Repeat intravital imaging of the murine spinal cord reveals degenerative and reparative responses of spinal axons in real-time following a contusive SCI

Rajaee, Arezoo; Geisen, Mariah E.; Sellers, Alexandra K.; Stirling, David P.

doi:10.1016/j.expneurol.2020.113258

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…Immunofluorescence staining of post-mortem tissue from Thy1YFP + transgenic mice showed that a significant increase in TOMM20 signal reflected the density of mitochondria in the axonal spheroids and endbulbs (Rajaee et al, 2020 ). The accumulation of mitochondria and tubulin polyglutamylation indicates the disruption of axonal transport, an important characteristic of axonal degeneration.…”

Section: Injurymentioning

confidence: 99%

“…However, observations in mice showed that the reduced growth capacity of mature neurons and scar tissue caused by reactive astrocytes form a physical barrier, and the upregulation of axon growth-inhibitory factors inhibit axon regeneration (Yiu and He, 2006 ). However, intravital imaging of murine spinal cord showed that the number of axons increases significantly from 7 to 14 days after injury compared to 3 days post-injury, indicating that a certain number of injured axons undergo endogenous repair (Rajaee et al, 2020 ), demonstrating that while the regeneration of axons is limited after SCI injury, it can still be improved.…”

Section: Injurymentioning

confidence: 99%

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Mitochondrial Behavior in Axon Degeneration and Regeneration

Wang

Huang

Shang

et al. 2021

Front. Aging Neurosci.

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Mitochondria are organelles responsible for bioenergetic metabolism, calcium homeostasis, and signal transmission essential for neurons due to their high energy consumption. Accumulating evidence has demonstrated that mitochondria play a key role in axon degeneration and regeneration under physiological and pathological conditions. Mitochondrial dysfunction occurs at an early stage of axon degeneration and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, defects in mitochondrial transport, and mitophagy dysregulation. The restoration of these defective mitochondria by enhancing mitochondrial transport, clearance of reactive oxidative species (ROS), and improving bioenergetic can greatly contribute to axon regeneration. In this paper, we focus on the biological behavior of axonal mitochondria in aging, injury (e.g., traumatic brain and spinal cord injury), and neurodegenerative diseases (Alzheimer's disease, AD; Parkinson's disease, PD; Amyotrophic lateral sclerosis, ALS) and consider the role of mitochondria in axon regeneration. We also compare the behavior of mitochondria in different diseases and outline novel therapeutic strategies for addressing abnormal mitochondrial biological behavior to promote axonal regeneration in neurological diseases and injuries.

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Section: Injurymentioning

confidence: 99%

Section: Injurymentioning

confidence: 99%

Mitochondrial Behavior in Axon Degeneration and Regeneration

Wang

Huang

Shang

et al. 2021

Front. Aging Neurosci.

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“…The fact that the ONL reflectivity resolves back to its usual hyporeflective appearance following the acute lesion phase mirrors the behavior of axonal spheroids which can resolve once axoplasmic flow is restored (45).…”

Section: Henle Fiber Layer Involvementmentioning

confidence: 85%

“…We previously discussed the potential mechanism by which viral nerve infection can lead to a disruption of axoplasmic flow and therefore the formation of axonal spheroids may signify the passage of virus to the photoreceptors and RPE. The hyper-autofluorescence signal observed from the RPE may therefore be a secondary response to RPE infection ( Figure 4 ) The fact that the ONL reflectivity resolves back to its usual hyporeflective appearance following the acute lesion phase mirrors the behavior of axonal spheroids which can resolve once axoplasmic flow is restored ( 45 ).…”

