Respiratory axon regeneration in the chronically injured spinal cord.
Respiratory axon regeneration in the chronically injured spinal cord.
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长期受伤的脊髓中的呼吸轴突再生。
DOI：
10.1016/j.nbd.2021.105389
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发表时间：
2021-07
影响因子：
6.1
通讯作者：
Lepore AC
中科院分区：
文献类型：
--
作者：
Cheng L;Sami A;Ghosh B;Goudsward HJ;Smith GM;Wright MC;Li S;Lepore AC
促进受损轴突的强大再生和这些生长的轴突群与适当的神经元靶点的突触重连接的结合是脊髓损伤（SCI）后的主要治疗目标。实现这一重要目标的一个关键障碍是，在成人中枢神经系统中，特别是在慢性脊髓损伤的情况下，神经元固有的无法延伸轴突。我们测试了一种针对磷酸酶和紧张素同系物的抑制肽（PTEN：一种神经元-内在轴突生长电位的中枢抑制剂）是否能通过重连关键呼吸神经回路，在慢性颈2级（C2）半切性脊髓损伤大鼠模型中恢复吸气膈功能。我们发现，从C2半切后8周开始，全身递送PTEN拮抗剂肽4 （PAP4）可促进损伤的球脊髓吻侧腹侧呼吸组（rVRG）轴突大量长距离再生，进入并穿过病变，并返回完整的尾侧C3-C5脊髓的膈运动神经元（PhMNs）。尽管有这种强大的rVRG轴突再生，PAP4只刺激了最小的膈功能恢复。此外，通过半切部位的再损伤完全去除pap4诱导的功能改善，表明通过损伤的轴突再生是这种部分功能恢复的原因。有趣的是，再生的rVRG轴突和PhMN靶点之间几乎没有形成假定的兴奋性单突触连接，这表明(1)rVRG-PhMN突触再连接受限至少在一定程度上是缺乏显著功能效应的原因；(2)慢性损伤的脊髓是再生轴突和突触后靶点之间实现突触发生的障碍。(3)解决这一挑战是提高慢性脊髓损伤治疗效果的潜在有效策略。总之，我们的研究展示了一种非侵入性和短暂的药物治疗慢性脊髓损伤的方法来修复控制膈呼吸功能的至关重要的神经回路，但也揭示了慢性损伤脊髓对回路可塑性的障碍。
Promoting the combination of robust regeneration of damaged axons and synaptic reconnection of these growing axon populations with appropriate neuronal targets represents a major therapeutic goal following spinal cord injury (SCI). A key impediment to achieving this important aim includes an intrinsic inability of neurons to extend axons in adult CNS, particularly in the context of the chronically-injured spinal cord. We tested whether an inhibitory peptide directed against phosphatase and tensin homolog (PTEN: a central inhibitor of neuron-intrinsic axon growth potential) could restore inspiratory diaphragm function by reconnecting critical respiratory neural circuitry in a rat model of chronic cervical level 2 (C2) hemisection SCI. We found that systemic delivery of PTEN antagonist peptide 4 (PAP4) starting at 8 weeks after C2 hemisection promoted substantial, long-distance regeneration of injured bulbospinal rostral Ventral Respiratory Group (rVRG) axons into and through the lesion and back toward phrenic motor neurons (PhMNs) located in intact caudal C3-C5 spinal cord. Despite this robust rVRG axon regeneration, PAP4 stimulated only minimal recovery of diaphragm function. Furthermore, re-lesion through the hemisection site completely removed PAP4-induced functional improvement, demonstrating that axon regeneration through the lesion was responsible for this partial functional recovery. Interestingly, there was minimal formation of putative excitatory monosynaptic connections between regrowing rVRG axons and PhMN targets, suggesting that (1) limited rVRG-PhMN synaptic reconnectivity was responsible at least in part for the lack of a significant functional effect, (2) chronically-injured spinal cord presents an obstacle to achieving synaptogenesis between regenerating axons and post-synaptic targets, and (3) addressing this challenge is a potentially-powerful strategy to enhance therapeutic efficacy in the chronic SCI setting. In conclusion, our study demonstrates a non-invasive and transient pharmacological approach in chronic SCI to repair the critically-important neural circuitry controlling diaphragmatic respiratory function, but also sheds light on obstacles to circuit plasticity presented by the chronically-injured spinal cord.
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慢性脊髓损伤后促进轴突再生和功能恢复的组合修复策略。
影响因子：
4.6
作者：
DePaul MA;Lin CY;Silver J;Lee YS
通讯作者：
Lee YS
正常成年大鼠脑中 PTEN 的差异表达及缺血大脑皮层中 PTEN 和 p-Akt 的上调
DOI：
10.1002/ar.20834
发表时间：
2009-04-01
影响因子：
2
作者：
Cai, Qi-Yan;Chen, Xing-Shu;Yao, Zhong-Xiang
通讯作者：
Yao, Zhong-Xiang
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
6.2
作者：
Goulao, Miguel;Ghosh, Biswarup;Lepore, Angelo C.
通讯作者：
Lepore, Angelo C.
影响因子：
2.9
作者：
Cao, Ying;Matsuyama, Kiyoji;Aoki, Mamoru
通讯作者：
Aoki, Mamoru