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

基本信息

批准号：
10265993
负责人：
JEFFERY ALLEN BOYCHUK
金额：
$ 22.67万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10265993
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 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

项目摘要

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 具有深远的影响。实验性中风后行为运动恢复恶化，实验性中风也会导致下肢运动指令在运动皮层区域出现异常和深刻的表现，而这些区域几乎没有表现出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。异常的下肢运动命令似乎是由于突触信号增加而机械地导致的在皮质脊髓系统内，该通路中尚未充分识别的连接处。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→投射到颈脊髓的L5PC）。（颈椎突出）被认为控制上肢功能，而 L5PC 则突出到腰椎脊髓（腰椎突出）被认为可以控制下肢功能，但鲜为人知的是是否是单身。 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。类似地，人们认识到 L5PCs 突触是相互连接的（L5PCs→L5PCs）。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 与实验性中风结合时，前运动皮层的后肢运动命令。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 与实验性中风结合时，前部运动皮层的运动命令。目标 3。测试时间， 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该提案旨在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。