Optic nerve injury-induced regeneration in the adult zebrafish is accompanied by spatiotemporal changes in mitochondrial dynamics

Beckers, An; Masin, Luca; Dyck, Annelies Van; Bergmans, Steven; Vanhunsel, Sophie; Zhang, Anyi; Verreet, Tine; Poulain, FabienneE; Farrow, Karl; Moons, Lieve

doi:10.4103/1673-5374.344837

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…Emerging evidence from in vitro and in vivo studies in spontaneously as well as experimentally induced regenerating models suggests that increased mitochondrial mobility is essential to enable successful axonal regrowth (Mar et al, 2014;Han et al, 2016;Zhou et al, 2016;Cartoni et al, 2017;Xu et al, 2017;Cheng et al, 2022). In line with this, we recently discovered that both the distribution and morphology of mitochondria change within RGCs during the different phases of axonal and dendritic regrowth induced by ONC injury in adult zebrafish (Beckers et al, 2023c).…”

Section: Introductionmentioning

confidence: 64%

“…We previously identified an antagonistic axon-dendrite interplay during spontaneous regeneration of adult zebrafish RGCs and revealed that the distribution and morphology of mitochondria spatiotemporally change in the different neuronal compartments upon ONC ( Beckers et al, 2019 , 2023c ). Based on these observations, we hypothesize that successful injury-induced regeneration requires the temporally organized, local reallocation of energy resources to individual neuronal compartments.…”

Section: Discussionmentioning

confidence: 99%

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A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons

Dyck

Masin

Bergmans

et al. 2023

Front. Mol. Neurosci.

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Unlike mammals, adult zebrafish are able to fully regenerate axons and functionally recover from neuronal damage in the mature central nervous system (CNS). Decades of research have tried to identify the mechanisms behind their spontaneous regenerative capacity, but the exact underlying pathways and molecular drivers remain to be fully elucidated. By studying optic nerve injury-induced axonal regrowth of adult zebrafish retinal ganglion cells (RGCs), we previously reported transient dendritic shrinkage and changes in the distribution and morphology of mitochondria in the different neuronal compartments throughout the regenerative process. These data suggest that dendrite remodeling and temporary changes in mitochondrial dynamics contribute to effective axonal and dendritic repair upon optic nerve injury. To further elucidate these interactions, we here present a novel adult zebrafish microfluidic model in which we can demonstrate compartment-specific alterations in resource allocation in real-time at single neuron level. First, we developed a pioneering method that enables to isolate and culture adult zebrafish retinal neurons in a microfluidic setup. Notably, with this protocol, we report on a long-term adult primary neuronal culture with a high number of surviving and spontaneously outgrowing mature neurons, which was thus far only very limitedly described in literature. By performing time-lapse live cell imaging and kymographic analyses in this setup, we can explore changes in dendritic remodeling and mitochondrial motility during spontaneous axonal regeneration. This innovative model system will enable to discover how redirecting intraneuronal energy resources supports successful regeneration in the adult zebrafish CNS, and might facilitate the discovery of new therapeutic targets to promote neuronal repair in humans.

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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons

Dyck

Masin

Bergmans

et al. 2023

Front. Mol. Neurosci.

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“…Sections were incubated with anti-pS6 antibody (1:500; Cell Signaling pS6 ribosomal protein S235/236 antibody 2211, made in rabbit with species cross-reactivity in zebrafish; Cell Signaling website; RRID, P62753) and anti-choline acetyltransferase (ChAT) antibody (1:500; ChAT, AB144P; Merck Millipore; RRID, AB_2079751, made in goat) overnight at 4°C in 2% normal donkey in PBS–Triton solution. This ChAT antibody was previously used for Western blotting in zebrafish ( Clemente et al, 2004 ; Beckers et al, 2023 ), and in the current study, it served as an anatomical marker of the NI ( Mueller et al, 2004 ; Henriques et al, 2019 ). After three washes with PBS, slides were incubated for 60 min at room temperature with secondary antibodies in PBS–Triton with 2% normal donkey blocking solution.…”

