Nerve Axons Research Articles

Ultrathin visible-light OCT endomicroscopy for in vivo ultrahigh-resolution neuroimaging in deep brain

Deep-brain neuroimaging, a task that demands high-resolution imaging techniques for visualizing intricate brain structures, assessing deep-seated disease histopathology, and offering real-time intervention guidance, is challenged by the resolution-depth trade-off of current methods. We propose an optical coherence tomography (OCT) endomicroscopy device for high-resolution in vivo imaging of deep brain microstructures and histopathology. A unique liquid shaping technique enables the direct fabrication of a microlens on the fiber tip of the imaging probe, optimizing imaging performance parameters, such as longitudinal focal shift, focused spot size, and working distance. In addition, a broadband visible-light source enhances axial resolution and OCT imaging contrast. As a result, the first monolithic visible-light OCT (vis-OCT) endomicroscope, with a submillimeter outer diameter (∼0.4 mm), is presented, achieving an ultrahigh resolution of 1.4 μm axial × 4.5 μm transverse in air. This compact probe allows minimally invasive in vivo deep-brain imaging in mice at a depth of 7.2 mm. Key regions in the mouse deep brain, such as the isocortex, corpus callosum, and caudate putamen, were successfully identified using our vis-OCT endomicroscope. In addition, we examined the myeloarchitectures and cytoarchitectures in the isocortex. Our findings demonstrate that the vis-OCT endomicroscope offers enhanced visualization of myelinated axon fibers and nerve fiber bundles compared to its 800 nm counterpart. This vis-OCT endomicroscope, overcoming resolution and imaging depth limitations of conventional methods, offers a novel tool for minimally invasive, ultrahigh-resolution in vivo deep brain neuroimaging.

Glial cell derived pathway directs regenerating optic nerve axons toward the CNS midline.

Several RGC intrinsic signaling pathways have been shown to enhance RGC survival and RGC axonal growth after optic nerve injury. Yet an unresolved challenge for regenerating RGC axons is to properly navigate the optic chiasm located at the Central Nervous System midline. Here, we use live-cell imaging in larval zebrafish to show that regrowing RGC axons initiate growth toward the midline and extend along a trajectory similar to their original projection. From a candidate genetic screen, we identify the glycosyltransferase Lh3 to be required during the process of regeneration to direct regrowing RGC axons toward the midline. Moreover, we find that mutants in collagen 18a1 (col18a1), a putative Lh3 substrate, display RGC axonal misguidance phenotypes similar to those we observe in lh3 mutants, suggesting that lh3 may act through col18a1 during regeneration. Finally, we show that transgenic lh3 expression in sox10+ presumptive olig2+ oligodendrocytes located near the optic chiasm restores directed axonal growth. Combined these data identify lh3 and col18a1 as part of a glial derived molecular pathway critical for guiding in vivo regenerating RGC axons towards and across the optic chiasm.

Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy: Unveiling Pathogenic Pathways and Targets.

Lesioned fascicles (LF) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood nerve barrier (BNB). While non-lesioned fascicles from T2D donors showed activation of neuroprotective pathways, lesioned fascicles lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful inter-organ communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.

