Peptidergic modulation of motor neuron output via CART signaling at C bouton synapses

Funding: This work was supported by the General Secretariat for Research and Technology (ARISTEIA II 4257, L.Z.), Fondation SANTE (L.Z.), a Marie Curie Re-Integration Grant (268323, L.Z.), the Hellenic Foundation for Research and Innovation (spinMNALS, 4013, L.Z.) and by a St. Andrews Restarting Research Fund (S.A.S. and G.B.M.). S.A.S. was funded by a Royal Society Newton International Fellowship (NIF/R1/180091) and a Natural Sciences and Engineering Research Council of Canada (NSERC) Postdoctoral Fellowship (NSERC-PDF-517295-2018) and M.M. by the National Scholarship Foundation (IKY).The intensity of muscle contraction, and therefore movement vigour, needs to be adaptable to enable complex motor behaviors. This can be achieved by adjusting the properties of motor neurons, which form the final common pathway for all motor output from the central nervous system. Here we identify novel roles for a neuropeptide, Cocaine and Amphetamine Regulated Transcript (CART), in the control of movement vigour. We reveal distinct, but parallel mechanisms by which CART and acetylcholine, both released at C bouton synapses on motor neurons, selectively amplify the output of subtypes of motor neurons that are recruited during intense movement. We find that mice with broad genetic deletion of CART or selective elimination of acetylcholine from C boutons exhibit deficits in behavioral tasks that require higher levels of motor output. Overall, these data uncover novel spinal modulatory mechanisms that control movement vigour to support movements that require a high degree of muscle force.Publisher PDFPeer reviewe