Disruption of Pre-Bötzinger Complex neuropeptidergic tonality controls fear and metabolic response

Summary Stress profoundly impacts systemic metabolism, yet the central circuits linking stress responses to peripheral metabolic regulation remain poorly defined. Here, we identify the preBötzinger complex (preBötC), a brainstem breathing rhythm generator, as a key stress-responsive hub coordinating metabolic adaptations. Using viral tracing, we show that preBötC neurons project to brown adipose tissue and liver, and that a subset of these projection neurons expresses the pituitary adenylate cyclase–activating polypeptide (PACAP) receptor PAC1R, positioning PACAP signaling as a critical modulator of this circuit. Whole-brain c-Fos mapping revealed robust preBötC activation under stress, while spatial transcriptomics demonstrated altered neuronal metabolic circuitry in preBötC following PAC1R ablation. PAC1R knockdown in preBötC combined with stress resulted in blunted respiratory rhythmicity, reduced sympathetic innervation, and suppression of energy expenditure and lipid metabolic pathways in brown fat, while reprogramming hepatic transcriptional networks toward amino acid metabolism and gluconeogenesis. These findings define a unique neuropeptidergic brainstem–periphery circuit integrating stress, respiration, and metabolism. Highlights PAC1R deletion in preBötC amplifies PTSD-like fear—greater generalization and freezing despite equal stress. PreBötC-PAC1R neurons send projections to BAT and liver, forming a respiratory-metabolic hub. Loss of PAC1R lifts the preBötC “brake,” raising resting breathing rate and magnifying stress-induced heart-rate spikes. Loss of PAC1R show systemic metabolic failures—glucose intolerance, lower VO₂ input, reduced energy expenditure, and weaker BAT sympathetic tone. Spatial transcriptomics reveal marked shifts in preBötC neuronal subpopulations after PAC1R ablation.