Optogenetic Approaches to Functional Recovery After Stroke

中风后功能恢复的光遗传学方法

• 批准号: 8670793
• 负责人: GARY K STEINBERG
• 金额: $ 19.6万
• 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/8670793
• 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）：中风是破坏大脑功能并导致神经元死亡的主要急性神经系统侮辱。在美国，每年约有80万人受到中风的影响，大多数幸存者经常生活长期残疾。功能 中风后可能发生恢复，并且当大脑修复并重建神经元之间的连接时，这种恢复归因于脑重塑和神经可塑性。脑刺激技术（例如电刺激或经颅磁刺激）已用于动物和人类中，以增强中风后的恢复。但是，涉及的神经回路和介导这种恢复的机制尚不清楚。此外，这些刺激技术非特异性刺激刺激部位附近的所有细胞类型，从而导致不希望的副作用。在此提案中，我们将使用光遗传学方法在中风后特异性刺激神经元，并检查对功能恢复和潜在机制的影响。光遗传学是一种新型策略，它利用光敏藻类蛋白（例如ChannelRhopopsin（Chr2））以快速而精确的方式操纵大脑中特定细胞基团的兴奋性。光遗传学刺激可以提高神经元兴奋性，可能导致神经营养因子释放，增强轴突吐剂/突触发生和脑血流增加，所有这些对中风后的功能恢复都很重要。因此，我们假设原发性运动皮层（M1）中神经元的光遗传学刺激可以增强内源性修复/可塑性机制并促进中风后恢复。我们将使用在神经元启动子下表达CHR2的转基因小鼠系来检验我们的假设。我们的初步数据表明，小鼠ipsilesiles原发性运动皮层中神经元的光遗传刺激改善了中风后其行为恢复。在AIM 1中，我们将使用感觉运动行为测试来评估中风后各个大脑区域的光遗传神经元刺激后的功能恢复。我们将在中风的恢复阶段开始刺激，并确定促进中风恢复的最佳脑刺激靶标。在AIM2中，我们将研究驱动这种恢复的潜在机制，包括脑血流的变化，神经营养因素的释放，轴突发芽和突触发生。我们的研究将促进中风后恢复后恢复后的内源性修复和可塑性机制的理解，并确定促进恢复的最佳脑刺激靶标。了解修复和恢复过程中所涉及的蛋白质和过程可能会导致对能够促进中风后恢复的治疗药物靶标的新发现。