Sensory Flicker Stimulation of 5xFAD Mice Activates Immune Pathways in a Frequency and Time Dependent Manner

We previously showed that exposing wild-type mice to 40Hz, but not 20Hz, visual flickering stimulation led to activation of MAPK and NFκB pathway signaling in the visual cortex within 15mins of stimulation and up-regulation of cytokines/chemokines that modulate microglia activity after 1hr. These observed frequency-dependent effects suggest that targeted frequencies, as well as durations of stimulation, hold the potential to fine-tune the effects of sensory stimulation on immune pathways, as well as possibly other pathways with the potential to correct the molecular changes associated with Alzheimer’s disease. To test this, we exposed 5xFAD mice and wild-type littermates to different frequencies of audio/visual flicker stimulation (ambient light, 10Hz, 20Hz, 40Hz) for durations of 0.5hr, 1hr, or 4hr, then used bulk RNAseq to profile transcriptional changes within the visual cortex and hippocampus. Within 5xFAD mice, we found that 1hr of stimulation yielded up-regulation immune-related pathways, but that these were no longer observed after 4hr of stimulation. In contrast, all three frequencies yielded consistent up-regulation of neurotransmission pathways at 1hr and 4hr. Importantly, a subset of genes sets were co-regulated between the visual cortex and hippocampus, suggesting that combined visual/audio flicker can target deep brain regions affected by Alzheimer’s disease. Collectively, our data indicate that specific durations and frequencies of audio/visual stimulation can be used to elicit particular changes in brain immunity and neuronal functions, supporting the importance of this non-invasive methodology to tune the brain for treatment of diverse neurological diseases