Stroke is a major acute neurological insult that disrupts brain function and causes neuron death. Each year about 800,000 people are affected by stroke in the United States, and most survivors often live with long-term disability. Functional recovery can occur after stroke, and this recovery is attributed to brain remodeling and neuroplasticity, when the brain repairs and rebuilds connections between neurons. Brain stimulation techniques such as electrical stimulation or transcranial magnetic stimulation have been used in animals and humans to enhance recovery after stroke. However, the neural circuits involved and the mechanisms mediating this recovery are not well understood. In addition, these stimulation techniques non-specifically stimulate all cell types near the stimulation site, leading to undesired side effects. In this proposal, we will use the optogenetic approach to specifically stimulate neurons after stroke and examine the effects on functional recovery and the underlying mechanisms. Optogenetics is a novel strategy that utilizes light-sensitive algal proteins, such as Channelrhodopsin (ChR2), to manipulate the excitability of specific cell groups in the brain, in a fast and precise manner. Optogenetic stimulation can increase neuronal excitability, potentially leading to release of neurotrophic factors, enhancement of axonal spouting/synaptogenesis and increased cerebral blood flow, all of which are important in functional recovery after stroke. Therefore, we hypothesize that optogenetic stimulation of neurons in the primary motor cortex (M1) can augment endogenous repair/plasticity mechanisms and promote recovery after stroke. We will use a transgenic mouse line expressing ChR2 under a neuronal promoter to test our hypothesis. Our preliminary data show that optogenetic stimulation of neurons in the ipsilesional primary motor cortex of mice improved their behavioral recovery after stroke.
In Aim 1, we will use sensorimotor behavior tests to evaluate functional recovery after optogenetic neuronal stimulation in various brain regions after stroke. We will start stimulation during the recovery phase of stroke and determine the most optimal brain stimulation target for promoting stroke recovery.
In Aim2, we will investigate the underlying mechanisms that drive this recovery, including changes in cerebral blood flow, release of neurotrophic factors, axonal sprouting and synaptogenesis. Our study will advance the understanding of endogenous repair and plasticity mechanisms underlying recovery after stroke, as well as determine the most optimal brain stimulation target to promote recovery. Understanding the proteins and processes involved during repair and recovery could lead to novel discoveries of therapeutic drug targets able to facilitate recovery after stroke.

Public Health Relevance

Stroke, the leading cause of disability in the US, has very limited treatment options. There is often recovery of various levels of function after stroke, however, and our goal is to use the optogenetic technique to specifically stimulate neurons following stroke in order to promote recovery and to investigate the underlying mechanisms that drive this recovery. Understanding these repair/plasticity mechanisms will be tremendously helpful to developing effective treatments that promote recovery after stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Chen, Daofen
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Ito, Masaki; Aswendt, Markus; Lee, Alex G et al. (2018) RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke. Stroke 49:2191-2199
Shah, Aatman M; Ishizaka, Shunsuke; Cheng, Michelle Y et al. (2017) Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke. Sci Rep 7:46612
Cheng, Michelle Y; Aswendt, Markus; Steinberg, Gary K (2016) Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery. Neurotherapeutics 13:325-40
George, Paul M; Steinberg, Gary K (2015) Novel Stroke Therapeutics: Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments. Neuron 87:297-309
Cheng, Michelle Y; Wang, Eric H; Woodson, Wyatt J et al. (2014) Optogenetic neuronal stimulation promotes functional recovery after stroke. Proc Natl Acad Sci U S A 111:12913-8