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: 10534142
• 负责人: JEFFERY ALLEN BOYCHUK
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534142
• 关键词: Action Potentials; Address; Adhesives; Affect; Animals; Anterior; Area; Axon; Behavioral; Biology; Cells; Cerebrovascular Circulation; Cervical; Cervical spinal cord structure; Color; Complex; Consumption; Corticospinal Tracts; DNA cassette; Dedications; Diabetes Mellitus; Diet; Electrical Stimulation of the Brain; Electromyography; Energy consumption; Evidence based treatment; Excision; Exhibits; Fatty acid glycerol esters; Fluorescence; Food; Forelimb; Future; Goals; High Fat Diet; Hindlimb; Human; Impairment; Individual; Injury; Ischemic Stroke; Knowledge; Label; Light; Limb structure; Lower Extremity; Lumbar spinal cord structure; Measures; Metabolic; Middle Cerebral Artery Occlusion; Modeling; Motor; Motor Cortex; Motor Neurons; Motor Pathways; Motor Skills; Movement; Mus; Neurons; Obesity; Optics; Output; Pathway interactions; Pattern; Physiology; Property; Pyramidal Cells; Recovery; Resistance; Risk Factors; Role; Signal Transduction; Site; Skeletal Muscle; Slice; Source; Spinal; Spinal Cord; Stroke; Synapses; System; Techniques; Testing; Tissues; Transgenic Organisms; Upper Extremity; Variant; Vertebral column; Viral; Virus; Visualization; clinically relevant; comorbidity; dietary control; disability; evidence base; experimental study; foot; in vivo; middle cerebral artery; mortality; motor behavior; motor control; motor deficit; motor impairment; motor recovery; nerve supply; neural circuit; neurotransmission; novel; novel therapeutics; patch clamp; post stroke; skills; stroke recovery; stroke therapy; targeted treatment

SUMMARY / ABSTRACT Comorbid metabolic conditions of stroke, including obesity and diabetes, worsen stroke injury and reduce the capacity for stroke recovery. Given that stroke and these comorbid metabolic conditions are highly prevalent, the goal of this project is to understand how their interactions mechanistically affect the corticospinal motor system using high fat diet (HFD) as a model of metabolic disruption. In preliminary testing, HFD profoundly worsens behavioral motor recovery after experimental stroke. HFD and experimental stroke also cause an abnormal and profound emergence of lower extremity motor commands in areas of motor cortex that show little of these commands in otherwise healthy conditions or with experimental stroke injury and control diet. These abnormal lower extremity motor commands appear to be mechanistically due to increased synaptic signaling within the corticospinal system at connections that have not been well identified in this pathway. Volitional skilled motor control of the extremities is primarily achieved by the corticospinal tract and this pathway is often damaged by stroke resulting in severe disability. 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 (CST= L5PCs→ spinal motor neurons→ skeletal muscle). L5PCs that project to cervical spinal cord (cervical-projecting) are thought to control upper extremity function whereas L5PCs that project to lumbar spinal cord (lumbar-projecting) are thought to control lower extremity function. What is less known is whether single L5PCs can innervate cervical and lumbar levels of spinal cord and thus contribute motor control to upper and lower extremities. Similarly, it is recognized that L5PCs synapse on one-another (L5PCs→L5PCs) however it is not known whether this is true between cervical-projecting L5PCs and lumbar-projecting L5PCs during stroke recovery. Experiments here will test these seldom studied connections of the corticospinal system because they may underpin the abnormal emergence of lower extremity motor commands that arise when HFD is combined with experimental stroke. To investigate these hypotheses, we propose 3 aims: Aim 1. Determine whether distribution and in vivo signaling of cervical- and lumbar-projecting L5PCs can support abnormal emergence of hindlimb motor commands in anterior motor cortex when HFD is combined with experimental stroke. Aim 2. Test whether physiology of cervical- and lumbar-projecting L5PCs can support abnormal emergence of hindlimb motor commands in anterior motor cortex when HFD is combined with experimental stroke. Aim 3. Test timing, duration and persistence of HFD to exacerbate upper and lower extremity deficits after experimental stroke injury. This proposal aims to determine the corticospinal circuits responsible for this abnormal plasticity of lower extremity motor control in order to guide its future targeted treatment as a novel therapy for stroke recovery in the context of clinically-relevant comorbid metabolic conditions.

总结/摘要 中风的共病代谢状况，包括肥胖和糖尿病，使中风损伤恶化，并减少了中风的发生。 中风恢复能力。考虑到中风和这些共病代谢状况非常普遍， 本项目的目标是了解它们之间的相互作用如何在机制上影响皮质脊髓运动 使用高脂饮食（HFD）作为代谢破坏的模型的系统。在初步测试中，HFD深刻地 实验性中风后的行为运动恢复。HFD和实验性中风也会导致 在运动皮层区域出现异常和深刻的下肢运动命令， 这些命令在其他健康的条件下或与实验性中风损伤和控制饮食。这些 异常的下肢运动指令似乎是由于突触信号的增加 在皮质脊髓系统内，在该通路中尚未很好地确定的连接处。意志熟练 四肢的运动控制主要由皮质脊髓束实现， 中风导致严重残疾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（L5 PC），到自身发出骨骼肌信号的脊髓运动神经元， 肌肉（CST= L5 PCs →脊髓运动神经元→骨骼肌）。L5 PCs投射至颈髓 L5 PCs（颈突）被认为控制上肢功能，而L5 PCs（腰突）被认为控制腰椎功能。 脊髓（腰椎突出）被认为控制下肢功能。不太清楚的是， L5 PCs可以支配颈、腰段脊髓，从而对上、下节段的运动控制起作用。 下肢类似地，认识到L5 PC彼此突触（L5 PC → L5 PC），然而， 尚不清楚卒中时颈突L5 PC和腰突L5 PC之间是否存在这种情况 复苏这里的实验将测试这些很少研究的皮质脊髓系统的连接，因为它们 可能是HFD合并时下肢运动指令异常出现的基础 实验性中风为了研究这些假设，我们提出了3个目标：目标1。确定是否 颈部和腰部投射L5 PC的分布和体内信号传导可以支持L5 PC的异常出现。 当HFD与实验性中风相结合时，后肢前运动皮层的运动命令。目标二。测试 颈、腰侧L5 PCs的生理功能是否支持后肢的异常出现 当HFD与实验性中风相结合时，前运动皮层的运动命令。目标3.测试时间， 实验性卒中后HFD加重上下肢功能障碍的持续时间和持续性 损伤这项建议旨在确定负责这种异常可塑性的皮质脊髓回路， 肢体运动控制，以指导其未来的靶向治疗作为一种新的治疗中风恢复， 临床相关的共病代谢状况的背景。