Activity Protects Spinal Premotor Interneurons from Microglial Phagocytosis and Transneuronal Degeneration After Corticospinal Injury

Spinal premotor circuits play a fundamental role in motor control. The corticospinal tract (CST) provides control signals to premotor circuits in the spinal cord, guiding voluntary skilled movements. Unilateral selective lesion of the CST in the medullary pyramidal tract (PTX) produces transneuronal degeneration, whereby Choline Acetyltransferase-positive (ChAT) premotor interneurons contralesionally undergo non-apoptotic degeneration by microglial phagocytosis. Evidence shows that transneuronal degeneration has an activity dependence: MCX inactivation produces transneuronal degeneration and spinal DC neuromodulation after PTX ameliorates it. This study expands our understanding of transneuronal degeneration mechanisms by examining the activity-dependence of degeneration vulnerability and the implications for motor recovery in a mouse model of a complete CST lesion model (bilateral PTX). We address four key unanswered questions: Are Chx10 (VGlut2) interneurons, the largest spinal interneuron class to receive direct synaptic connections from the CST vulnerable to transneuronal degeneration after CST loss; using DREADD neuromodulation, what are effective sources of presynaptic activation for protecting spinal premotor interneurons after CST loss; how are ameliorating transneuronal interneuron degeneration and reducing microglial activation associated; and does effective rescue of interneuron degeneration rescue grip strength after injury? Transneuronal degeneration is a pervasive pathophysiological change injury; CST lesion produces significant Chx10 interneuron loss. Multiple sources of neuronal DREADD activation—motor cortex, reticular formation, and spinal interneurons—are effective in ameliorating transneuronal degeneration. Interneuron rescue is strongly associated with ameliorating inflammation, showing potential causality between interneuron degeneration and inflammation after CST lesion. Finally, rescuing spinal interneurons was associated with restoring function. Our findings demonstrate the interplay between neuronal activity, microglia actions mediating transneuronal degeneration, and motor recovery following CNS injury.