Fig. 8: Proposed parallel circuits for cold defense.

The LPB → POA → DMH/RPa circuitry has been proposed before¹⁰ and the model updated by this study is shaded in grey color. Afferent cool/cold signals activate Vglut2⁺ neurons in the LPB. Among these cold-activated neurons (cFos⁺; 100%), 45% projected to the POA (mainly the MnPO, VMPO, and LPO), 38% projected to the DMH, and 20% projected to both regions. Of note, this percentage might be underestimated due to the limited retrograde efficiency. Projection-specific neural blockings suggest that both the LPB → POA and LPB → DMH pathways are required in cold defense, where the two pathways contribute equivalently and cumulatively to cold defense and therefore form a parallel circuit. Within the LPB → DMH pathway, 60% of LPB-innervated DMH neurons are Vgat⁺, while 20% of them are Vglut2⁺. Activation of the LPB → DMH pathway induces strong cold-defense responses, including increases in BAT thermogenesis, muscle shivering, heart rate, and locomotion. Both the DMH^Vgat and DMH^Vglut2 neurons are required to support the cold-defense function of the LPB → DMH pathway. Additionally, a subpopulation of SST⁺ neurons in the LPB targets DMH^LepR neurons to promote BAT thermogenesis selectively, suggesting a genetically defined neural projection controls specific cold-defense activities. Downstream of the DMH, the RPa or rostral medullary raphe region (rMR) is known to regulate BAT thermogenesis, muscle shivering, and heart rate, while the regulation of locomotion is not clear. This schematic was created with BioRender.com.