Shared transcriptomic signatures in perilesional and contralesional cortex after ischemic stroke

Stroke induces a transient period of heightened plasticity during which functional recovery is most pronounced. Experimental models have identified repair-associated processes in both the ipsilesional and contralesional cortex, indicating that stroke recovery involves regions both remote and near the lesion. However, most transcriptional studies have focused on the infarct core and peri-lesional cortex (PLC), leaving it unclear whether comparable molecular responses occur in the contralesional cortex (CLC), a region that undergoes substantial remodeling in the absence of direct tissue injury, necrosis, or widespread cellular infiltration. In addition, potential sex-dependent differences in these responses remain incompletely defined, despite known influences of biological sex on post-stroke inflammation and vascular remodeling. To address these gaps, we performed bulk RNA-sequencing of the PLC and CLC at 7 days after photothrombotic stroke, a subacute time point associated with the initiation of repair, in male and female mice. Despite distinct positions relative to the lesion, both regions exhibited robust upregulation of inflammatory signaling, including cytokine-, astrocyte-, and myeloid-lineage-associated pathways. The CLC did not demonstrate a distinct region-specific transcriptional profile; instead, shared signatures between PLC and CLC included genes strongly associated with reactive microglial phenotypes. This shared neuroinflammatory response was largely conserved across sexes. Consistent with these findings, male and female mice exhibited comparable corticospinal tract axonal sprouting originating from the CLC at 6 weeks post-stroke. Together, these findings support a shared neuroinflammatory transcriptional response as a prominent early feature of cortical regions associated with post-stroke plasticity.