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Retrograde Responses of Neurons and Associated Glial Cells to Axon...
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Retrograde Responses of Neurons and Associated Glial Cells to Axon Injury

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cells of the Nervous System".

Editor

Dr. Hakan Aldskogius

E-Mail Website
Collection Editor
Department of Neuroscience, Uppsala University, Uppsala, Sweden
Interests: neurons; microglia; peripheral nerve or dorsal root injury; injured spinal cord
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

This Special Issue is dedicated to recent and ongoing research on the cellular and molecular framework for the retrograde neuronal reaction. Neurons and associated glial cells, particularly astrocytes and microglia, respond to axon injury (axotomy) through an integrated process, which affects the neuron’s ability to survive, regenerate and maintain its synaptic connections. Axotomized motor neurons lose a large part of their presynaptic input, “synaptic stripping”, and peripherally axotomized sensory ganglion neurons display marked alterations in their central termination territories, “transganglionic changes”. The retrograde neuronal reaction is most commonly associated with the traumatic injury of peripheral or long distance projecting central axons, but is also a frequent consequence of, for example, stroke, traumatic brain injury, invasive malignancies, and metabolic disorders or toxin exposure, which compromise axonal integrity. In all these conditions, the outcome of the retrograde neuronal reaction will have a major impact on functional recovery. This Special Issue aims to cover research on how the retrograde neuronal reaction is triggered and maintained, the mechanisms involved for neuron survival or degeneration, as well as for neuron-glial, glial-glial and neuron-neuronal interactions, and how these processes come together to disrupt the affected neural circuitry, and the possibilities for its restoration through interventions with bioactive agents and rehabilitation. We look forward to your contribution.     

Dr. Hakan Aldskogius
Collection Editor

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Keywords

  • neuron regeneration
  • neuron degeneration
  • astrocyte
  • microglia
  • synaptic plasticity

Published Papers (7 papers)

