavioural state transitions.

DOI: 10.1038/s41586-024-08164-8

Source: https://www.nature.com/articles/s41586-024-08164-8