Activation des neurones noradrénergiques et onde calcique gliale : un disjoncteur du circuit moteur médiant l’arrêt du mouvement

Animals need to avoid threats in their environment to survive. While the escape circuitry has been well characterized, the circuit mechanisms contributing to motor arrests have remained poorly understood. Vertebrate locomotion involves a hierarchical system: the subthalamic nucleus signals the mesencephalic locomotor region, activating reticulospinal neurons that drive spinal circuits to excite motor neurons (Grillner and El Manira 2020; Silvia Arber and Costa 2018; Dubuc, Cabelguen, and Ryczko 2023). Despite the remarkably conserved blue-print organization of motor circuits in vertebrates, how motor arrest occurs remains elusive. A recent study in larval zebrafish (Mu et al 2019) showed that upon sensory-motor mismatch, motor arrest involves noradrenergic signaling eliciting a brain-wide glial calcium wave. However, if this noradrenaline-dependent glial calcium wave can be induced upon aversive cues and how the motor circuitry is disrupted to evoke motor arrest remains unknown. We leveraged the optical and genetic accessibility of larval zebrafish to investigate these questions. We found that two different aversive cues (sustained acousto-vestibular stimulus and acidic pH) recruited noradrenergic neurons, induced a glial calcium wave initiating in the rostral spinal cord and propagating bidirectionally to hindbrain and spinal cord. This glial calcium wave was dependent on alpha adrenergic signaling, demonstrating that the induction of noradrenaline-dependent glial calcium wave is generalizable to different aversive cues. We found that sustained activation of noradrenergic neurons is sufficient to induce motor arrest associated with extended periods inducing motor arrest with rolling behavior and reduction of heart rate reminiscent of tonic immobility. Such sustained noradrenergic neuron activation was sufficient to elicit a stereotyped glial calcium wave. At the level of motor circuits, sustained activation of noradrenergic neurons induced a refractory period during which locomotion cannot be induced by stimulating the caudal brainstem. Remarkably, sustained noradrenergic neuron activation did not alter the intrinsic excitability of motor neurons but reduced the synaptic inputs to motor neurons disrupt motor output. Altogether, we have identified circuit mechanisms involving the sustained noradrenergic neuron activation and subsequent trigging of glial calcium wave in mediating motor arrest by disrupting the motor circuitry at the level of synaptic inputs to motor neurons.