Gamma frequency entrainment attenuates amyloid load and modifies microglia

Abstract

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma and cellular pathologies is unclear. Here, we show reduced behaviorally-driven gamma before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease (AD). Optogenetically driving FS-PV-interneurons at gamma (40 Hz), but not other frequencies, reduced levels of amyloid-β (A β)1-40 and A β1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia and histological analysis confirmed increased microglia co-localization with A β. Subsequently, we designed a non-invasive 40 Hz light-flickering paradigm that reduced A β1-40 and A β1-42 levels in visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate AD-associated pathology.

A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex

“…This approach could also be implemented within transgenic animals (Reijmers et al, 2007) to further expand the number of cell types targeted. The results of our experiment stimulating excitatory neurons at 40 Hz are consistent with previous reports that periodic stimulation with blue laser light can activate and entrain ChR2-expressing neurons (Boyden et al, 2005) and LFP power at those frequencies (Iaccarino et al, 2016). Interestingly, we also found that periodic silencing of the inhibitory neurons could also entrain cortical rhythms, likely through disinhibition of the excitatory neurons and/or post-illumination rebound of inhibitory neurons (Chuong et al, 2014) or both.…”

Microglia in Alzheimer’s disease

“…RNA sequencing analysis showed an increase in phagocytic genes, such as Cd68, β 2 -microglobulin (B2m), Icam, and lysozyme 2 (Lyz2), and in the proliferation markers Csf1, Csf1r, and Csf2ra. Notably, levels of proinflammatory genes (Il1b, Il6, Cd11b) and antiinflammatory genes (Igf1) were not changed (158), suggesting that it is possible to use immunomodulation to polarize microglia toward a beneficial activation state that is characterized…”

“…Gamma oscillations arise from the activation of local circuits of excitatory and fast-spiking inhibitory neurons resonating at 20-50 Hz, and changes in gamma oscillation have been observed in neurological diseases (158). Interestingly, entraining gamma oscillation at 40 Hz in 5xFAD mice induced amyloid reductions that were associated with an increase in microglial numbers and morphological changes such as soma enlargement and shortening of processes loaded with Aβ.…”

Transcranial Low-Level Laser Therapy for Depression and Alzheimer’s Disease

“…2). Interesting, a recent study by Iaccarino et al demonstrated that entraining gamma oscillations (20 to 40 Hz), which is different from LLLT, may provide systemic effects in the brain to attenuate AD-related pathology through modulation of microglia [48]. Further study in gamma oscillations and LLLT is warranted to examine whether it will have therapeutic effects in human AD.…”