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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE255004 | GEO | 2025/06/13

REPOSITORIES: GEO

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Project description:Gamma oscillations (20-50Hz) are a common local field potential signature in many brain regions that are generated by a resonant circuit between fast-spiking parvalbumin (PV)-positive interneurons and pyramidal cells. Changes in the magnitude and frequency of gamma have been observed in several neuropsychiatric disorders. However, it is unclear how disruptions in gamma oscillations affect cellular pathologies seen in these disorders. Here, we investigate this using the 5XFAD mouse model of Alzheimer’s disease (AD) and find reduced power and magnitude of behaviorally driven gamma oscillatory activity — even before the onset of plaque formation or measurable cognitive decline. Because of the early onset, we aimed to determine if exogenous manipulations of gamma could influence the progression of disease pathology. We find that driving PV-positive neurons at gamma frequency (40Hz) using channelrhodopsin-2 reduced total levels of amyloid-β (Aβ) 40 and 42 isoforms in the hippocampus of 5XFAD mouse. Driving PV-positive neurons at other frequencies, or driving excitatory neurons, did not reduce Aβ levels. Furthermore, driving PV-positive neurons reduced enlarged endosomes in hippocampal neurons and cleavage intermediates of APP in 5XFAD mouse. Gene expression profiling revealed a neuroprotective response with morphological transformation of microglia and markedly increased phagocytosis of Aβ by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that drives 40Hz gamma activity in mouse visual cortex. The light-flickering paradigm profoundly reduced Aβ40 and Aβ42 levels in the visual cortex of pre-symptomatic mice and greatly mitigated plaque load in the visual cortex of aged, symptomatic mice. This reduction was completely blocked by a GABA-A antagonist, providing further support for an essential role of GABAergic signaling in mediating neuroprotective gamma activity. Overall, our findings uncover a dramatic and previously unappreciated function of the brain’s endogenous gamma rhythms in reducing the production and increasing the clearance of Aβ peptides, whose accumulation is believed to drive the pathogenesis of AD.

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

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