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bioRxiv · 10.1101/2025.11.27.690920

Dorsomedial hypothalamus cold-sensitive neurons drive shivering thermogenesis

Zhang, S.·Zhang, H.·Huang, Z.·Wu, S.·Zhang, Z.·He, W.·Li, D.·Yang, X.·Wang, Y.·Huang, L.·Liu, R.·Hou, S.-T.
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Abstract

Hypothermia, a decline in core body temperature below 35{degrees}C in homeotherms, elicits rapid, asynchronous involuntary shivering thermogenesis; however, the hypothalamic neurons responsible for initiating this response remain uncharacterized. Here, retrograde transsynaptic tracing combined with RNA-seq identified a distinct population of VGLUT2-positive neurons enriched with Calbindin D28k (CALB1) within the dorsomedial hypothalamic nucleus (DMHCalb1/Vglut2). Convergent evidence from chemogenetic, optogenetic, fiber photometry calcium imaging, and electromyography (EMG) experiments demonstrated that these neurons selectively mediate hypothermia-triggered shivering thermogenesis. Bidirectional perturbation of DMHCalb1/Vglut2 activity modulated shivering intensity, while CALB1-negative VGLUT2-expressing DMH neurons were responsible for non-shivering thermogenesis (NST). Genetic ablation of afferent inputs from LSI/POA/VLPAG projecting to DMHCalb1/Vglut2, as well as ex vivo pharmacological synaptic blockade, failed to eliminate shivering responses during hypothermia, indicating that their activation is independent of canonical cold-responsive circuits. Hypothermia significantly suppressed transient A-type K (IA) currents, without affecting delayed rectifier K (IK) currents, accompanied by a pronounced reduction in the IA inactivation time constant relative to normothermic 36 {degrees}C. Collectively, hypothermia elevates DMHCalb1/Vglut2 excitability through IA-dependent reshaping of action potential dynamics. Shortened action potential repolarization and afterhyperpolarization duration cooperatively boost neuronal firing, constituting an intrinsic mechanism for DMHCalb1/Vglut2 neuron-driven shivering initiation.

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Zhang, S., Zhang, H., Huang, Z., Wu, S., Zhang, Z., He, W., Li, D., Yang, X., Wang, Y., Huang, L., Liu, R., Hou, S.-T.. 2025-12-01. Dorsomedial hypothalamus cold-sensitive neurons drive shivering thermogenesis. https://doi.org/10.1101/2025.11.27.690920

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