CORTICOSPINAL MECHANISMS FOR HIGH FAT DIET IMPEDING STROKE RECOVERY

高脂肪饮食阻碍中风恢复的皮质脊髓机制

• 批准号: 10302996
• 负责人: JEFFERY ALLEN BOYCHUK
• 金额: $ 5.66万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302996
• 关键词: Activities of Daily Living; Address; Animals; Anterior; Back; Behavioral; Biology; Brain; Brain Mapping; Cells; Chronic; Complex; Corticospinal Tracts; Dependovirus; Development; Electric Stimulation; Exhibits; Fiber Optics; Funding; Future; Goals; Green Fluorescent Proteins; Health; High Fat Diet; Hindlimb; Individual; Injections; Injury; Institution; Knowledge; Laboratories; Laboratory mice; Lasers; Lesion; Light; Location; Lower Extremity; Lumbar spinal cord structure; Measures; Microelectrodes; Middle Cerebral Artery Occlusion; Motor; Motor Cortex; Motor Neurons; Motor Pathways; Motor output; Movement; Mus; Neurons; Optics; Outcome; Output; Parents; Pathway interactions; Photosensitivity; Physiologic pulse; Physiology; Population; Presynaptic Terminals; Principal Investigator; Pyramidal Cells; Quality of life; Recovery; Rehabilitation therapy; Research; Research Personnel; Rotarod Performance Test; Satellite Viruses; Scientist; Serotyping; Signal Transduction; Site; Skeletal Muscle; Source; Speed; Spinal; Spinal Cord; Stimulus; Stroke; Structure; Synapses; Techniques; Technology; Testing; Therapeutic; Training; United States National Institutes of Health; Variant; Viral; Virus; Volition; base; career; career development; disability; experimental group; experimental study; genetic manipulation; improved; injured; kinematics; microstimulation; motor control; motor impairment; neural circuit; optogenetics; post stroke; post-doctoral training; reconstruction; relating to nervous system; spinal cord and brain injury; stroke model; stroke recovery; success; therapeutic target

ABSTRACT The goal of this project is to provide funding support to an excellent young scientist who qualifies as a underrepresented individual per NIH criteria. This funding will provide key support to allow this individual to contribute to stroke research and form an independent career following their professional goals to become a principal investigator of their own laboratory. Stroke is a key health issue and its chronic motor impairments continue to be a major source of disability and detriment to activities of daily living and quality of life. An important knowledge gap for this health issue is the need to understand the neuronal control of volitional lower extremity movement both during healthy and stroke-injured conditions. This proposal addresses this knowledge gap by using two sophisticated brain stimulation techniques to activate and test the lower extremity cortical motor control pathway. In Aim 1, we propose to use electrical Long Train Intracortical Microstimulation (LT-ICMS) to stimulate motor cortex as it has not previously been used to study stroke recovery in laboratory mice. Further, LT-ICMS produces more complex motor outputs (relative to other forms of brain stimulation), that may be more ethologically-relevant, and the timing of its neural activation may more closely match natural brain activity during wake-behaving movement. We seek to expand on preliminary findings that suggest there are specific forms of LT-ICMS-measured cortical remodeling during poor and exceptional stroke recovery that may guide how we treat individuals after stroke. In Aim 2, we propose to use optogenetics to specifically stimulate the corticospinal circuitry responsible for movement of the lower extremities. The canonical view of the corticospinal tract is that it is a synaptic circuit, from layer 5 pyramidal cells (L5PCs) in motor cortex, to spinal motor neurons that themselves signal skeletal muscle. L5PCs that project to lumbar spinal cord (lumbar-projecting) are thought to control lower extremity function. Here we propose to introduce photo-sensitive channelrhodopsin variant 2 (ChR2) into lumbar-projecting L5PCs by back-tracing these neurons from lumbar spinal cord using adeno- associated virus of retrograde serotype (AAVrg). This AAVrg targets axonal terminals and results in genetic manipulation of the targeted cells without spreading further across additional synapses. We then plan to deliver intracortical optical blue light, using the same pulse parameters as electrical LT-ICMS, to selectively activate lumbar-projecting L5PCs in motor cortex by stimulating their artificial ChR2. Given that blue light stimuli will selectively activate neurons that express ChR2, this approach will allow direct testing of corticospinal circuitry responsible for movement of the lower extremities using highly-specific targeting of this cell population in order to guide future therapeutic treatment based on its precise deficits after stroke. Together, these aims provide a careful and rigorous determination of how voluntary lower extremity function is changed during stroke recovery and give an opportunity for an underrepresented investigator to continue their research and academic success.

抽象的 该项目的目标是为有资格成为一名优秀的年轻科学家提供资金支持 根据 NIH 标准，代表性不足的个人。这笔资金将提供关键支持，使此人能够 为中风研究做出贡献，并按照自己的职业目标成为一名独立的职业 他们自己实验室的首席研究员。中风是一个关键的健康问题及其慢性运动障碍 仍然是残疾和损害日常生活活动和生活质量的主要根源。一个重要的 这个健康问题的知识差距是需要了解下肢意志的神经控制 在健康和中风受伤的情况下进行运动。该提案通过以下方式解决了这一知识差距 使用两种复杂的大脑刺激技术来激活和测试下肢皮质运动控制 途径。在目标 1 中，我们建议使用电长列皮质内微刺激 (LT-ICMS) 来刺激 运动皮层，因为它以前没有被用来研究实验室小鼠的中风恢复。此外，LT-ICMS 产生更复杂的运动输出（相对于其他形式的大脑刺激），这可能更 与行为学相关，并且其神经激活的时间可能更接近于自然大脑活动 唤醒行为运动。我们寻求扩展初步发现，表明存在特定形式的 LT-ICMS 测量的中风恢复不良和异常期间的皮质重塑可能会指导我们如何 治疗中风后的个体。在目标 2 中，我们建议使用光遗传学来特异性刺激皮质脊髓 负责下肢运动的电路。皮质脊髓束的经典观点是 它是一个突触回路，从运动皮层中的第 5 层锥体细胞 (L5PC) 到脊髓运动神经元， 它们本身发出骨骼肌的信号。投射到腰部脊髓（腰部投射）的 L5PC 被认为 控制下肢功能。在这里我们建议引入光敏通道视紫红质变体2 （ChR2）通过使用腺-从腰脊髓回溯这些神经元进入腰椎投射L5PCs 逆行血清型相关病毒（AAVrg）。该 AAVrg 靶向轴突末端并导致遗传 操纵目标细胞而不进一步扩散到额外的突触。然后我们计划交付 皮质内光学蓝光，使用与电 LT-ICMS 相同的脉冲参数，选择性激活 通过刺激人工 ChR2，在运动皮层中投射腰椎 L5PC。鉴于蓝光刺激会 选择性激活表达 ChR2 的神经元，这种方法将允许直接测试皮质脊髓回路 通过高度特异性地靶向该细胞群来负责下肢的运动 根据中风后的精确缺陷指导未来的治疗。这些目标共同提供了 仔细而严格地确定中风恢复期间自愿下肢功能如何变化 并为代表性不足的研究者提供继续研究和学术成功的机会。