Benjamin T. Noble

Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local cues from neighboring glia likely help mold these maladaptive neuronal networks. Here, we used a mouse model of SCI to show that microglia surrounded active glutamatergic interneurons and subsequently coordinated multi-segmental excitatory synaptogenesis and expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions. Depleting microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity in autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression. Forced turnover of microglia in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity. Additional data show that microglia-dependent autonomic plasticity required expression of triggering receptor expressed on myeloid cells 2 (Trem2) and α2δ-1–dependent synaptogenesis. These data suggest that microglia are primary effectors of autonomic neuroplasticity and dysautonomia after SCI in mice. Manipulating microglia may be a strategy to limit autonomic complications after SCI or other forms of neurologic disease.

Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post‐injury (wpi). We also detected new myelin formation over 2 months post‐injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination. We also examined electrophysiological changes during peak oligogenesis and a potential mechanism driving OL progenitor cell (OPC) contact with axons. Results reveal peak in remyelination occurs during the 3rd mpi, and that myelin generation continues for at least 6 mpi. Further, motor evoked potentials significantly increased during peak remyelination, suggesting enhanced axon potential conduction. Interestingly, two indices of demyelination, nodal protein spreading and Nav1.2 upregulation, were also present chronically after SCI. Nav1.2 was expressed through 10 wpi and nodal protein disorganization was detectable throughout 6 mpi suggesting chronic demyelination, which was confirmed with EM. Thus, demyelination may continue chronically, which could trigger the long‐term remyelination response. To examine a potential mechanism that may initiate post‐injury myelination, we show that OPC processes contact glutamatergic axons in the injured spinal cord in an activity‐dependent manner. Notably, these OPC/axon contacts were increased 2‐fold when axons were activated chemogenetically, revealing a potential therapeutic target to enhance post‐SCI myelin repair. Collectively, results show the surprisingly dynamic nature of the injured spinal cord over time and that the tissue may be amenable to treatments targeting chronic demyelination.