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（由应用提供）：脊髓损伤（SCI）是一种破坏性神经损伤，可以破坏行走，体感应，排尿和其他重要自主功能所需的上升和下降的神经元回路。大多数SCI患者在解剖学和功能上不完整的脊髓损伤（I-SCI）遭受不同程度的神经功能障碍。尽管中枢神经系统（CNS）轴突的长距离再生并未发生在哺乳动物中，但临床和实验研究表明，在I-SCI之后，考虑了赞助者的恢复。对啮齿动物和非人类私人的实验研究表明，绕过脊柱病变的脊柱上运动区和宽松的脊柱内中继电路之间的突触重组可以重新建立脑饰通信，并在I-SCI后引起显着的运动恢复。相应的继电器电路形成也可能在半脂肪中风患者的运动恢复中起作用。不幸的是，对控制这种功能有意义的脊柱内回路可塑性的细胞和分子机制的有限理解已被排除在疗法中的发展，从而增强了这种赞助发生的恢复过程。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因子，神经活动变化后，中等的合成强度和结构合成可塑性。为了应对潜水中枢神经系统的损伤，在渐变和区域的结构和功能下，星形胶质细胞共同称为反应性星形胶质细胞增多症。 SCI后，围绕病变的疤痕形成，反应性星形胶质细胞是不可或缺的炎症调节剂。 SCI后有意义的有意义的电路重塑的脊髓区域中非尺寸形成的反应性周神经元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作用。当前研究的目的是描述星形胶质细胞调节脊柱内突触重组的基本分子机制，而SCI后的主导运动恢复。在AIM 1中，我将使用体内星形胶质细胞特异性转录组学方法来划定会周神经元星形胶质细胞基因表达的关键变化，这些变化是I-SCI小鼠模型中赞助运动恢复的基础。在AIM 2中，我将使用神经解剖学追踪，肌电图和体内星形胶质细胞特异性遗传操作来评估周期神经胶质细胞反应性的功能相关性，以在I-SCI后恢复中脊柱上神经胶质细胞反应性。总之，这些研究将是鉴定星形胶质细胞分子途径的关键第一步，这些途径可能是热靶向以增强功能相关的可塑性并促进I-SCI后神经系统功能恢复的关键第一步。此类发现也与脑损伤，中风或神经退行性疾病（例如多发性硬化症）患者有关，其中在保存组织中利用神经系统循环的突触可塑性可能是促进神经系统功能恢复的关键。