In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration
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RESEARCH ARTICLE
Open Access
In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration Alison Jane Canty1*†, Johanna Sara Jackson2†, Lieven Huang3, Antonio Trabalza3, Cher Bass3, Graham Little3, Maria Tortora3, Shabana Khan3 and Vincenzo De Paola3,4*
Abstract Background: 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. Results: 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 singleaxon-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. (Continued on next page)
* Correspondence: [email protected]; [email protected] † Alison Jane Canty and Johanna Sara Jackson contributed equally to this work. 1 Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, Australia 3 Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and i
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