Astrocyte regulation of neural plasticity after CNS injury

脊髓损伤(Sci)是一种毁灭性的神经损伤，可扰乱上行和下行。 行走、躯体感觉、排尿和其他重要的自主神经功能所必需的神经回路。这个 大多数脊髓损伤患者患有解剖和功能不全脊髓损伤(i-sci)， 会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 中枢神经系统(CNS)轴突在哺乳动物中不存在，临床和实验研究表明 脊髓损伤后神经功能的自然恢复。啮齿动物和非人类的实验研究 灵长类动物提示脊髓上运动束之间的突触重组和脊髓内的继发 绕过脊髓损伤的回路可以重新建立大脑-脊髓通讯，并产生显著的 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 控制这种有功能意义的脊髓内回路的可塑性已经排除了治疗学的发展 增强这一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 和发育过程中的回路发育，以及适度的突触强度和结构突触可塑性 伴随着神经活动的变化。针对不同的中枢神经系统损伤，星形胶质细胞经历分级和 局部明显的结构和功能变化统称为反应性星形胶质细胞增多症。在SCI之后， 病损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。这个 功能性脊髓区非瘢痕形成反应性神经周星形胶质细胞的功能 脊髓损伤后有意义的电路重构尚不清楚，但潜在的作用包括调节突触的恢复。 和神经保护。当前研究的目标是描述基本的分子机制。 星形胶质细胞通过其调节脊髓内突触重组和自发运动恢复 在SCI之后。这项研究将检验压倒一切的假设，即脊髓I-SCI后，脊髓神经周围星形胶质细胞 在备用组织中经历调节和促进脊髓内突触的转录图谱的变化 自发运动恢复背后的可塑性和回路重塑。在目标1中，我将使用特定于星形胶质细胞 转录学描绘神经周围星形胶质细胞基因表达的变化 脊髓损伤顶端关键脊髓回路重组区内脊髓上-脊髓内突触的可塑性。 在目标2中，我将评估神经元周星形胶质细胞反应性与棘上-棘内突触的相关性。 重塑和运动恢复。在目标3中，我将比较星形胶质细胞调控的机制 脊髓损伤上方重组区的椎上-椎内可塑性及其调节 下方失神经运动中枢内的感觉运动回路重组。总而言之，这些研究将 作为识别星形胶质细胞分子通路的关键第一步，这些分子通路可能在治疗上 旨在增强功能相关的可塑性，促进脊髓损伤后神经功能的恢复。

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.