In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration.
In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration.
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DOI：
10.1186/s12915-020-00869-2
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发表时间：
2020-11-18
期刊：
影响因子：
5.4
通讯作者：
De Paola V
中科院分区：
文献类型：
--
作者：
Canty AJ;Jackson JS;Huang L;Trabalza A;Bass C;Little G;Tortora M;Khan S;De Paola V
尽管在损伤和患病的神经系统中广泛发生轴突和突触损失，但这些关键变性过程的细胞和分子机制仍不完全清楚。沃勒变性（Wallerian degeneration，WD）是损伤后轴突丢失的一种严格调节形式，其在脊髓、视神经和周围神经系统（peripheral nervous system，PNS）的大的有髓纤维束中已被深入研究。然而，较少的研究，集中在WD在复杂的神经元回路的哺乳动物大脑，这些主要是基于传统的终点组织学方法。然而，尸检分析，不能捕捉事件的确切顺序，也不能评估的影响，精心制作的树枝状和突触结构的退化过程中，由于非同步和可变的性质，WD在各个轴突。为了全面了解WD在神经系统中的时空动态和突触机制，我们确定了调节小鼠大脑皮层内WD的因素。我们通过颅窗和荧光膜报告器将单轴突分辨率多光子成像与激光显微手术相结合。> 150个单独损伤的兴奋性皮质轴突的纵向成像揭示了阈值长度，低于该阈值长度，损伤的轴突一致地经历快速发作形式的WD（roWD）。roWD的启动时间平均比WD在神经系统其他区域的启动时间早20倍，执行速度慢3倍。皮质轴突WD和roWD依赖于突触密度，但不依赖于轴突的复杂性。最后，药理学和遗传操作表明，烟酰胺腺嘌呤二核苷酸（NAD+）依赖性途径可以延迟皮质roWD独立于受损神经元的转录，进一步保护的分子机制控制WD在哺乳动物神经系统的不同领域。我们的数据说明了如何在体内延时成像可以提供新的见解的时空动力学和轴突损失的突触机制，并评估在受伤的哺乳动物大脑的治疗干预。
Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborisation and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons. To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started on average 20 times earlier and was executed 3 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed that a nicotinamide adenine dinucleotide (NAD+)-dependent pathway could delay cortical roWD independent of transcription in the damaged neurons, demonstrating further conservation of the molecular mechanisms controlling WD in different areas of the mammalian nervous system. Our data illustrate how in vivo time-lapse imaging can provide new insights into the spatiotemporal dynamics and synaptic mechanisms of axon loss and assess therapeutic interventions in the injured mammalian brain.
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影响因子：
82.9
作者：
Breckwoldt, Michael;Pfister, Franz M. J.;Misgeld, Thomas
通讯作者：
Misgeld, Thomas
影响因子：
48
作者：
Farrar, Matthew J.;Bernstein, Ida M.;Schlafer, Donald H.;Cleland, Thomas A.;Fetcho, Joseph R.;Schaffer, Chris B.
通讯作者：
Schaffer, Chris B.
影响因子：
16.6
作者：
Dhar, Matasha;Brenner, Joshua M.;Sakimura, Kenji;Kano, Masanobu;Nishiyama, Hiroshi
通讯作者：
Nishiyama, Hiroshi
DOI：
10.1073/pnas.0900222106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Dray, Cyril;Rougon, Genevieve;Debarbieux, Franck
通讯作者：
Debarbieux, Franck
影响因子：
16.6
作者：
Canty, A. J.;Huang, L.;De Paola, V.
通讯作者：
De Paola, V.