Astrocyte regulation of intraspinal plasticity and spontaneous recovery after SCI

 描述(申请人提供)：脊髓损伤(SCI)是一种毁灭性的神经损伤，可扰乱行走、躯体感觉、排尿和其他重要自主神经功能所需的上行和下行神经回路。大多数脊髓损伤患者患有不完全脊髓损伤(I-SCI)，导致不同程度的神经功能障碍。虽然哺乳动物中枢神经系统(CNS)轴突不存在远距离再生，但临床和实验研究表明，脊髓损伤后神经功能有相当大的自发恢复。在啮齿动物和非人类灵长类动物上的实验研究表明，脊髓上运动束和备用的脊髓内中继电路之间的突触重组可以重建脑-脊髓通讯，并在脊髓损伤后产生显著的运动恢复。相应的继发回路的形成也可能在偏瘫卒中患者的运动恢复中发挥作用。不幸的是，对支配这种有功能意义的脊髓内回路可塑性的细胞和分子机制的有限了解阻碍了治疗学的发展以增强这一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环路发育的重要调节者，在神经活动发生变化后具有中等的突触强度和结构突触可塑性。为了应对不同的中枢神经系统损伤，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多症。脊髓损伤后，损伤周围形成瘢痕的反应性星形胶质细胞是必不可少的炎症调节因子。脊髓损伤后，非瘢痕形成、反应性神经周星形胶质细胞在经历有意义的电路重塑的脊髓区域的功能尚不清楚，但可能的作用包括调节突触恢复和神经保护。本研究的目的是描述星形胶质细胞调控脊髓损伤后脊髓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的转录转录方法来描绘神经周围星形胶质细胞基因表达的关键变化，这些变化是导致I-SCI小鼠模型自发运动恢复的基础。在目标2中，我将使用神经解剖学、肌电图和体内星形胶质细胞特异的遗传操作来评估脊髓损伤后神经节细胞周围星形胶质细胞反应性与脊髓上-脊髓内突触重构和运动恢复的功能相关性。总之，这些研究将是确定星形胶质细胞分子通路的关键的第一步，这些通路可能是治疗的靶点，以增强功能相关的可塑性，促进脊髓损伤后神经功能的恢复。这些发现也与创伤性脑损伤、中风或多发性硬化症等神经退行性疾病的患者相关，在这些疾病中，从治疗的角度利用备用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。

 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.