Optogenetic Approaches to Functional Recovery After Stroke

中风后功能恢复的光遗传学方法

• 批准号: 8492882
• 负责人: GARY K STEINBERG
• 金额: $ 23.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492882
• 关键词: Acute; Adhesives; Adverse effects; Affect; Animals; Area; Automobile Driving; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cells; Cerebrovascular Circulation; Cessation of life; Data; Dentate nucleus; Depressed mood; Drug Targeting; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; FGF2 gene; Genes; Goals; Grant; Growth; Growth Associated Protein 43; Halorhodopsins; Human; Immunohistochemistry; Label; Laser-Doppler Flowmetry; Lead; Life; Light; Mediating; Motor; Motor Cortex; Mus; Neurologic; Neuronal Plasticity; Neurons; Outcome; Phase; Presynaptic Terminals; Process; Proteins; Recovery; Recovery of Function; Site; Stroke; Survivors; Synapses; Synaptophysin; Techniques; Testing; Therapeutic; Transcranial magnetic stimulation; Transgenic Mice; United States; Vascular Endothelial Growth Factors; axon growth; axonal sprouting; behavior test; biotinylated dextran amine; brain remodeling; brain repair; cell type; disability; effective therapy; improved; microbial; millisecond; neural circuit; neuronal excitability; neurotrophic factor; novel; novel strategies; optogenetics; post stroke; pre-clinical; promoter; public health relevance; repaired; stroke recovery; synaptogenesis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：中风是一种严重的急性神经损伤，可破坏脑功能并导致神经元死亡。在美国，每年大约有80万人受到中风的影响，大多数幸存者往往长期残疾。功能