A parabrachial-hypothalamic parallel circuit governs cold defense in mice

Summary Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Remarkable advances have been made in understanding how neurocircuits centered in the hypothalamic preoptic area (POA), the brain’s thermoregulation center, control warm defense, whereas mechanisms by which the POA regulates cold defense remain unclear. Here, we confirmed that the pathway from the lateral parabrachial nucleus (LPB) to the POA, is critical for cold defense. Parallel to this pathway, we uncovered that a pathway from the LPB to the dorsomedial hypothalamus (DMH), namely the LPB→DMH pathway, is also essential for cold defense. Projection-specific blockings revealed that both pathways provide an equivalent and cumulative contribution to cold defense, forming a parallel circuit. Specifically, activation of the LPB→DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and physical activity. Further, we identified a subpopulation of somatostatin + neurons in the LPB that target the DMH to promote BAT thermogenesis. Therefore, we reveal a parabrachial-hypothalamic parallel circuit in governing cold defense in mice. This not only enables resilience to hypothermia but also provides a scalable and robust network in heat production, reshaping our understanding of how neural circuits regulate essential homeostatic behaviors.