Astrocyte regulation of intraspinal plasticity and spontaneous recovery after SCI

星形胶质细胞对脊髓损伤后椎管内可塑性和自发恢复的调节

• 批准号: 9123306
• 负责人: Joshua Evan Burda
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123306
• 关键词: Animals; Astrocytes; Attenuated; Axon; Biochemical; Brain; Bypass; Cicatrix; Clinical Research; Communication; Coupled; Data; Development; Electromyography; Exhibits; Extracellular Matrix; Fiber; Gene Expression; Genes; Hindlimb; Inflammation; Injury; Lesion; Locomotor Recovery; Mammals; Molecular; Motor; Multiple Sclerosis; Mus; Natural regeneration; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Pathway interactions; Patients; Phase; Play; Process; RNA; Recovery; Regulation; Research; Research Proposals; Rodent; Role; 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; Walking; astrogliosis; axon guidance; central nervous system injury; daily functioning; disability; experience; genetic manipulation; grasp; improved outcome; in vivo; injured; insight; knock-down; loss of function; motor recovery; mouse model; neural circuit; neuroprotection; new therapeutic target; nonhuman primate; prevent; public health relevance; regenerative; relating to nervous system; research study; response; synaptogenesis; therapeutic development; therapy development; transcriptomics

 DESCRIPTION (provided by applicant): 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. Corresponding relay circuit formation may also play a role in motor recovery in hemipalegic stroke patients. 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. In Aim 1, I will use an in vivo, astrocyte-specific transcriptomics approach to delineat key changes in perineuronal astrocyte gene expression that underlie spontaneous locomotor recovery in a mouse model of I-SCI. In Aim 2, I will use neuroanatomical tract tracing, electromyography and in vivo astrocyte-specific genetic manipulations to assess the functional relevance of perineuronal astrocyte reactivity for supraspinal- intraspinal synaptic remodeling and locomotor recovery after I-SCI. 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. Such findings are also relevant to patients with traumatic brain injury, stroke or neurodegenerative disease such as multiple sclerosis, in which therapeutically harnessing synaptic plasticity of neural circuitry in spared tissue may be a key to promoting recovery of neurological function.

 描述（由申请人提供）：脊髓损伤（SCI）是一种毁灭性的神经损伤，会破坏行走、躯体感觉、排尿和其他重要自主功能所必需的上行和下行神经回路。大多数 SCI 患者患有解剖学和功能不完整。脊髓损伤（I-SCI）导致不同程度的神经功能障碍，尽管中枢神经系统（CNS）轴突的长距离再生不会发生在哺乳动物中，但临床上。实验研究表明，I-SCI 后神经功能有相当大的自发恢复。对啮齿动物和非人类灵长类动物的实验研究表明，脊髓上运动束和绕过脊髓损伤的脊柱内中继回路之间的突触重组可以重新建立脑-脊髓通讯。 ，并在 I-SCI 后引起显着的运动恢复，相应的中继电路形成也可能在偏瘫中风患者的运动恢复中发挥作用，不幸的是，对控制这种功能的细胞和分子机制的了解有限。有意义的椎管内回路可塑性阻碍了治疗方法的开发，以增强这种自发发生的恢复过程，星形胶质细胞是发育过程中突触发生和回路发育的关键调节剂，并且在神经活动变化后具有适度的突触强度和结构突触可塑性。星形胶质细胞在结构和功能上经历分级和区域性的明显变化，统称为反应性星形胶质细胞增生，在 SCI 后，病变周围形成疤痕的反应性星形胶质细胞是不可或缺的调节剂。脊髓损伤后进行具有功能意义的回路重塑的非疤痕形成性反应性神经周围星形胶质细胞的功能尚不清楚，但潜在的作用包括调节突触恢复和神经保护。星形胶质细胞在 SCI 后调节脊柱内突触重组和自发运动恢复的基本分子机制 在目标 1 中，我将使用体内星形胶质细胞特异性转录组学方法来研究。描绘 I-SCI 小鼠模型自发运动恢复背后的神经元周围星形胶质细胞基因表达的关键变化。在目标 2 中，我将使用神经解剖束追踪、肌电图和体内星形胶质细胞特异性遗传操作来评估神经元周围星形胶质细胞的功能相关性。 I-SCI 后椎上-椎内突触重塑和运动恢复的反应性，这些研究将成为迈向关键的第一步。确定星形胶质细胞分子途径，这些途径可以作为治疗目标，以增强功能相关的可塑性并促进 I-SCI 后神经功能的恢复，这些发现也与患有创伤性脑损伤、中风或多发性硬化症等神经退行性疾病的患者有关，其中治疗利用这些途径。幸存组织中神经回路的突触可塑性可能是促进神经功能恢复的关键。