Grant: Project Grant

Little is known about the spinal circuits that control standing. However, during our recent survey of neurons that generate muscle spasms, we unexpectedly found that excitatory propriospinal neurons (V3 neurons) produce robust standing when they are activated, even after SCI. V3 neurons may be ideally suited to maintaining posture, as they directly innervate extensor motoneurons controlling limb and axial muscles, and are innervated extensively by sensory and supraspinal inputs. We will thus test the hypothesis that V3 neurons form a spinal circuit that controls standing, and activation of V3 neurons can restore standing after V3 activity is lost with SCI. We also hypothesize that after chronic SCI increased excitability in these neurons helps restore some sensory-evoked postural tone that may be promoted by stimulating nerves that innervate V3 neurons, providing a clinically applicable access to this key neural circuit. This will be examined both in awake mice with optogenetic activation or inhibition of V3 neurons where we will record limb kinematics and EMG, and in the isolated whole adult in vitro spinal cord where we will make direct intracellular recordings from V3 neurons and the motoneurons they innervate. Finally, we will examine whether the postural standing that can be obtained by V3 neuron activation can be used as a basis for training mice to stand after SCI, and explore whether the current clinical use of epidural spinal cord stimulation is mediated by V3 neurons that might be better targeted directly. Overall, these experiments will shed light on how spinal postural motor circuits are controlled by V3 neurons, and how these neurons can be harnessed to restore standing after SCI.