Optogenetic stimulation of cholinergic projection neurons as an alternative for deep brain stimulation for Alzheimers treatment

James Mancuso, Yuanxin Chen, Zhen Zhao, Xuping Li, Zhong Xue, Stephen T.C. Wong

Research output: Chapter in Book/Report/Conference proceedingConference contribution

2 Scopus citations


Deep brain stimulation (DBS) of the cholinergic nuclei has emerged as a powerful potential treatment for neurodegenerative disease and is currently in a clinical trial for Alzheimer's therapy. While effective in treatment for a number of conditions from depression to epilepsy, DBS remains somewhat unpredictable due to the heterogeneity of the projection neurons that are activated, including glutamatergic, GABAergic, and cholinergic neurons, leading to unacceptable side effects ranging from apathy to depression or even suicidal behavior. It would be highly advantageous to confine stimulation to specific populations of neurons, particularly in brain diseases involving complex network interactions such as Alzheimer's. Optogenetics, now firmly established as an effective approach to render genetically-defined populations of cells sensitive to light activation including mice expressing Channelrhodopsin-2 specifically in cholinergic neurons, provides just this opportunity. Here we characterize the light activation properties and cell density of cholinergic neurons in healthy mice and mouse models of Alzheimer's disease in order to evaluate the feasibility of using optogenetic modulation of cholinergic synaptic activity to slow or reverse neurodegeneration. This paper is one of the very first reports to suggest that, despite the anatomical depth of their cell bodies, cholinergic projection neurons provide a better target for systems level optogenetic modulation than cholinergic interneurons found in various brain regions including striatum and the cerebral cortex. Additionally, basal forebrain channelrhodopsin-expressing cholinergic neurons are shown to exhibit normal distribution at 60 days and normal light activation at 40 days, the latest timepoints observed. The data collected form the basis of ongoing computational modeling of light stimulation of entire populations of cholinergic neurons.

Original languageEnglish (US)
Title of host publicationPhotonic Therapeutics and Diagnostics IX
StatePublished - 2013
EventPhotonic Therapeutics and Diagnostics IX - San Francisco, CA, United States
Duration: Feb 2 2013Feb 7 2013

Publication series

NameProgress in Biomedical Optics and Imaging - Proceedings of SPIE
ISSN (Print)1605-7422


OtherPhotonic Therapeutics and Diagnostics IX
Country/TerritoryUnited States
CitySan Francisco, CA


  • Cholinergic neurons
  • Neurodegeneration
  • Neurophotonics
  • Optogenetics
  • Two-photon

ASJC Scopus subject areas

  • Atomic and Molecular Physics, and Optics
  • Electronic, Optical and Magnetic Materials
  • Biomaterials
  • Radiology Nuclear Medicine and imaging


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