Mapping the pain pathway: The VPL–S1HL–ACC circuit's role in central post-stroke pain

Central post-stroke pain (CPSP) is a chronic neuropathic condition driven by central sensitization, often resulting in poor clinical outcomes. Neural circuits play a critical role in modulating chronic pain. To elucidate the mechanisms underlying CPSP, we established a mouse model via intracranial injection of type IV collagenase. cFos immunofluorescence and in vivo calcium imaging identified pain-associated activated nuclei. Using viral tracing, optogenetics, chemogenetics, and behavioral assays, we mapped a neural circuit comprising the ventral posterolateral thalamic nucleus (VPL), the hindlimb primary somatosensory cortex (S1HL), and the anterior cingulate cortex (ACC). In CPSP mice, ipsilateral S1HL^CaMKIIα and ACC^CaMKIIα neurons exhibited robust activation. Chemogenetic manipulation further demonstrated that activation of these neurons induced pain behaviors, whereas their inhibition alleviated pain. Notably, specific activation of the S1HL^CaMKIIα-ACC^CaMKIIα circuit produced mechanical allodynia, and optogenetic stimulation of VPL^CaMKIIα projections to S1HL similarly evoked pain responses while enhancing ACC neuronal firing. These findings underscore the critical role of the VPL-S1HL-ACC circuit in pain abnormalities and provide novel insights into the central sensitization underlying CPSP, suggesting promising therapeutic strategies for its management.