BackgroundThe spinal cord is limited in its capacity to repair after damage caused by injury or disease. However, propriospinal (PS) neurons in the spinal cord have demonstrated a propensity for axonal regeneration after spinal cord injury. They can regrow and extend axonal projections to re-establish connections across a spinal lesion. We have previously reported differential reactions of two distinct PS neuronal populations—short thoracic propriospinal (TPS) and long descending propriospinal tract (LDPT) neurons—following a low thoracic (T10) spinal cord injury in a rat model. Immediately after injury, TPS neurons undergo a strong initial regenerative response, defined by the upregulation of transcripts to several growth factor receptors, and growth associated proteins. Many also initiate a strong apoptotic response, leading to cell death. LDPT neurons, on the other hand, show neither a regenerative nor an apoptotic response. They show either a lowered expression or no change in genes for a variety of growth associated proteins, and these neurons survive for at least 2 months post-axotomy. There are several potential explanations for this lack of cellular response for LDPT neurons, one of which is the distance of the LDPT cell body from the T10 lesion. In this study, we examined the molecular response of LDPT neurons to axotomy caused by a proximal spinal cord lesion.ResultsUtilizing laser capture microdissection and RNA quantification with branched DNA technology, we analyzed the change in gene expression in LDPT neurons following axotomy near their cell body. Expression patterns of 34 genes selected for their robust responses in TPS neurons were analyzed 3 days following a T2 spinal lesion. Our results show that after axonal injury nearer their cell bodies, there was a differential response of the same set of genes evaluated previously in TPS neurons after proximal axotomy, and LDPT neurons after distal axotomy (T10 spinal transection). The genetic response was much less robust than for TPS neurons after proximal axotomy, included both increased and decreased expression of certain genes, and did not suggest either a major regenerative or apoptotic response within the population of genes examined.ConclusionsThe data collectively demonstrate that the location of axotomy in relation to the soma of a neuron has a major effect on its ability to mount a regenerative response. However, the data also suggest that there are endogenous differences in the LDPT and TPS neuronal populations that affect their response to axotomy. These phenotypic differences may indicate that different or multiple therapies may be needed following spinal cord injury to stimulate maximal regeneration of all PS axons.

中文翻译：

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病灶邻近度对脊髓横断损伤后长降序本体脊髓神经元再生反应的影响

背景脊髓在损伤或疾病造成损伤后的修复能力有限。然而，脊髓中的本体脊髓 (PS) 神经元显示出脊髓损伤后轴突再生的倾向。它们可以再生和延伸轴突突起，以重新建立跨脊柱病变的连接。我们之前曾报道过在大鼠模型中发生低胸段 (T10) 脊髓损伤后，两种不同的 PS 神经元群——短胸椎本体脊髓 (TPS) 和长降序本体脊髓束 (LDPT) 神经元的不同反应。受伤后，TPS 神经元立即经历强烈的初始再生反应，其定义是对几种生长因子受体和生长相关蛋白的转录上调。许多还会引发强烈的细胞凋亡反应，导致细胞死亡。另一方面，LDPT 神经元既不显示再生反应，也不显示凋亡反应。它们显示出各种生长相关蛋白的基因表达降低或没有变化，并且这些神经元在轴突切开后至少存活 2 个月。对于 LDPT 神经元缺乏细胞反应有几种可能的解释，其中之一是 LDPT 细胞体与 T10 病变的距离。在这项研究中，我们检查了 LDPT 神经元对由近端脊髓损伤引起的轴突切开术的分子反应。结果利用激光捕获显微切割和 RNA 定量和分支 DNA 技术，我们分析了 LDPT 神经元在其细胞体附近的轴突切开术后基因表达的变化. 在 T2 脊髓损伤后 3 天，分析了 34 个基因在 TPS 神经元中的强烈反应的表达模式。我们的结果表明，在靠近细胞体的轴突损伤后，在近端轴突切断后的 TPS 神经元和远端轴突切断（T10 脊椎横断）后的 LDPT 神经元中，先前评估的同一组基因存在差异反应。近端轴突切断术后的 TPS 神经元的遗传反应远不如 TPS 神经元强，包括某些基因的表达增加和减少，并且在检查的基因群中没有表明主要的再生或细胞凋亡反应。结论数据共同表明该位置与神经元胞体相关的轴突切断术对其产生再生反应的能力有重大影响。然而，数据还表明 LDPT 和 TPS 神经元群的内源性差异会影响它们对轴突切开术的反应。这些表型差异可能表明脊髓损伤后可能需要不同或多种疗法来刺激所有 PS 轴突的最大再生。