Astrocyte regulation of neural plasticity after CNS injury

星形胶质细胞对中枢神经系统损伤后神经可塑性的调节

基本信息

批准号：
10004175
负责人：
Joshua Evan Burda
金额：
$ 24.55万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004175
关键词：
Anatomy Animals Astrocytes Attenuated Axon Biochemical Brain Bypass Cicatrix Clinical Research Communication Coupled Data Development Electromyography Exhibits Gene Expression Genetic Transcription Inflammation Injury Lesion Locomotor Recovery Mammals Mediating Molecular Motor Multiple Sclerosis Mus Natural regeneration Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neuronal Plasticity Neurons Pathway interactions Patients Phagocytes Phase Process Recovery Recovery of Function Regulation Research Research Proposals Rodent Role Sensory Signal Pathway Signal Transduction Spinal Spinal Cord Spinal Injuries Spinal cord injury Spinal cord injury patients Stat3 protein Stroke Structure Synapses Synaptic plasticity TBI Patients Testing Therapeutic Time Tissues Urination Virus Walking astrogliosis axon guidance axon injury axonal sprouting central nervous system injury daily functioning disability experience experimental study grasp improved outcome in vivo injury recovery insight loss of function motor recovery neural circuit neurological recovery neuroprotection neuroregulation new therapeutic target nonhuman primate prevent regenerative relating to nervous system response synaptogenesis therapeutic development therapeutic target therapy development transcriptomics

项目摘要

Spinal cord injury (SCI) is a devastating neurologic insult that can disrupt ascending and descending neural circuits necessary for walking, somatosensation, urination and other vital autonomic functions. The majority of SCI patients suffer from anatomically and functionally incomplete spinal cord injury (I-SCI) that results in varying degrees of neurological dysfunction. Although long-distance regeneration of central nervous system (CNS) axons does not occur in mammals, clinical and experimental studies demonstrate considerable spontaneous recovery of neurological function after I-SCI. Experimental studies in rodents and non-human primates indicate that synaptic reorganization between supraspinal motor tracts and spared intraspinal relay circuits that bypass a spinal lesion can re-establish brain-cord communication, and give rise to remarkable motor recovery after I-SCI. Unfortunately, a limited understanding of the cellular and molecular mechanisms governing this functionally meaningful intraspinal circuit plasticity has precluded development of therapeutics to augment this spontaneously occurring recovery process. Astrocytes are critical regulators of synaptogenesis and circuit development during development, and moderate synaptic strength and structural synaptic plasticity following changes in neural activity. In response to diverse CNS injuries, astrocytes undergo graded and regionally distinct changes in structure and function collectively referred to as reactive astrogliosis. After SCI, scar-forming, reactive astrocytes surrounding lesions are indispensible regulators of inflammation. The functions of non-scar-forming, reactive perineuronal astrocytes in spinal cord regions undergoing functionally meaningful circuit remodeling after SCI are not clear, but potential roles include regulation of synapse recovery and neuroprotection. The objective of the current study is to delineate fundamental molecular mechanisms through which astrocytes modulate intraspinal synaptic reorganization and spontaneous locomotor recovery after SCI. This research will test the overriding hypothesis that after I-SCI, intraspinal perineuronal astrocytes in spared tissue undergo changes in transcriptional profile that modulate and promote intraspinal synaptic plasticity and circuit remodeling underlying spontaneous locomotor recovery. In Aim 1, I will use astrocyte-specific transcriptomics to delineate changes in perineuronal astrocyte gene expression that underlie supraspinal-intraspinal synaptic plasticity within key spinal circuit reorganizing zones rostral to an I-SCI lesion. In Aim 2, I will assess the relevance of perineuronal astrocyte reactivity for supraspinal-intraspinal synaptic remodeling and motor recovery. In Aim 3, I will compare mechanisms through which astrocytes regulate supraspinal-intraspinal plasticity in reorganizing zones above an I-SCI lesion, with those regulating sensorimotor circuit reorganization within the denervated motor centers below. Together, these studies will serve as a critical first step towards identifying astrocyte molecular pathways that may be therapeutically targeted to enhance functionally relevant plasticity and promote recovery of neurological function after I-SCI.

脊髓损伤 (SCI) 是一种毁灭性的神经损伤，会扰乱上升和下降功能行走、躯体感觉、排尿和其他重要自主功能所必需的神经回路。这大多数 SCI 患者患有解剖学和功能性不完全性脊髓损伤 (I-SCI)，导致不同程度的神经功能障碍。虽然中枢神经的远距离再生哺乳动物中不存在中枢神经系统（CNS）轴突，临床和实验研究表明相当多的 I-SCI 后神经功能自发恢复。啮齿动物和非人类的实验研究灵长类动物表明脊髓上运动束和脊髓内中继之间的突触重组绕过脊髓损伤的回路可以重新建立脑索通讯，并产生显着的效果 I-SCI 后运动恢复。不幸的是，对细胞和分子机制的了解有限控制这种具有功能意义的椎管内回路可塑性阻碍了治疗方法的开发增强这种自发发生的恢复过程。星形胶质细胞是突触发生的关键调节者和发育过程中的电路发育，以及适度的突触强度和结构突触可塑性随着神经活动的变化。为了应对不同的中枢神经系统损伤，星形胶质细胞经历分级和结构和功能的区域性明显变化统称为反应性星形胶质细胞增生。 SCI之后，病变周围形成疤痕的反应性星形胶质细胞是炎症不可或缺的调节因子。这脊髓区域非疤痕形成反应性神经周围星形胶质细胞的功能正在发生功能性改变 SCI 后有意义的电路重塑尚不清楚，但潜在的作用包括调节突触恢复和神经保护。当前研究的目的是描绘基本分子机制星形胶质细胞通过其调节椎管内突触重组和自发运动恢复 SCI之后。这项研究将检验最重要的假设，即 I-SCI 后，椎管内神经周围星形胶质细胞在幸存的组织中，转录谱发生变化，调节和促进椎管内突触自发运动恢复的可塑性和回路重塑。在目标 1 中，我将使用星形胶质细胞特异性转录组学描绘神经元周围星形胶质细胞基因表达的变化 I-SCI 病变头端关键脊髓回路重组区内的椎上-椎内突触可塑性。在目标 2 中，我将评估神经周围星形胶质细胞反应性与椎上-椎内突触的相关性重塑和运动恢复。在目标 3 中，我将比较星形胶质细胞调节的机制 I-SCI 病变上方重组区的椎上-椎内可塑性，以及调节区域下面失神经运动中心内的感觉运动回路重组。这些研究共同将作为确定可能具有治疗作用的星形胶质细胞分子途径的关键第一步旨在增强功能相关可塑性并促进 I-SCI 后神经功能的恢复。