Histamine-tuned subicular circuit mediates alert-driven accelerated locomotion in mice

The locomotive action involves diverse coordination, necessitating the integration of multiple motor neural circuits. However, the precise circuitry mechanism governing emotion-driven accelerated locomotion remains predominantly elusive. Here we dissect projections from the tuberomammillary nucleus (TMN) to subiculum (SUB) which promote alert-driven accelerated locomotion. We find that TMN histaminergic neurons respond to high-speed locomotion in both natural and alert acceleration. The TMN-SUB circuit is sufficient but not essential for amplifying accelerated locomotion from low to high-speed movement in basal condition, but it is both sufficient and necessary in alert condition for modulating accelerated locomotion during high-speed escape behavior. TMN histaminergic neuron activates SUB glutamatergic "fast locomotor cell" that projects to retrosplenial granular cortex (RSG) mainly through histamine H2 receptor (H2R). This study reveals the critical role of the histamine-tuned SUB circuit in alert-driven accelerated locomotion in mice, providing a theoretical foundation for comprehending neural circuit mechanisms of instinctive behaviors under alert.