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

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.