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2022

20 pages, 6508 KiB  
Article
The Time Course of MHC-I Expression in C57BL/6J and A/J Mice Correlates with the Degree of Retrograde Gliosis in the Spinal Cord following Sciatic Nerve Crush
by Bruno Henrique de Melo Lima, André Luis Bombeiro, Luciana Politti Cartarozzi and Alexandre Leite Rodrigues de Oliveira
Cells 2022, 11(23), 3710; https://doi.org/10.3390/cells11233710 - 22 Nov 2022
Cited by 4 | Viewed by 2340
Abstract
The pleiotropic role of the major histocompatibility complex class I (MHC-I) reflects the close association between the nervous and immune systems. In turn, MHC-I upregulation postinjury is associated with a better regenerative outcome in isogenic mice following peripheral nerve damage. In the present [...] Read more.
The pleiotropic role of the major histocompatibility complex class I (MHC-I) reflects the close association between the nervous and immune systems. In turn, MHC-I upregulation postinjury is associated with a better regenerative outcome in isogenic mice following peripheral nerve damage. In the present work, we compared the time course of neuronal, glial, and sensorimotor recovery (1, 3, 5, 7, and 28 days after lesion—dal) following unilateral sciatic nerve crush in A/J and C57BL/6J mice. The A/J strain showed higher expression of MHC-I (7 dal, ** p < 0.01), Iba-1 (microglial reaction, 7 dal, *** p < 0.001), and GFAP (astrogliosis, 5 dal, * p < 0.05) than the C57BL/6J counterpart. Synaptic coverage (synaptophysin) was equivalent in both strains over time. In addition, mRNA expression of microdissected spinal motoneurons revealed an increase in cytoskeleton-associated molecules (cofilin, shp2, and crmp2, * p < 0.05), but not trkB, in C57BL/6J mice. Gait recovery, studied by the sciatic functional index, was faster in the A/J strain, despite the equivalent results of C57BL/6J at 28 days after injury. A similar recovery was also seen for the nociceptive threshold (von Frey test). Interestingly, when evaluating proprioceptive recovery, C57BL/6J animals showed an enlarged base of support, indicating abnormal ambulation postinjury. Overall, the present results reinforce the role of MHC-I expression in the plasticity of the nervous system following axotomy, which in turn correlates with the variable recovery capacity among strains of mice. Full article
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17 pages, 8269 KiB  
Article
Cellular Sources and Neuroprotective Roles of Interleukin-10 in the Facial Motor Nucleus after Axotomy
by Elizabeth M. Runge, Deborah O. Setter, Abhirami K. Iyer, Eric J. Regele, Felicia M. Kennedy, Virginia M. Sanders and Kathryn J. Jones
Cells 2022, 11(19), 3167; https://doi.org/10.3390/cells11193167 - 9 Oct 2022
Cited by 4 | Viewed by 2962
Abstract
Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) identify the [...] Read more.
Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) identify the temporal and cell-specific induction of IL-10 expression in the facial motor nucleus and (2) elucidate the neuroprotective capacity of this expression after axotomy. Immunohistochemistry revealed that FMN constitutively produced IL-10, whereas astrocytes were induced to make IL-10 after FNA. Il10 mRNA co-localized with microglia before and after axotomy, but microglial production of IL-10 protein was not detected. To determine whether any single source of IL-10 was critical for FMN survival, Cre/Lox mouse strains were utilized to selectively knock out IL-10 in neurons, astrocytes, and microglia. In agreement with the localization data reflecting concerted IL-10 production by multiple cell types, no single cellular source of IL-10 alone could provide neuroprotection after FNA. These findings suggest that coordinated neuronal and astrocytic IL-10 production is necessary for FMN survival and has roles in neuronal homeostasis, as well as neuroprotective trophism after axotomy. Full article
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36 pages, 3085 KiB  
Review
The Role of Microglia in Neuroinflammation of the Spinal Cord after Peripheral Nerve Injury
by Tana S. Pottorf, Travis M. Rotterman, William M. McCallum, Zoë A. Haley-Johnson and Francisco J. Alvarez
Cells 2022, 11(13), 2083; https://doi.org/10.3390/cells11132083 - 30 Jun 2022
Cited by 45 | Viewed by 8600
Abstract
Peripheral nerve injuries induce a pronounced immune reaction within the spinal cord, largely governed by microglia activation in both the dorsal and ventral horns. The mechanisms of activation and response of microglia are diverse depending on the location within the spinal cord, type, [...] Read more.
Peripheral nerve injuries induce a pronounced immune reaction within the spinal cord, largely governed by microglia activation in both the dorsal and ventral horns. The mechanisms of activation and response of microglia are diverse depending on the location within the spinal cord, type, severity, and proximity of injury, as well as the age and species of the organism. Thanks to recent advancements in neuro-immune research techniques, such as single-cell transcriptomics, novel genetic mouse models, and live imaging, a vast amount of literature has come to light regarding the mechanisms of microglial activation and alluding to the function of microgliosis around injured motoneurons and sensory afferents. Herein, we provide a comparative analysis of the dorsal and ventral horns in relation to mechanisms of microglia activation (CSF1, DAP12, CCR2, Fractalkine signaling, Toll-like receptors, and purinergic signaling), and functionality in neuroprotection, degeneration, regeneration, synaptic plasticity, and spinal circuit reorganization following peripheral nerve injury. This review aims to shed new light on unsettled controversies regarding the diversity of spinal microglial-neuronal interactions following injury. Full article
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Graphical abstract

