HD‐tDCS Restores Perivascular AQP4 Polarization via PPARγ Modulation to Enhance Glymphatic Clearance After Intracerebral Hemorrhage in Mice

Impaired perivascular aquaporin 4 (AQP4) polarization and glymphatic dysfunction after intracerebral hemorrhage (ICH) may delay hematoma and perihematomal edema resolution. The effects of high-definition transcranial direct current stimulation (HD-tDCS) on glymphatic transport and recovery after ICH, as well as the underlying mechanisms, are investigated in a collagenase-induced mouse model. HD-tDCS (anodal stimulation, 0.1 mA, 10 min daily) significantly enhances cerebrospinal fluid influx, improves interstitial solute clearance, reduces intracerebral tracer retention, and increases drainage to the deep cervical lymph nodes, as assessed by in vivo two-photon imaging, contrast-enhanced MRI, and ex vivo tracer analysis. HD-tDCS also accelerates hematoma and edema resolution, reduces midline shift and diffusion abnormalities, and improves neurological outcomes. Mechanistically, ICH induces astrocytic proinflammatory activation together with impaired perivascular AQP4 polarization, whereas HD-tDCS upregulates peroxisome proliferator-activated receptor gamma (PPARγ), suppresses proinflammatory astrocyte activation, and restores perivascular AQP4 localization. Astrocyte-specific knockdown or pharmacologic inhibition of PPARγ attenuates HD-tDCS-induced AQP4 repolarization, glymphatic recovery, and neurological improvement. These findings indicate that HD-tDCS promotes hematoma and edema resolution after ICH in association with PPARγ-dependent astrocyte remodeling, AQP4 repolarization, and glymphatic restoration.