Sex-dependent alterations in motor cortex after spinal cord injury and implications in neurodegeneration risk

Patients with spinal cord injuries often suffer from multiple complications, including cognitive impairments after recovering from the primary injury. The molecular mechanism linking spinal cord injury and brain abnormalities, however, remains elusive and has been largely attributed to neuroinflammation. In this work, we assessed persistent compositional and molecular changes in the motor cortex at 30 days post injury, a commonly perceived chronic stage, using a rat T10 contusion injury model. Brain slices and neurons isolated from the motor cortex were assessed using immunohistochemistry and RNA-sequencing, respectively. We observed significant changes in cellular composition in the motor cortex including a decreased neuron to astrocyte ratio, and alterations in the morphology of neurons and astrocytes, indicating changes in functionality. Comparison of transcriptomic data collected at a sub-acute stage, namely 7 days post injury, with that at 30 days post injury, identified persistent and de novo (genes uniquely altered at 30 dpi.) changes that occur primarily after recovery from the spinal cord injury, enriched for neuronal and synaptic function related pathways. Strikingly, male and female rats showed distinct transcriptomic alterations at 30 days post injury, with males showing neuron-related changes and females showing alterations in metabolism- and extracellular matrix-related pathways. These molecular differences were accompanied by better functional recovery in females, as reflected by significantly higher BBB scores, suggesting sex-dependent molecular changes induced in the motor cortex. Collectively, our study lays the foundation for understanding sexual dimorphism in the brain after spinal cord injury and, more cautiously, points to a plausible association between spinal cord injury and molecular changes linked to pathways previously implicated in neurodegeneration.