![]() We found significantly enhanced LFP gamma power in 8-month-old P301S in response to 40-Hz stimulation in V1, CA1, and PFC ( Figures 2A and S2A–S2C). ![]() Although we aimed to test the potential for neuroprotection early in pathological progression, we confirmed that 40-Hz stimulation could entrain neural oscillations even in conditions of neurodegeneration first. We observed no significant changes in either 40-Hz or 80-Hz spectral power in V1 during 80-Hz stimulation compared to light-occluded periods ( Figure S1H–S1J). To determine whether this increase in low gamma power and coherence is specific to 40-Hz stimulation, we exposed C57BL/6J mice to 80-Hz stimulation (50% duty cycle) ( Figure S1G). As a whole, these data show that 40-Hz stimulation enhances local as well as coordinated inter-areal oscillatory activities across V1, CA1, SS1, and PFC. As we observed with acute 40-Hz stimulation, LFPs recorded on day 43 from V1, SS1, CA1, and PFC showed significantly enhanced 40-Hz gamma power during visible 40-Hz stimulation ( Figure S1E), and significantly increased 30–50-Hz gamma WPLI between V1-CA1, V1-SS1, V1-PFC, and CA1-PFC, compared to light-occluded periods ( Figure S1F). Next, as we planned to examine the effects of a chronic GENUS paradigm (with the longest at 6 weeks’ duration), we carried out long-term multi-site LFP recordings as mice were exposed to 40-Hz stimulation for 6 weeks to determine whether gamma entrainment persists after repeated exposure to the stimuli. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer’s disease.
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