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
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Nature. 2025 Jan;637(8044):137-144. doi: 10.1038/s41586-024-08164-8. Epub 2024 Nov 6.
Neuropeptides have important roles in neural plasticity, spiking and behaviour. 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 (PVH) integrate neuropeptide signals to modulate feeding-related fast synaptic transmission and titrate the transition to satiety. We show that hunger-promoting AgRP axons release the neuropeptide NPY to decrease the second messenger cAMP in PVH 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 release, thereby sustaining elevated cAMP in PVH 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.
神经肽在神经可塑性、神经冲动发放及行为中发挥着重要作用。然而，关于它们在清醒大脑中的时空传递、整合及功能，仍存在许多基本问题。在此，我们研究了下丘脑室旁核（PVH）中表达促黑素细胞激素4受体（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，并调节向饱腹感的转变。我们发现，促进饥饿的刺鼠肽基因相关蛋白（AgRP）轴突释放神经肽神经肽Y（NPY），以降低PVH神经元中的第二信使环磷酸腺苷（cAMP）水平，而促进饱腹感的促阿片黑素皮质素原（POMC）轴突释放神经肽α-促黑素（αMSH），以增加cAMP水平。每次释放事件都是全或无的、随机的，并且可以影响直径约100微米区域内的多个神经元。释放后，NPY和αMSH肽相互竞争以控制cAMP——在进食状态下，高浓度的αMSH会减弱NPY信号的幅度和持续性，而在禁食状态下，高浓度的NPY会减弱αMSH信号。进食通过同时提高αMSH释放和抑制NPY释放来解决这种竞争，从而在整个进餐过程中维持PVH神经元中升高的cAMP水平。反过来，升高的cAMP促进每一口进食相关兴奋性输入的增强，从而在数分钟内逐渐促进饱腹感。我们的研究结果突出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。
