Brainstem neuropeptidergic neurons link a neurohumoral axis to satiation

Hunger is evolutionarily hardwired to ensure that an animal has sufficient energy to survive and reproduce. Just as important as knowing when to start eating is knowing when to stop eating. Here, using spatially resolved single-cell phenotyping, we characterize a population of neuropeptidergic neurons in the brainstem's dorsal raphe nucleus (DRN) and describe how they regulate satiation. These neurons track food from sensory presentation through ingestion, integrate these signals with slower-acting humoral cues, and express cholecystokinin (CCK). These CCK neurons bidirectionally regulate meal size, driving a sustained meal termination signal with a built-in delay. They are also well positioned to sense and respond to ingestion: they express a host of metabolic signaling factors and are integrated into an extended network known to regulate feeding. Together, this work demonstrates how DRN CCK neurons regulate satiation and identifies a likely conserved cellular mechanism that transforms diverse neurohumoral signals into a key behavioral output.