Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex

Abstract

Despite the widespread occurrence of axon degeneration in the injured and diseased nervous system, the mechanisms of the degenerative process remain incompletely understood. In particular, the factors that regulate how individual axons degenerate within their native environment in the mammalian brain are unknown. Longitudinal imaging of >120 individually injured cortical axons revealed a threshold length below which injured axons undergo a rapid-onset form of Wallerian degeneration (ROWD). ROWD consistently starts 10 times earlier and is executed 4 times slower than classic Wallerian degeneration (WD). ROWD is dependent on synaptic density, unlike WD, but is independent of axon complexity. Finally, we provide both pharmacological and genetic evidence that a Nicotinamide Adenine Dinucleotide (NAD+)-dependent pathway controls cortical axon ROWD independent of transcription in the damaged neurons. Thus, our data redefine the therapeutic window for intervention to maintain neurological function in injured cortical neurons, and support the use of in vivo optical imaging to gain unique insights into the mechanisms of axon degeneration in the brain.