Upregulation of breathing rate during running exercise by central locomotor circuits

While respiratory adaptation to exercise is compulsory to cope with the increased metabolic supply to body tissues and with the necessary clearing of metabolic waste, the neural apparatus at stake remains poorly identified. Using viral tracing, ex vivo and in vivo optogenetic and chemogenetic interference strategies in mice, we unravel interactive locomotor and respiratory networks nodes that mediate the respiratory rate increase that accompanies a running exercise. We show that the mesencephalic locomotor region (MLR) and the lumbar spinal locomotor pattern generator (lumbar CPG), which respectively initiate and execute the locomotor behavior, access the respiratory network through distinct entry points. The MLR directly projects onto the inspiratory rhythm generator, the preBotzinger complex (preBotC), and can trigger a moderate increase of respiratory frequency, prior to, or even in the absence of, locomotion. In contrast, the lumbar CPG projects onto the retrotrapezoid nucleus (RTN) that in turn contacts the preBotC to enforce, during effective locomotion, higher respiratory frequencies. These data expand, on the one hand, the functional implications of the MLR beyond locomotor initiation to a bona fide respiratory modulation. On the other hand, they expand the adaptive respiratory ambitions of the RTN beyond chemoception to "locomotor- ception".