Optogenetic neuronal stimulation promotes functional recovery after stroke

Edited by Anders Bjorklund, Lund University, Lund, Sweden, and approved July 17, 2014 (received for review March 3, 2014)
August 18, 2014
111 (35) 12913-12918

Significance

Stroke is the leading cause of disability in the United States and has very limited treatment options. Brain stimulation techniques that promote recovery after stroke are a promising area of research; however, current stimulation techniques nonspecifically activate/inhibit the target area, which not only leads to undesired side effects but also makes it difficult to understand which cell types and mechanisms drive recovery. We used the optogenetic technique to specifically stimulate only neurons after stroke and demonstrate that selective neuronal stimulations can activate beneficial mechanisms and promote recovery. Understanding the cell type and mechanisms driving recovery may identify potential drug targets for stroke treatment, as well as ultimately help develop precise brain stimulation techniques for stroke therapy.

Abstract

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area’s excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.

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Acknowledgments

We thank Robin Lemmens, Paul Kalanithi, and Marion Buckwalter for helpful discussions; Cindy H. Samos for scientific editing of the manuscript; Charu Ramakrishnan and Maisie Lo for their helpful technical discussions on optogenetic-related techniques; and Corinne Bart, Alex Bautista, and Aatman Shah for their technical assistance in some of the experiments. This work was supported in part by National Institutes of Health National Institute of Neurological Disorders and Stroke Grant 1R21NS082894, Russell and Elizabeth Siegelman, and Bernard and Ronni Lacroute (G.K.S.). G.K.S. is a member of the Medtronic Neuroscience Strategic Advisory Board.

Supporting Information

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pnas.1404109111.sm02.wmv
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pnas.1404109111.sm04.wmv

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 111 | No. 35
September 2, 2014
PubMed: 25136109

Classifications

Submission history

Published online: August 18, 2014
Published in issue: September 2, 2014

Keywords

  1. stroke recovery
  2. channelrhodopsin

Acknowledgments

We thank Robin Lemmens, Paul Kalanithi, and Marion Buckwalter for helpful discussions; Cindy H. Samos for scientific editing of the manuscript; Charu Ramakrishnan and Maisie Lo for their helpful technical discussions on optogenetic-related techniques; and Corinne Bart, Alex Bautista, and Aatman Shah for their technical assistance in some of the experiments. This work was supported in part by National Institutes of Health National Institute of Neurological Disorders and Stroke Grant 1R21NS082894, Russell and Elizabeth Siegelman, and Bernard and Ronni Lacroute (G.K.S.). G.K.S. is a member of the Medtronic Neuroscience Strategic Advisory Board.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Michelle Y. Cheng1 [email protected]
Departments of aNeurosurgery,
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Eric H. Wang
Departments of aNeurosurgery,
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Wyatt J. Woodson
Departments of aNeurosurgery,
Bioengineering, and
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Stephanie Wang
Departments of aNeurosurgery,
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Guohua Sun
Departments of aNeurosurgery,
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Alex G. Lee
Psychiatry and Behavioral Sciences,
Ahmet Arac
Departments of aNeurosurgery,
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305
Lief E. Fenno
Bioengineering, and
Neuroscience PhD Program,
Karl Deisseroth
Bioengineering, and
Psychiatry and Behavioral Sciences,
Cracking the Neural Code (CNC) Program,
Howard Hughes Medical Institute, and
Gary K. Steinberg1 [email protected]
Departments of aNeurosurgery,
Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA 94305

Notes

1
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: M.Y.C., L.E.F., and G.K.S. designed research; M.Y.C., E.H.W., W.J.W., S.W., G.S., A.G.L., and A.A. performed research; A.G.L. and K.D. contributed new reagents/analytic tools; M.Y.C. and G.K.S. analyzed data; and M.Y.C. and G.K.S. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Optogenetic neuronal stimulation promotes functional recovery after stroke
    Proceedings of the National Academy of Sciences
    • Vol. 111
    • No. 35
    • pp. 12569-12953

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