Astrocyte regulation of neural plasticity after CNS injury

脊髓损伤（SCI）是一种破坏性的神经损伤，可以破坏上行和下行 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。的 大多数SCI患者患有解剖学上和功能上不完全的脊髓损伤（I-SCI）， 导致不同程度的神经功能障碍虽然中枢神经的长距离再生 虽然哺乳动物中不存在中枢神经系统（CNS）轴突，但临床和实验研究表明， I-SCI后神经功能的自发恢复。啮齿动物和非人类的实验研究 灵长类动物表明，脊髓上运动束和备用脊髓内中继之间的突触重组， 绕过脊髓损伤的回路可以重建脑脊髓通信，并引起显着的 脊髓损伤后运动功能恢复不幸的是，对细胞和分子机制的了解有限， 控制这种功能上有意义的脊柱内回路可塑性阻碍了治疗方法的发展， 增强这种自发的恢复过程。星形胶质细胞是突触发生的重要调节因子 和电路的发展过程中，和中等突触强度和结构突触可塑性 神经活动的变化。星形胶质细胞对不同的中枢神经系统损伤作出反应， 结构和功能的区域性不同变化统称为反应性星形胶质细胞增生。SCI之后， 损伤周围的瘢痕形成、反应性星形胶质细胞是炎症不可缺少的调节剂。的 脊髓区域非瘢痕形成的反应性神经元周围星形胶质细胞的功能 SCI后有意义的回路重塑尚不清楚，但潜在的作用包括调节突触恢复 和神经保护。目前研究的目的是阐明基本的分子机制 星形胶质细胞通过该通路调节脊髓内突触重组和自发运动恢复 SCI之后这项研究将验证最重要的假设，即在I-SCI后，脊髓内神经元周围星形胶质细胞 在备用组织中，转录谱发生变化，调节和促进脊髓内突触 可塑性和回路重塑的基础自发运动恢复。在目标1中，我将使用星形胶质细胞特异性 转录组学描述神经元周星形胶质细胞基因表达的变化， 在I-SCI损伤的喙侧关键脊髓回路重组区域内的脊髓上-脊髓内突触可塑性。 在目标2中，我将评估神经元周星形胶质细胞反应性与脊髓上-脊髓内突触的相关性。 重塑和运动恢复在目标3中，我将比较星形胶质细胞调节 在I-SCI损伤上方的重组区中的棘上-棘内可塑性， 感觉运动回路重组在下面的失神经运动中心。这些研究将 作为确定星形胶质细胞分子通路的关键的第一步， 目的是增强功能相关的可塑性，促进I-SCI后神经功能的恢复。

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.