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Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer’s disease model mice

Nature Neuroscience volume 26, pages 570–578 (2023)Cite this article

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Abstract

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer’s disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-β 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.

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Fig. 1: Effect of acute 40-Hz visual simulation on Aβ load and microglia.
Fig. 2: Effect of chronic 7-d 40-Hz visual simulation.
Fig. 3: In vivo monitoring of plaques and microglia.
Fig. 4: A 40-Hz visual simulation does not engage native gamma oscillations.
Fig. 5: A 40-Hz flickering stimulation is aversive.

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Data availability

The data that support the main findings of this study are publicly available on the Buzsáki Lab web page (https://buzsakilab.com/wp/resources/). Supplementary data used from the Allen Brain Institute can be found at https://allensdk.readthedocs.io/en/latest/visual_coding_neuropixels.html. Source data are provided with this paper.

Code availability

The code used for this study was adapted from the buzcode repository (https://github.com/buzsakilab/buzcode).

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Acknowledgements

We thank D. Adler, M. Valero, E. M. Sigurdsson, the Experimental Pathology research core at NYU and Life Canvas for their experimental support. This work was supported by NRSA grant no. 5TL1TR001447-07 (M.S.), a DFG Walter Benjamin fellowship (grant no. NI 2057/1-1) (N.N.), the Alzheimer’s Association grant no. AARFD-17-533584 (A.M.-A.), grant no. R01 AG075840 (M.J.S.), the Fisher Center for Alzheimer’s Research Foundation (M.J.S.) NIH grants no. MH122391 and no. U19 NS107616 (G.B.).

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Authors and Affiliations

  1. Neuroscience Institute, Langone Medical Center, New York University, New York, NY, USA

    Marisol Soula, Yiyao Zhang, Annika Dhingra, Noam Nitzan & György Buzsáki

  2. Department of Physiology and Neuroscience, Langone Medical Center, New York University, New York, NY, USA

    Alejandro Martín-Ávila & György Buzsáki

  3. Skirball Institute of Biomolecular Medicine, Langone Medical Center, New York University, New York, NY, USA

    Alejandro Martín-Ávila & Wen-Biao Gan

  4. Department of Neurology and Psychiatry, Langone Medical Center, New York University, New York, NY, USA

    Martin J. Sadowski & György Buzsáki

  5. Department of Biochemistry and Molecular Pharmacology, Langone Medical Center, New York University, New York, NY, USA

    Martin J. Sadowski

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Contributions

M.S., M.J.S., W.-B.G. and G.B. designed the research. M.S., Y.Z. and A.M.-A. performed the research. M.S., A.D., Y.Z. and N.N. analyzed the data. G.B. and M.S. wrote the paper.

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Correspondence to György Buzsáki.

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Extended data

Extended Data Fig. 1 Histological analysis.

a, b) Heatmaps of Aβ plaque load in various coronal sections in 5xFAD mice after sham (a) and 40-Hz flicker (b) stimulation. c) Representative coronal sections of Aβ expression (LifeCanvas Technologies, Cambridge, MA 02141). Was replicated in n = 2 mice. d) Posterior visual cortex section (marked by red dash lines), used for quantification of V1. e) Group difference (medians, interquartile ranges, maxima and minima) of the percent area occupied by plaques after sham (n = 11 mice) and 40-Hz flicker (n = 13 mice) stimulation (ns, not significant by Wilcoxon test: p = 0.12). f) Cortex plaque load variability among six cohorts (mean + /− s.d; two-sided Wilcoxon test; p = 0.915, p = 0.0368, p = 0.879, p = 0.988, p = 0.0878, p = 0.379; ns, not significant).

Source data

Extended Data Fig. 2 ELISA analysis by groups.

a, b) Group difference (medians, interquartile ranges, maxima and minima) Aβ40 peptide levels in the (a) hippocampus and (b) V1 separated by sex (ns, not significant; two-sided Wilcoxon test). (n = 7 male and n = 5 female 40-Hz treated; n = 7 male and n = 4 female non-treated controls) c, d) Group difference (medians, interquartile ranges, maxima and minima) Aβ42 peptide levels in the (c) hippocampus (p = 0.38; p = 1;p = 0.19; p = 0.19 two-sided Wilcoxon Test) and (d) V1 (p = 0.02; p = 0.46;p = 0.68; p = 0.73; two-sided Wilcoxon Test) separated by sex and ELISA test. To test the reliability and consistency of the ELISA method, we performed two separated analyses for Aβ42 from the same aliquot samples on different days separated by one week (sample 1, sample2). The corresponding aliquots in the two tests are connected by lines. (n = 7 male and n = 5 female 40-Hz treated; n = 7 male and n = 4 female non-treated controls) e) The correlation between the two ELISA tests in c and d. Two conclusions may be drawn from this repeated analysis. First, the two tests were correlated strongly and significantly (R = 0.78). Second, the values of the second ELISA test were, on average, lower. This latter observation suggests that some epitope degradation of the sample may take place with time. These findings points to further potential sources of variability across studies, which may have different delays between tissue processing and ELISA Analysis.

