Stochastic neuropeptide signals compete to calibrate the rate of satiation

Stephen X. Zhang (), Angela Kim, Joseph C. Madara, Paula K. Zhu, Lauren F. Christenson, Andrew Lutas, Peter N. Kalugin, Praneel S. Sunkavalli, Yihan Jin, Akash Pal, Lin Tian, Bradford B. Lowell and Mark L. Andermann ()
Additional contact information
Stephen X. Zhang: Harvard Medical School
Angela Kim: Harvard Medical School
Joseph C. Madara: Harvard Medical School
Paula K. Zhu: Harvard Medical School
Lauren F. Christenson: Harvard Medical School
Andrew Lutas: Harvard Medical School
Peter N. Kalugin: Harvard Medical School
Praneel S. Sunkavalli: Harvard Medical School
Yihan Jin: University of California, Davis
Akash Pal: University of California, Davis
Lin Tian: University of California, Davis
Bradford B. Lowell: Harvard Medical School
Mark L. Andermann: Harvard Medical School

Nature, 2025, vol. 637, issue 8044, 137-144

Abstract: 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 satiety2–6. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08164-8

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