Shared Transcriptomic Signatures in Perilesional and Contralesional Cortex

Stroke induces a transient period of heightened plasticity during which functional recovery is most pronounced. Work in rodent models of stroke has identified key mechanisms in both the ipsilesional and contralesional cortex that contribute to functional and structural post-stroke plasticity. To date, most gene expression studies have focused on the infarct core and the immediately surrounding tissue, peri-lesional cortex (PLC). We sought to understand whether the contralesional cortex (CLC), a region that shows robust structural and molecular remodeling despite its distance from the lesion, mounts a distinct transcriptional response to stroke. Direct comparisons of molecular pathways governing these regions, particularly across sexes, are limited. To address this gap, we performed bulk RNA sequencing of the PLC and CLC at 7 days post-stroke, a critical time point for initiating repair, in male and female mice. Our results indicate that despite distinct positions from the lesion, both regions share a robust upregulation of inflammatory signaling, with Gene Ontology enrichment indicating activation of cytokine signaling, leukocyte activation, and gliogenesis pathways. Further analysis of this shared gene expression signature revealed reactive microglia signaling as the dominant pathway. Surprisingly, the CLC did not show a distinct transcriptional response. These findings were consistent across males and females, which also showed similar CLC-derived corticospinal tract axonal sprouting at 6 weeks post-stroke. Together, these findings support a shared microglia-centered neuroinflammatory transcriptional response in the PLC and CLC and suggest that microglial reactivity is a key early process for post-stroke cortical plasticity in both male and female mice.