Source data

Extended Data Fig. 3 Allen Brain Institute 4-Hz light response.

a) Peristimulus time histograms showing the responses of individual neurons (bottom panels) and the average (mean ± s.e.m.) response per area, from primary visual cortex (VISp), the 3 major hippocampal areas (DG, dentate gyrus), the thalamus (TH) and midbrain (MB). b) Anatomical locations of 35,910 units included in the dataset, color coded according to their modulation index. c) Box and whisker plot (medians, interquartile ranges, maxima and minima) showing the distributions of modulation index in the different areas p = 0, p = 0, p = 0, p = 0, p = 0, p = 4.9e-14, p = 0.013,p = 0.999,p = 0.970, p = 8.97e-19, p = 0.0006, p = 0.0434, p = 0.940, p = 0.359, p = 0.962 for VISp-CA1, VISp-CA3, VISp-DG, VISp-TH, VISp-MB, CA1-CA3, CA1-DG, CA1-TH, CA1-MB, CA3-DG, CA3-TH, CA3-MB, DG-TH,DG-MB,TH-MB, respectively; KW; *p < 0.05, **p < 0.01, ***p < 0.001. d) Bar graph shows the fractions of significantly modulated cells per area (VISp: 1597/3439; CA1: 1225/5833; CA3:145/835; TH:2329/6249; MB: 638/1908) (n = 49 mice).

Source data

Extended Data Fig. 4 Electrophysiological methods.

a) Relationship between electrode impedance and 40-Hz power in the hippocampus. Note that artifactual 40-Hz power can occur at high impedance sites. b) Power spectra in a high impedance channel in the hippocampus during 40-Hz stimulation and no-stimulation epochs (10 s on, 10 s off). Note large peak at 40-Hz during stimulation. c) Example artifacts at a high-impedance channels (red traces) in the hippocampus show 40-Hz when the light is turned on. d) Comparison (medians, interquartile ranges, maxima and minima) of the two methods we used to quantify phase modulation of spikes: bootstrap and Rayleigh’s methods (Example from the hippocampus; ns, nonsignificant p = 0.193; two-sided Wilcoxon test). Vector length distribution. Vertical red lines separate nonsignificant and significant events. (59 sessions in 15 mice). e) Significant difference (medians, interquartile ranges, maxima and minima) in the vector lengths of neurons statistically modulated by 40-Hz in different brain regions. Note that despite very few CA1 and EC neurons show significant phase-locking to 40-Hz stimuli (Fig. 2), the few that do show comparable vector lengths in all three structures (***p < 0.001; V1:p = 3.12e-41;CA1: p = 1.6e-30; EC: p = 0.239; two-sided Wilcoxon test) (V1 = 14 sessions in 5 mice, EC = 7 sessions in 3 mice, CA1 = 59 sessions in 15 mice). f) Example raster plots of significantly modulated putative interneurons in CA1 (red) and EC (orange) regions. g) Separation of putative pyramidal cells from interneurons using spike duration and burst index. Bar graphs show the fraction of significantly modulated putative pyramidal cells and interneurons.

Source data

Extended Data Fig. 5 Firing rates changes during stead state driving at 40-Hz stimulation.

Firing rates of all neurons during onset and offset of 40-Hz trains every 10 second for the visual cortex (a; two-sided paired t-test; p = 0.0066), hippocampus (b; two-sided paired t-test; p = 0.2581), and entorhinal cortex (c; two-sided paired t-test; p = 0.2629), respectively. Bin size= 0.005 s. 40-Hz modulated cells are marked by color circles.

Source data

Extended Data Fig. 6 Aversive response to 40-Hz flicker and control Ach.

a) Time spent in the 40-Hz compartment versus in the compartment with continuous light (n = 14 mice). b) Ach response to continuous white light (mean + /− s.e.m; p = 0.59, two-tailed paired t-test; n = 5 mice). Note lack of sustained activity, in contrast to the sustained Ach activation with 40-Hz flickering light (Fig. 4).

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2.

Reporting Summary

Heatmaps of Aβ plaque load in the whole brain of a 5xFAD mouse and a 40-Hz flicker light-treated mouse (method: LifeCanvas Technologies, Cambridge, MA 02141).

Representative video of two-photon z-stack before 40-Hz flicker and after 1 h of 40-Hz flicker stimulation. Bottom: RGB fluorescence scale in real time for both conditions. Green: Methoxy-X04. Red: Microglia.

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Soula, M., Martín-Ávila, A., Zhang, Y. et al. Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer’s disease model mice. Nat Neurosci 26, 570–578 (2023). https://doi.org/10.1038/s41593-023-01270-2

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