The effects of activity on propriospinal neuron morphology and connectivity

活动对本体脊髓神经元形态和连接的影响

基本信息

批准号：
10284936
负责人：
Brandon Lee Brown
金额：
$ 3.34万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284936
关键词：
Anatomy Animal Housing Animal Model Animals Area Axon Behavior Behavioral Behavioral Assay Breathing Cells Cervical Chest Clinical Data Dendrites Dependovirus Ensure Enterobacteria phage P1 Cre recombinase Forelimb GTP-Binding Proteins Gait Genes Genetic Transcription Growth and Development function Hindlimb Human Injections Injury Kentucky Label Lateral Lentivirus Limb structure Locomotion Locomotor Recovery Mentors Messenger RNA Morphology Motor Muscle Nervous system structure Neuraxis Neuronal Plasticity Neurons Ontology Outcome Output Pathology Pathway interactions Pattern Periodicity Physical Rehabilitation Physical activity Positioning Attribute Postdoctoral Fellow Presynaptic Terminals Rabies Rabies virus Recording of previous events Recovery of Function Regulation Rehabilitation therapy Research Rodent Role Sensory Signal Transduction Source Specificity Spinal Spinal Cord Contusions Spinal Ganglia Spinal cord injury Synapses System Therapeutic Intervention Training Transcriptional Regulation Vertebrates Viral base career central pattern generator improved kinematics neuronal excitability neuroregulation new therapeutic target receptor reconstruction skills transcriptome sequencing white matter

项目摘要

Project Summary. The majority of human spinal cord injuries (SCI) are anatomically incomplete, potentially leaving propriospinal pathways, which may relay information past the injury epicenter, intact. Following SCI in rodents, descending motor tracts sprout and increasingly contact descending propriospinal neurons (DPNs), forming detour circuits to relay signals caudal to the injury. However, no studies have evaluated the potential for ascending PNs to form bottom-up detour circuits post-SCI. We previously found that silencing long ascending PNs (LAPNs), which directly connect the lumbar and cervical spinal enlargements, disrupted coordination at each limb girdle. Surprisingly, silencing this anatomically intact pathway post-SCI improved locomotor function. Thus, it is critical to evaluate LAPN plasticity, and determine how this plasticity might be refined by therapeutic interventions. To do so, LAPN somatic and dendritic morphology will be characterized using a dual-viral system to specifically label LAPNs. We will also use a multi-viral system with a highly modified rabies virus to identify the sources of direct synaptic input to LAPNs. Increased physical activity and rehabilitative training are known to improve locomotor function and anatomical outcomes post-SCI. To evaluate the impact of physical activity and rehabilitative training on LAPN plasticity and locomotor function post-SCI, we will alter activity levels by housing animals in tiny cages or in large cages to restrict or facilitate activity. Animals in large cages will also receive rehabilitative training, which mimics clinical rehabilitation. Further understanding SCI-induced neuroplasticity, and how physical activity and rehabilitative training impact this plasticity will further our understanding of SCI pathology and provide new therapeutic targets. Working closely with my mentors, we have developed a training plan that will broaden my scientific skills, facilitate independent scientific thought, and cultivate skills needed to be a productive postdoctoral fellow. The Kentucky Spinal Cord Injury Research Center provides clinical and scientific expertise in SCI and related fields, and has a history of successfully preparing trainees for current and next stages in their careers. Hypothesis. Pre-SCI we hypothesize that DPNs, reticulospinals, and sensory afferents will provide input to LAPNs. Post-SCI we anticipate 1) LAPN dendrite orientation change, 2) LAPNs will be increasingly contacted by sensory afferents to form bottom-up detour circuits, and 3) increased activity plus rehabilitative training post- SCI will improve locomotor function, impact dendrite reorganization, and refine detour circuits. Aim 1. Characterize the somatic and dendritic morphology of LAPNs, and identify the sources of direct synaptic input onto LAPNs. Aim 2. Evaluate the effects of activity and rehabilitative training on locomotor function, LAPN morphology, and the sources of direct synaptic inputs to LAPNs after T10 contusive spinal cord injury.

项目摘要。大多数人类脊髓损伤（SCI）在解剖学上是不完整的，可能使本体脊髓通路保持完整，该通路可以将信息传递到损伤中心。继SCI之后啮齿类动物，下降运动束萌芽并越来越多地接触下降固有脊髓神经元（DPN），形成迂回电路来传递损伤尾部的信号。然而，没有研究评估其潜力使上升的 PN 在 SCI 后形成自下而上的绕行电路。我们之前发现长时间沉默直接连接腰椎和颈椎增大的上升 PN（LAPN）被破坏各肢带的协调性。令人惊讶的是，脊髓损伤后沉默这条解剖学上完整的通路得到了改善运动功能。因此，评估 LAPN 可塑性并确定这种可塑性如何至关重要通过治疗干预加以完善。为此，将表征 LAPN 体细胞和树突形态使用双病毒系统特异性标记 LAPN。我们还将使用具有高度改良狂犬病病毒以确定 LAPN 直接突触输入的来源。增加体力活动和众所周知，康复训练可以改善脊髓损伤后的运动功能和解剖结果。评估体力活动和康复训练对 SCI 后 LAPN 可塑性和运动功能的影响，我们将通过将动物关在小笼子或大笼子中来限制或促进活动来改变活动水平。大笼子里的动物还将接受模仿临床康复的康复训练。更远了解 SCI 引起的神经可塑性，以及体力活动和康复训练如何影响它可塑性将进一步加深我们对 SCI 病理学的理解并提供新的治疗靶点。密切合作我们与我的导师一起制定了一项培训计划，该计划将扩大我的科学技能，促进独立科学思想，并培养成为一名富有成效的博士后研究员所需的技能。肯塔基州脊髓损伤研究中心提供 SCI 及相关领域的临床和科学专业知识，并拥有成功地为学员做好当前和下一阶段职业生涯的准备。假设。在 SCI 发生之前，我们假设 DPN、网状脊髓和感觉传入神经将为 LAPN。 SCI 后，我们预计 1) LAPN 树突方向发生变化，2) LAPN 将被越来越多地接触通过感觉传入形成自下而上的迂回回路，以及3）增加活动加上术后康复训练 SCI 将改善运动功能、影响树突重组并完善绕行回路。目标 1. 表征 LAPN 的体细胞和树突形态，并确定直接来源 LAPN 上的突触输入。目标 2. 评估活动和康复训练对运动功能、LAPN 形态和功能的影响 T10 挫伤性脊髓损伤后 LAPN 的直接突触输入来源。