Section: Methodsmentioning

confidence: 99%

The Dorsal Part of the Anterior Tuberal Nucleus Responds to Auditory Stimulation in Zebrafish (Danio rerio)

Corrales Parada,

Mayer,

Chagnaud

2024

eNeuro

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The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae. In this study, we examined the involvement of the anterior tuberal nucleus (AT) in auditory processing in adult zebrafish. Our tract-tracing experiments revealed that the dorsal subdivision of AT is strongly bidirectionally connected to the central nucleus of the torus semicircularis (TSc), a major auditory nucleus in fishes. Immunohistochemical visualisation of the ribosomal protein S6 (pS6) phosphorylation to map neural activity in response to auditory stimulation substantiated this finding: the dorsal but not the ventral part of AT responded strongly to auditory stimulation. A similar response to auditory stimulation was present in the TSc but not in the nucleus isthmi (NI), a visual region, which we used as a control for testing if the pS6 activation was specific to the auditory stimulation. We also measured the time course of pS6 phosphorylation, which was previously unreported in teleost fish. After auditory stimulation, we found that pS6 phosphorylation peaked between 100-130 minutes and returned to baseline levels after 190 minutes. This information will be valuable for the design of future pS6 experiments. Our results suggest an anatomical and functional subdivision of AT, where only the dorsal part connects to the auditory network and processes auditory information.Significant statementWe investigated the involvement of the anterior tuberal nucleus in zebrafish in auditory processing. Our study revealed a functional and anatomical subdivision of this region. We show that its dorsal subdivision is strongly connected to the central nucleus of the torus semicircularis, a major auditory nucleus in fishes. pS6 phosphorylation, as an indirect marker of neuronal activity after auditory stimulation, substantiated that only the dorsal anterior tuberal nucleus, processes auditory information. We also show that after auditory stimulation, pS6 phosphorylation peaked between 100-130 minutes and returned to baseline levels after 190 minutes, providing valuable information for future studies.

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“…Axonal regeneration is an extremely energy demanding process and over the years mitochondria have emerged as critical players. The transport of functional mitochondria to the axons and their accumulation at the growth cone is crucial for regeneration [5][6][7][8][9] . However, injury has been reported to depolarize the local population of mitochondria in axons 7,10 and sustained axonal ATP depletion is one of the main causes of Wallerian degeneration 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Local glycolysis supports injury-induced axonal regeneration

Masin,

Bergmans,

Van Dyck

et al. 2024

Preprint

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Successful axonal regeneration following injury requires the effective allocation of energy. Mitochondria play a pivotal role, accumulating at the tips of growing axons to fuel regeneration. However, how axons withstand the initial disruption in mitochondrial energy production caused by the injury, and subsequently initiate regrowth is poorly understood. Using retinal cultures in a multicompartment microfluidic device, we observed increased regrowth and enhanced mitochondrial trafficking in the axons of retinal ganglion cells with the deletion of both Pten and Socs3. While wild-type axons relied on mitochondrial metabolism, after injury, in the absence of Pten and Socs3, energy production was demonstrated to be supported by local glycolysis. Slowing down glycolysis in these axons impaired both regrowth and energy production. Together, these observations reveal that glycolytic ATP, combined with sustained mitochondrial transport, is essential for injury-induced axonal regrowth, providing new insights into the metabolic underpinnings of axonal regeneration.

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Optic nerve injury-induced regeneration in the adult zebrafish is accompanied by spatiotemporal changes in mitochondrial dynamics

Cited by 6 publications

References 28 publications

A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons

A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons

The Dorsal Part of the Anterior Tuberal Nucleus Responds to Auditory Stimulation in Zebrafish (Danio rerio)

Local glycolysis supports injury-induced axonal regeneration

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