Stochastic neuropeptide signals compete to calibrate the rate of satiation.

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.