Endogenous stem cell activation and voluntary exercise differentially influence improvements in motor recovery after chronic spinal cord injury

The ependymal cell layer lining the central canal of the spinal cord forms a key endogenous neural stem cell niche in adult mammals, and enhancing its activity may promote repair following spinal cord injury (SCI). We investigated the independent and combined effects of voluntary free wheel running and PNU120596 (PNU), a positive allosteric modulator of α7 nicotinic acetylcholine receptors, on functional recovery and endogenous plasticity after chronic thoracic contusion SCI. Four weeks post-injury, female rats received PNU or vehicle, with or without access to running wheels, for six weeks. Free wheel running robustly improved behavioural recovery and sensory function. Partial information decomposition showed that recovery in the combined treatment group was driven mainly by unique contributions from exercise, while kinematic analyses revealed synergistic informational contributions of exercise and PNU on joint coordination and gait symmetry. Exercise predominantly enhanced cell proliferation and glial lineage differentiation caudal to the lesion, while PNU was associated with selective changes rostrally. Recovery was not explained by running distance alone. Specific exercise parameters (bout frequency, duration, and velocity) were associated with behavioural outcomes and biased cell-fate decisions, with running velocity and bout duration linked to astrocytic and oligodendrocytic differentiation, respectively. These findings demonstrate region-specific actions of exercise and cholinergic modulation on functional recovery and endogenous plasticity after chronic SCI. They show that rehabilitation efficacy depends not only on engaging in exercise, but on how exercise is performed and how it interacts with neuro-modulatory state, supporting a minimally invasive strategy for chronic SCI rehabilitation.