Cellular coding of ingestion in the caudal brainstem

The termination of a meal is triggered by sensory feedback from the stomach and intestines that reports on ingested food^1-10 and is relayed to the caudal nucleus of the solitary tract (cNTS) in the brainstem^11-14. This sensory feedback is thought to gradually intensify as a meal progresses, resulting in the progressive activation of cNTS circuits that promote satiety^15,16, but this idea has never been tested by recording the single-cell activity of cNTS neurons while animals eat. Here, we have used a preparation for calcium imaging in the caudal brainstem of behaving animals¹⁷ to characterize how food ingestion is encoded in the cNTS. We find that when food is delivered directly to the stomach, most cNTS neurons exhibit ramping activation over many minutes that tracks cumulative food consumed and depends on canonical gut-brain pathways. However, when the same food is consumed by mouth, this widespread ramping activation is gone, and most cNTS neurons instead exhibit phasic, seconds-timescale responses to oral contact with food. We show that these rapid responses are driven by a combination of mechanical, gustatory and nutritive signals from the mouth and throat and do not require traditional gut-brain pathways, including gut-innervating vagal afferents, although GI feedback modulates their duration. We show that one source of this rapid input is descending projections from the paraventricular hypothalamus, which track ingestion dynamics and are required for proper meal termination. These findings reveal that sensory feedback from the stomach and intestines, which is directly transmitted to the cNTS and thought to be critical for satiety, is not the major driver of cNTS activity during ingestion. Instead, these circuits make extensive use of rapid, pregastric signals that report on the dynamics of behavior.