Ministrokes in channelrhodopsin-2 transgenic mice reveal widespread deficits in motor output despite maintenance of cortical neuronal excitability.
We evaluated the effects of ministrokes targeted to individual pial arterioles on motor function in Thy-1 line 18 channelrhodopsin-2 (ChR2) transgenic mice within the first hours after ischemia. Using optogenetics, we directly assessed both the excitability and motor output of cortical neurons in a manner independent of behavioral state or training. Occlusion of individual arterioles within the motor cortex led to a ministroke that was verified using laser speckle contrast imaging. Surprisingly, ministrokes targeted to a relatively small region of the forelimb motor map, with an ischemic core of 0.07 ± 0.03 mm(2), impaired motor responses evoked from points across widespread areas of motor cortex even 1.5 mm away. Contrasting averaged ChR2-evoked electroencephalographic, spinal (ChR2 evoked potential), and electromyographic responses revealed a mismatch between measures of cortical excitability and motor output within 60 min after stroke. This mismatch suggests that apparently excitable cortical neurons (even >1 mm into peri-infarct areas, away from the infarct core) were impaired in their capacity to generate spinal potentials leading to even more severe deficits in motor output at muscles. We suggest that ischemia, targeted to a subset of motor cortex, leads to relatively small reductions in excitability within motor cortex, and cumulative depression of both descending spinal circuits and motor output in response to the activation of widespread cortical territories even outside of the area directly affected by the ischemia.
Department of Psychiatry, Brain Research Center, Department of Zoology, and International Collaboration on Repair Discoveries, University of British Columbia at Vancouver, Vancouver, British Columbia V6T 1Z3, Canada.
Eitan
E
Anenberg
Pamela
P
Arstikaitis
Yoichi
Y
Niitsu
Thomas C
TC
Harrison
Jamie D
JD
Boyd
Brett J
BJ
Hilton
Wolfram
W
Tetzlaff
Timothy H
TH
Murphy
D000818:Animals; D000075402:Channelrhodopsins; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D062308:Optogenetics / Q000379:methods; D020127:Recovery of Function / Q000502:physiology*; D020521:Stroke / Q000503:physiopathology*
D000075402:Channelrhodopsins
channelrhodopsin-2; motor-mapping; mouse; optogenetics; plasticity; stroke