Multisensory gamma stimulation mitigates the effects of demyelination induced by cuprizone in male mice

Demyelination is characterized by the loss of the myelin sheath that surrounds nerve fibers and myelin-supporting cells in the nervous system. This leads to increased vulnerability of axons to damage, resulting in significant atrophy and neuro-axonal degeneration. Demyelination is a common pathological feature in a wide range of diseases of the central nervous system (CNS). Multiple pathomolecular processes contribute to brain damage, including demyelination, neuroinflammation, oligodendrocyte (OLs) cell death, and progressive neuronal dysfunction. In this study, we used the cuprizone (CPZ) mouse model to investigate long-term non-invasive gamma entrainment using sensory stimulation (GENUS) as a potential therapeutic intervention for promoting myelination and reducing neuroinflammation. Our results demonstrate that GENUS effectively mitigated demyelination, stimulated oligodendrogenesis in the corpus callosum (CC), and preserved functional integrity and synaptic plasticity. Additionally, GENUS attenuated OLs ferroptosis-induced cell death. Furthermore, chronic GENUS exhibited a marked reduction in brain inflammation, decreasing both microgliosis and astrogliosis and proinflammatory molecules, such as high mobility group box 1 (HMGB1), complement component 1q (C1q) and complement C3 (C3). Considering the pro-remyelination and anti-neuroinflammatory effects observed with GENUS, these findings suggest its potential as a therapeutic approach for demyelinating disorders.