Title: State-dependent control of feeding in orbitofrontal cortex

Abstract: Feeding decisions depend on internal state, yet the higher-order cortical circuitry that flexibly influences consummatory behavior remains unclear. We combined genetically encoded calcium imaging with projection-specific optogenetics to dissect the role of orbitofrontal cortex (OFC) ensembles and their outputs to dorsal raphe nucleus (DRN) during feeding. Single-cell resolution activity imaging revealed that OFC responses aligned to feeding are heterogeneous: one neuronal subpopulation was time-locked to consumption during hunger, while a distinct set that was largely quiescent during hunger became active with satiety. These feeding-linked responses were enriched among OFC neurons projecting to DRN relative to non-projection-defined OFC cells. One-photon optogenetic manipulations of these OFC → DRN neurons revealed strong, state-dependent effects. In hungry mice, activation of this top-down circuit increased food intake, while inhibition suppressed intake. In sated mice, the same optogenetic inhibition surprisingly promoted overeating. Finally, single-cell resolution holographic activation of identified OFC → DRN feeding-responsive ensembles (8 cells per mouse) increased food consumption, while activating the same number of feeding-responsive OFC neurons without projection identity did not alter feeding, establishing an all-optical approach to probe the causal contributions of activity- and projection-defined ensembles in vivo. Together, these results demonstrate that small, projection-defined OFC → DRN ensembles encode and causally control consummatory behavior, with effects gated by internal state. By linking ensemble heterogeneity, long-range connectivity, and state-dependent behavior, this work reveals critical insights about how higher-order brain regions, conserved from mouse to human, govern flexible feeding, with important implications for the etiology and treatment of eating disorders.

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