TY - GEN
T1 - Optogenetic stimulation of cholinergic projection neurons as an alternative for deep brain stimulation for Alzheimers treatment
AU - Mancuso, James
AU - Chen, Yuanxin
AU - Zhao, Zhen
AU - Li, Xuping
AU - Xue, Zhong
AU - Wong, Stephen T.C.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Cholinergic neurons
KW - Neurodegeneration
KW - Neurophotonics
KW - Optogenetics
KW - Two-photon
UR - http://www.scopus.com/inward/record.url?scp=84878171074&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878171074&partnerID=8YFLogxK
U2 - 10.1117/12.2004379
DO - 10.1117/12.2004379
M3 - Conference contribution
AN - SCOPUS:84878171074
SN - 9780819493347
T3 - Progress in Biomedical Optics and Imaging - Proceedings of SPIE
BT - Photonic Therapeutics and Diagnostics IX
T2 - Photonic Therapeutics and Diagnostics IX
Y2 - 2 February 2013 through 7 February 2013
ER -