Section: Evidence For Neuronal Involvementmentioning

confidence: 99%

Proposing a Neurotropic Etiology for Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Relentless Placoid Chorioretinitis

et al. 2022

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PurposeTo reassess the underlying pathophysiology of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and relentless placoid chorioretinitis (RPC) through comparison with the non-inoculated eye of the von Szily animal model of neurotropic viral retinal infection.MethodsNarrative review.ResultsLiterature reports of isolated neurotropic viral entities and rising serological viral titers in APMPPE after presentation support a potential direct infective etiology. In general, viral transport along axons results in mitochondrial stasis and disruption of axoplasmic flow. Clinical manifestations of axoplasmic flow disruption in APMPPE/RPC may signify the passage of virus along the neuronal pathway. From a case series of 11 patients, we demonstrate a timely, spatial, and proportional association of optic disc swelling with APMPPE lesion occurrence. Signs within the inner retina appear to precede outer retinal lesions; and acute areas of outer nuclear layer (ONL) hyperreflectivity appear to be the result of coalescence of multiple hyperreflective foci resembling axonal spheroids (which occur as a consequence of axoplasmic disruption) and follow the Henle fiber layer neurons. Underlying areas of retinal pigment epithelium (RPE) hyper-autofluorescence follow ONL hyperreflectivity and may signify localized infection. Areas of apparent choriocapillaris hypoperfusion mirror areas of RPE/Bruch’s membrane separation and appear secondary to tractional forces above. Increases in choroidal thickness with lesion occurrence and focal areas of choriocapillaris hypoperfusion are observed in both APMPPE/RPC and the von Szily model.ConclusionsThe neurotrophic infection model provides significant advantages over the existing primary choriocapillaris ischemia hypothesis to account for the range of imaging signs observed in APMPPE and RPC.

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“…The location and mild injury for imaging experiments was chosen to limit breathing and motion artifacts and allow enough surviving dorsal column axons to assess secondary axonal degeneration respectively. 39 …”

Section: Methodsmentioning

confidence: 99%

Direct Ryanodine Receptor-2 Knockout in Primary Afferent Fibers Modestly Affects Neurological Recovery after Contusive Spinal Cord Injury

Orem

Morehouse

Ames

et al. 2022

Neurotrauma Reports

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Neuronal ryanodine receptors (RyR) release calcium from internal stores and play a key role in synaptic plasticity, learning, and memory. Dysregulation of RyR function contributes to neurodegeneration and negatively impacts neurological recovery after spinal cord injury (SCI). However, the individual role of RyR isoforms and the underlying mechanisms remain poorly understood. To determine whether RyR2 plays a direct role in axonal fate and functional recovery after SCI, we bred Advillin -Cre: tdTomato (Ai9) reporter mice with “floxed” RyR2 mice to directly knock out (KO) RyR2 function in dorsal root ganglion neurons and their spinal projections. Adult 6- to 8-week-old RyR2KO and littermate controls were subjected to a contusive SCI and their dorsal column axons were imaged in vivo using two-photon excitation microscopy. We found that direct RyR2KO in dorsal column primary afferents did not significantly alter secondary axonal degeneration after SCI. We next assessed behavioral recovery after SCI and found that direct RyR2KO in primary afferents worsened open-field locomotor scores (Basso Mouse Scale subscore) compared to littermate controls. However, both TreadScan™ gait analysis and overground kinematic gait analysis tests revealed subtle, but no fundamental, differences in gait patterns between the two groups after SCI. Subsequent removal of spared afferent fibers using a dorsal column crush revealed similar outcomes in both groups. Analysis of primary afferents at the lumbar (L3–L5) level similarly revealed no noticeable differences between groups. Together, our results support a modest contribution of dorsal column primary afferent RyR2 in neurological recovery after SCI.

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Repeat intravital imaging of the murine spinal cord reveals degenerative and reparative responses of spinal axons in real-time following a contusive SCI

Cited by 7 publications

References 44 publications

Mitochondrial Behavior in Axon Degeneration and Regeneration

Mitochondrial Behavior in Axon Degeneration and Regeneration

Proposing a Neurotropic Etiology for Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Relentless Placoid Chorioretinitis

Direct Ryanodine Receptor-2 Knockout in Primary Afferent Fibers Modestly Affects Neurological Recovery after Contusive Spinal Cord Injury

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