Abstract
Vascular cognitive impairment (VCI), a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH), remains devoid of effective therapeutic strategies. While hyperbaric oxygen therapy (HBOT) has shown promise in mitigating neurological damage, its molecular mechanisms remain incompletely elucidated. Here, we demonstrate that HBOT confers robust neuroprotection against CCH-induced VCI through the microRNA-137-3p (miR-137-3p)/TNF receptor-associated factor 3 (TRAF3) signaling axis. In a mouse model of CCH, prolonged HBOT administration significantly improved cognitive performance across multiple behavioral domains-including spatial, recognition, and contextual memory-concomitant with enhanced cerebral blood flow and oxygen saturation. Mechanistically, HBOT upregulated hippocampal miR-137-3p, which directly targeted TRAF3, leading to suppression of the TAK1/NF-κB pathway and attenuation of neuroinflammation and neuronal apoptosis. Using neuron-astrocyte-microglia tri-culture systems, we established that miR-137-3p agonism recapitulated HBOT-mediated neuroprotection, whereas TRAF3 overexpression exacerbated inflammatory and apoptotic cascades. Our findings identify the miR-137-3p/TRAF3/NF-κB pathway as a critical effector of HBOT efficacy, offering a promising therapeutic target for vascular cognitive impairment.