CORTICOSPINAL MECHANISMS FOR HIGH FAT DIET IMPEDING STROKE RECOVERY

摘要/摘要 中风的共同代谢状况，包括肥胖和糖尿病，加重了中风的伤害，减少了 中风恢复能力。鉴于中风和这些并存的新陈代谢疾病非常普遍， 这个项目的目标是了解它们的相互作用是如何机械地影响皮质脊髓运动的。 使用高脂肪饮食(HFD)作为代谢紊乱模型的系统。在初步测试中，HFD深刻地 加重实验性中风后的行为运动恢复。HFD和实验性中风也会导致 运动皮质区域出现异常而深刻的下肢运动指令，很少显示 在其他健康条件下或有实验性中风损伤的情况下进行这些命令并控制饮食。这些 由于突触信号的增加，异常的下肢运动指令似乎是机械性的 在皮质脊髓系统内，在这个通路中还没有被很好地识别的连接。意志娴熟 四肢的运动控制主要是通过皮质脊髓束实现的，这一通路经常受到损害 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， 从运动皮质中的第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=L5pCs、→、脊髓运动神经元、→骨骼肌)。投射到颈髓的L5PC (颈部投射)被认为控制上肢功能，而L5PC投射到腰椎 脊髓(腰部突出)被认为控制着腿部的功能。不太为人所知的是，单身 L5PC可支配颈髓和腰椎水平的脊髓，从而促进对上、下段脊髓的运动控制。 四肢受伤。类似地，人们认识到L5PC在彼此之间突触(L5PC→L5PC)，然而它是 尚不清楚卒中时颈椎L5PC和腰椎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联系，因为它们 可能支持合并HFD时出现的下肢运动指令的异常出现 有实验性的中风。为了研究这些假设，我们提出了三个目标：目标1.确定 颈椎和腰椎投射的L5PC的分布和体内信号转导可支持异常的出现 当HFD合并实验性卒中时，后肢运动控制在前部运动皮质。目标2.测试 颈椎和腰椎突出的L5PC的生理功能是否支持后肢的异常出现 当HFD合并实验性卒中时，前运动皮质中的运动指令。目标3.测试时间， HFD加重实验性卒中后上肢和下肢功能障碍的持续时间和持久性 受伤。这项建议旨在确定导致LOWER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康复的一种新疗法 与临床相关的共病代谢状况的背景。

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.