30 pages, 2182 KiB  
Review
Events Occurring in the Axotomized Facial Nucleus
by Kazuyuki Nakajima and Takashi Ishijima
Cells 2022, 11(13), 2068; https://doi.org/10.3390/cells11132068 - 29 Jun 2022
Cited by 6 | Viewed by 2505
Abstract
Transection of the rat facial nerve leads to a variety of alterations not only in motoneurons, but also in glial cells and inhibitory neurons in the ipsilateral facial nucleus. In injured motoneurons, the levels of energy metabolism-related molecules are elevated, while those of [...] Read more.
Transection of the rat facial nerve leads to a variety of alterations not only in motoneurons, but also in glial cells and inhibitory neurons in the ipsilateral facial nucleus. In injured motoneurons, the levels of energy metabolism-related molecules are elevated, while those of neurofunction-related molecules are decreased. In tandem with these motoneuron changes, microglia are activated and start to proliferate around injured motoneurons, and astrocytes become activated for a long period without mitosis. Inhibitory GABAergic neurons reduce the levels of neurofunction-related molecules. These facts indicate that injured motoneurons somehow closely interact with glial cells and inhibitory neurons. At the same time, these events allow us to predict the occurrence of tissue remodeling in the axotomized facial nucleus. This review summarizes the events occurring in the axotomized facial nucleus and the cellular and molecular mechanisms associated with each event. Full article
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26 pages, 8956 KiB  
Article
Chronic Chemogenetic Activation of the Superior Colliculus in Glaucomatous Mice: Local and Retrograde Molecular Signature
by Marie Claes, Emiel Geeraerts, Stéphane Plaisance, Stephanie Mentens, Chris Van den Haute, Lies De Groef, Lut Arckens and Lieve Moons
Cells 2022, 11(11), 1784; https://doi.org/10.3390/cells11111784 - 29 May 2022
Cited by 5 | Viewed by 3780
Abstract
One important facet of glaucoma pathophysiology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic brain targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Previous research has [...] Read more.
One important facet of glaucoma pathophysiology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic brain targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Previous research has shown that stimulation of neuronal activity in a primary retinal target area—i.e., the superior colliculus—promotes RGC survival in an acute mouse model of glaucoma. To build further on this observation, we applied repeated chemogenetics in the superior colliculus of a more chronic murine glaucoma model—i.e., the microbead occlusion model—and performed bulk RNA sequencing on collicular lysates and isolated RGCs. Our study revealed that chronic target stimulation upon glaucomatous injury phenocopies the a priori expected molecular response: growth factors were pinpointed as essential transcriptional regulators both in the locally stimulated tissue and in distant, unstimulated RGCs. Strikingly, and although the RGC transcriptome revealed a partial reversal of the glaucomatous signature and an enrichment of pro-survival signaling pathways, functional rescue of injured RGCs was not achieved. By postulating various explanations for the lack of RGC neuroprotection, we aim to warrant researchers and drug developers for the complexity of chronic neuromodulation and growth factor signaling. Full article
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13 pages, 2264 KiB  
Article
Satellite Glial Cells and Neurons in Trigeminal Ganglia Are Altered in an Itch Model in Mice
by Meytal Cohen, Rachel Feldman-Goriachnik and Menachem Hanani
Cells 2022, 11(5), 886; https://doi.org/10.3390/cells11050886 - 4 Mar 2022
Cited by 4 | Viewed by 3160
Abstract
Itch (pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood, and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, [...] Read more.
Itch (pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood, and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, which may lead to abnormal neuronal activity, and hence to pain, but there is no information whether such changes take place in an itch model. We studied changes in neurons and satellite glial cells (SGCs) in trigeminal ganglia in an itch model in mice using repeated applications of 2,4,6-trinitro-1-chlorobenzene (TNCB) to the external ear over a period of 11 days. Treated mice showed augmented scratching behavior as compared with controls during the application period and for several days afterwards. Immunostaining for the activation marker glial fibrillary acidic protein in SGCs was greater by about 35% after TNCB application, and gap junction-mediated coupling between neurons increased from about 2% to 13%. The injection of gap junction blockers reduced scratching behavior, suggesting that gap junctions contribute to itch. Calcium imaging studies showed increased responses of SGCs to the pain (and presumed itch) mediator ATP. We conclude that changes in both neurons and SGCs in sensory ganglia may play a role in itch. Full article
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9 pages, 963 KiB  
Review
How Is Peripheral Injury Signaled to Satellite Glial Cells in Sensory Ganglia?
by Menachem Hanani
Cells 2022, 11(3), 512; https://doi.org/10.3390/cells11030512 - 1 Feb 2022
Cited by 16 | Viewed by 5128
Abstract
Injury or inflammation in the peripheral branches of neurons of sensory ganglia causes changes in neuronal properties, including excessive firing, which may underlie chronic pain. The main types of glial cell in these ganglia are satellite glial cells (SGCs), which completely surround neuronal [...] Read more.
Injury or inflammation in the peripheral branches of neurons of sensory ganglia causes changes in neuronal properties, including excessive firing, which may underlie chronic pain. The main types of glial cell in these ganglia are satellite glial cells (SGCs), which completely surround neuronal somata. SGCs undergo activation following peripheral lesions, which can enhance neuronal firing. How neuronal injury induces SGC activation has been an open question. Moreover, the mechanisms by which the injury is signaled from the periphery to the ganglia are obscure and may include electrical conduction, axonal and humoral transport, and transmission at the spinal level. We found that peripheral inflammation induced SGC activation and that the messenger between injured neurons and SGCs was nitric oxide (NO), acting by elevating cyclic guanosine monophosphate (cGMP) in SGCs. These results, together with work from other laboratories, indicate that a plausible (but not exclusive) mechanism for neuron-SGCs interactions can be formulated as follows: Firing due to peripheral injury induces NO formation in neuronal somata, which diffuses to SGCs. This stimulates cGMP synthesis in SGCs, leading to their activation and to other changes, which contribute to neuronal hyperexcitability and pain. Other mediators such as proinflammatory cytokines probably also contribute to neuron-SGC communications. Full article
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