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: 10065530
• 负责人: JEFFERY ALLEN BOYCHUK
• 金额: $ 33.41万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065530
• 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; Diabetes Mellitus; Diet; Electrical Stimulation of the Brain; 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; Movement; Mus; Neurons; Obesity; Optics; Output; Pathway interactions; Pattern; Physiology; Property; Pyramidal Cells; Recovery; Resistance; Risk Factors; 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; Volition; clinically relevant; comorbidity; dietary control; disability; evidence base; experimental study; foot; in vivo; injury recovery; 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; 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.

摘要/摘要 中风的共病代谢状况，包括肥胖和糖尿病，会加重中风损伤并降低中风的发生率。 中风恢复的能力。鉴于中风和这些合并代谢疾病非常普遍， 该项目的目标是了解它们的相互作用如何机械地影响皮质脊髓运动 使用高脂肪饮食（HFD）作为代谢破坏模型的系统。在初步测试中，HFD 深刻 实验性中风后行为运动恢复恶化。 HFD 和实验性中风也会导致 在几乎没有表现出的运动皮层区域中，下肢运动命令出现异常和深刻的变化 在其他健康条件或实验性中风损伤和控制饮食的情况下执行这些命令。这些 异常的下肢运动指令似乎是由于突触信号传导增加所致 皮质脊髓系统内的连接尚未在该通路中得到很好的识别。意志熟练 四肢的运动控制主要由皮质脊髓束实现，该通路经常受损 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 (L5PC) 到本身向骨骼发出信号的脊髓运动神经元 肌肉（CST = L5PC→脊髓运动神经元→骨骼肌）。投射到颈脊髓的 L5PC （颈椎突出）被认为控制上肢功能，而 L5PC 则突出到腰椎 绳索（腰椎突出）被认为可以控制下肢功能。鲜为人知的是，是否单身 L5PCs 可以支配脊髓的颈椎和腰椎水平，从而有助于上、下肢的运动控制。 下肢。类似地，人们认识到 L5PCs 突触彼此相连（L5PCs→L5PCs），但它是 尚不清楚中风期间颈椎突出的 L5PC 和腰椎突出的 L5PC 之间是否存在这种情况 恢复。这里的实验将测试这些很少被研究的皮质脊髓系统的连接，因为它们 可能会导致 HFD 联合使用时出现的下肢运动指令异常出现 与实验性中风。为了研究这些假设，我们提出了 3 个目标： 目标 1. 确定是否 颈椎和腰椎突出的 L5PC 的分布和体内信号传导可以支持异常出现 当 HFD 与实验性中风相结合时，前运动皮层的后肢运动指令。目标 2. 测试 颈椎和腰椎突出的 L5PC 的生理学是否可以支持后肢的异常出现 当 HFD 与实验性中风相结合时，前运动皮层的运动指令。目标 3. 测试时机， HFD 的持续时间和持续性会加剧实验性卒中后的上肢和下肢缺陷 受伤。该提案的目的是确定导致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中风恢复的新型疗法 临床相关的共病代谢状况的背景。