Bed nucleus of the stria terminalis neurons encode and retrieve cytokine-specific responses in male mice

The brain monitors peripheral inflammatory states and coordinates adaptive immune and physiological responses to maintain homeostasis. Specific brain regions process motor and sensory information from defined body regions, forming a somatotopic homunculus. Whether an analogous brain organizational principle exists for decoding peripheral cytokine signals and coordinating physiological responses is unknown. Here, using targeted recombination in active populations combined with serial two-photon tomography in male mice, we show that systemically administered tumor necrosis factor (TNF), a pro-inflammatory cytokine, or interleukin-10 (IL-10), an anti-inflammatory cytokine, prominently activate largely distinct neuronal populations within the bed nucleus of the stria terminalis (BNST) compared to other cytokine-responsive brain regions. TNF-responsive neurons localize predominantly within the protein kinase C delta positive oval subnucleus, whereas IL-10-responsive neurons reside mainly outside this subregion. Cross-cytokine challenge experiments confirm that the majority of these neuronal populations are selectively reactivated by their cognate cytokine, establishing cytokine-specific encoding within the BNST. Chemogenetic reactivation of TNF-TRAPed BNST neurons recapitulates TNF-induced hypothermia and elevates serum IL-6 and monocyte chemoattractant protein-1 (MCP-1) levels, whereas reactivation of IL-10-TRAPed neurons suppresses serum TNF, IL-6, and MCP-1 levels and attenuates hypothermia during endotoxemia. These findings demonstrate that the BNST houses parallel neuroimmune circuits that independently drive divergent pro-inflammatory and anti-inflammatory responses. Our studies reveal the BNST as a central node for decoding peripheral cytokine information and orchestrating distinct physiological outputs, and that the neuroimmune circuits within it constitute the substrate of immunengrams.