Stochastic neuropeptide signals compete to calibrate the rate of satiation

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; University of California System; University of California Davis; University of California System; University of California Davis; Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); Max Planck Society
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3052
• DOI: 10.1038/s41586-024-08164-8
• 发表日期: 2025-01-02
• 关键词: food cue responses; paraventricular nucleus; pomc neurons; receptor; brain; camp; agrp; hypothalamus; transmission; DYNAMICS

摘要

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 satiety2-6. 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 alpha MSH to increase cAMP. Each release event is all-or-none, stochastic and can impact multiple neurons within an approximately 100-mu m-diameter region. After release, NPY and alpha MSH peptides compete to control cAMP-the amplitude and persistence of NPY signalling is blunted by high alpha MSH in the fed state, while alpha MSH signalling is blunted by high NPY in the fasted state. Feeding resolves this competition by simultaneously elevating alpha MSH 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. Release of hunger-promoting and satiety-promoting neuropeptides drives opposing changes in the second messenger cAMP in awake mouse paraventricular hypothalamic MC4R neurons, thereby regulating synaptic plasticity and the transition to satiety with each bite of food.