Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition

Anthony J. Martorell, Abigail L. Paulson, Ho Jun Suk, Fatema Abdurrob, Gabrielle T. Drummond, Webster Guan, Jennie Z. Young, David Nam Woo Kim, Oleg Kritskiy, Scarlett J. Barker, Vamsi Mangena, Stephanie M. Prince, Emery N. Brown, Kwanghun Chung, Edward S. Boyden, Annabelle C. Singer, Li Huei Tsai

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)

Abstract

We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function. Auditory stimulation combined with light-induced gamma oscillations in the hippocampus CA1 and auditory cortex regions of the brain reduces amyloid levels and improves memory in animal models of Alzheimer's disease.

Original languageEnglish
Pages (from-to)256-271.e22
JournalCell
Volume177
Issue number2
DOIs
Publication statusPublished - 2019 Apr 4

Bibliographical note

Funding Information:
We are grateful to members of the Tsai, Singer, and Boyden laboratories for technical assistance and comments on the paper. This work was supported by NIH (R01-NS109226 to A.C.S. T32 NS007480-18 to A.L.P. RF1-AG047661 to L.-H.T. U01-NS090473 to K.C. U01MH117072 to K.C. T32 GM007484 to A.J.M. R01-EY023173 to E.S.B. and R01-GM104948 and DP1-OD003646 to E.N.B.); Packard Award in Science and Engineering (to A.C.S. and K.C.); Friends and Alumni of Georgia Tech, Lane Family (to A.C.S.); Fulton County Elder Health Science Fellowship, Wright Family (to A.L.P.); Robert and Renee Belfer Family Foundation (to L.-H.T.); Halis Family Foundation (to L.-H.T.); JPB Foundation (to L.-H.T. and PIIF and PNDRF to K.C.); Burroughs Wellcome Fund Career Awards at the Scientific Interface (to K.C.); Searle Scholars Program (to K.C.); NARSAD Young Investigator Award (to K.C.); NCSOFT Cultural Foundation (to K.C.); Integrative Neuronal Systems (to A.J.M.); MIT Champions of the Brain Fellowship (to A.J.M.); Henry E. Singleton Fellowship (to A.J.M.); William C. and Margaret H. Rousseau Fellowship (to W.G.); SITA Foundation Fellowship (to V.M.); Samsung Fellowship (to H.-J.S.); MIT Aging Brain Initiative (to L.-H.T. and E.S.B.), John Doerr, Edward and Kay Poitras (to E.S.B.); HHMI-Simons Fellowship (to E.S.B.); Open Philanthropy, Charles Hieken (to E.S.B.); and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (to E.N.B.). A.J.M. A.C.S. A.L.P. J.Z.Y, E.N.B. E.S.B. K.C. and L.-H.T. designed experiments. A.C.S. and A.L.P. performed and analyzed electrophysiology data. S.M.P. assisted with electrophysiology experiments. A.J.M. and D.N.-W.K. performed and analyzed ELISA experiments. O.K. performed western blots. A.J.M. performed behavior experiments. D.N.-W.K. and F.A. analyzed behavior experiments. A.J.M. D.N.-W.K. and F.A. performed and analyzed imaging experiments. F.A. performed and analyzed 3D microglia clustering quantification. G.T.D. W.G. and V.M. performed and analyzed whole brain SHIELD experiments. A.J.M. D.N.-W.K. and F.A. performed auditory and combined GENUS experiments. H.-J.S. and A.C.S. engineered auditory and combined GENUS sounds and equipment. A.J.M. A.C.S, A.L.P, J.Z.Y. F.A. and L.-H.T. wrote the manuscript. All authors read and revised the manuscript. L.-H.T. and E.S.B. are co-Scientific Founders and serve on the scientific advisory board of Cognito Therapeutics, Inc. A.C.S. owns shares of Cognito Therapeutics, Inc.

Funding Information:
We are grateful to members of the Tsai, Singer, and Boyden laboratories for technical assistance and comments on the paper. This work was supported by NIH ( R01-NS109226 to A.C.S., T32 NS007480-18 to A.L.P., RF1-AG047661 to L.-H.T., U01-NS090473 to K.C., U01MH117072 to K.C., T32 GM007484 to A.J.M., R01-EY023173 to E.S.B., and R01-GM104948 and DP1-OD003646 to E.N.B.); Packard Award in Science and Engineering (to A.C.S. and K.C.); Friends and Alumni of Georgia Tech, Lane Family (to A.C.S.); Fulton County Elder Health Science Fellowship, Wright Family (to A.L.P.); Robert and Renee Belfer Family Foundation (to L.-H.T.); Halis Family Foundation (to L.-H.T.); JPB Foundation (to L.-H.T. and PIIF and PNDRF to K.C.); Burroughs Wellcome Fund Career Awards at the Scientific Interface (to K.C.); Searle Scholars Program (to K.C.); NARSAD Young Investigator Award (to K.C.); NCSOFT Cultural Foundation (to K.C.); Integrative Neuronal Systems (to A.J.M.); MIT Champions of the Brain Fellowship (to A.J.M.); Henry E. Singleton Fellowship (to A.J.M.); William C. and Margaret H. Rousseau Fellowship (to W.G.); SITA Foundation Fellowship (to V.M.); Samsung Fellowship (to H.-J.S.); MIT Aging Brain Initiative (to L.-H.T. and E.S.B.), John Doerr, Edward and Kay Poitras (to E.S.B.); HHMI-Simons Fellowship (to E.S.B.); Open Philanthropy, Charles Hieken (to E.S.B.); and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital , Boston, Massachusetts (to E.N.B.).

Publisher Copyright:
© 2019 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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