Work

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

Year: 2025

Type: article

Abstract: 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. • VPL CaMKIIα , S1HL CaMKIIα , and ACC CaMKIIα are activated in CPSP model mice. • We discovered the existence of a VPL CaMKIIα –S1HL CaMKIIα –ACC CaMKIIα circuit. • VPL CaMKIIα –S1HL CaMKIIα circuit activation enhances ACC action potential firing.

Source: Brain Research Bulletin

DOI: 10.1016/j.brainresbull.2025.111406