A Mini-Review on Gene Therapy in Glaucoma and Future Directions

Glaucoma is a group of optic neuropathies characterized by the degeneration of retinal ganglion cells and the loss of their axons in the optic nerve. The only approved therapies for the treatment of glaucoma are topical medications and surgical procedures aimed at lowering intraocular pressure. Gene therapy involves the insertion, removal, or modification of genetic material within cells to repair or compensate for the loss of a gene’s function. It describes a process or technology that enables the genetic modification of cells to produce a therapeutic effect. However, changing the genetic material alone does not extend the duration of overexpression of proteins that combat disease, nor does it facilitate the production of new proteins for this purpose. We reviewed the literature concerning the use of gene therapy in the treatment of glaucoma and explored the future directions that this innovation may offer. Three genes associated with glaucoma have been identified within these loci: myocilin/trabecular meshwork glucocorticoid response (TIGR) (GLC1A), optineurin (GLC1E), and WDR36 (GLC1G). Among these, the most extensively studied glaucoma gene is myocilin (a TM-inducible glucocorticoid response gene). Building on previous successes, researchers have begun to apply genetic therapeutic approaches to alleviate or reduce symptoms associated with ocular hypertension (OHT) and glaucoma-like optic neuropathy (GON). It is evident that several therapeutic strategies exist that modulate aqueous humor production and flow, thereby regulating intraocular pressure (IOP) and protecting retinal ganglion cells (RGCs) from apoptosis. With the emergence of gene therapy as a potentially viable approach to preserving vision, new methods for managing glaucoma may soon become available. Genomic therapy is a promising treatment option for glaucoma patients and has significant potential for widespread clinical application.

Suppression of Visceral Nociception by Selective C-Fiber Transmission Block Using Temporal Interference Sinusoidal Stimulation.

Chronic visceral pain management remains challenging due to limitations in selective targeting of C-fiber nociceptors. This study investigates temporal interference stimulation (TIS) on dorsal root ganglia (DRG) as a novel approach for selective C-fiber transmission block. We employed (1) GCaMP6 recordings in mouse whole DRG using a flexible, transparent microelectrode array for visualizing L6 DRG neuron activation, (2) ex vivo single-fiber recordings to assess sinusoidal stimulation effects on peripheral nerve axons, (3) in vivo behavioral assessment measuring visceromotor responses (VMR) to colorectal distension in mice, including a TNBS-induced visceral hypersensitivity model, and (4) immunohistological analysis to evaluate immediate immune responses in DRG following TIS. We demonstrated that TIS (2000 Hz and 2020 Hz carrier frequencies) enabled tunable activation of L6 DRG neurons, with the focal region adjustable by altering stimulation amplitude ratios. Low-frequency (20-50 Hz) sinusoidal stimulation effectively blocked C-fiber and Aδ-fiber transmission while sparing fast-conducting A-fibers, with 20 Hz showing highest efficacy. TIS of L6 DRG reversibly suppressed VMR to colorectal distension in both control and TNBS-induced visceral hypersensitive mice. The blocking effect was fine-tunable by adjusting interfering stimulus signal amplitude ratios. No apparent immediate immune responses were observed in DRG following hours-long TIS. In conclusion, TIS on lumbosacral DRG demonstrates promise as a selective, tunable approach for managing chronic visceral pain by effectively blocking C-fiber transmission. This technique addresses limitations of current neuromodulation methods and offers potential for more targeted relief in chronic visceral pain conditions.

Reverse-engineered models reveal differential membrane properties of autonomic and cutaneous unmyelinated fibers.

Unmyelinated C-fibers constitute the vast majority of axons in peripheral nerves and play key roles in homeostasis and signaling pain. However, little is known about their ion channel expression, which controls their firing properties. Also, because of their small diameters (~ 1 μm), it has not been possible to characterize their membrane properties using voltage clamp. We developed a novel library of isoform-specific ion channel models to serve as the basis functions of our C-fiber models. We then developed a particle swarm optimization (PSO) framework that used the isoform-specific ion channel models to reverse engineer C-fiber membrane properties from measured autonomic and cutaneous C-fiber conduction responses. Our C-fiber models reproduced experimental conduction velocity, chronaxie, action potential duration, intracellular threshold, and paired pulse recovery cycle. The models also matched experimental activity-dependent slowing, a property not included in model optimization. We found that simple conduction responses, characterizing the action potential, were controlled by similar membrane properties in both the autonomic and cutaneous C-fiber models, but complicated conduction response, characterizing the afterpotenials, were controlled by differential membrane properties. The unmyelinated C-fiber models constitute important tools to study autonomic signaling, assess the mechanisms of pain, and design bioelectronic devices. Additionally, the novel reverse engineering approach can be applied to generate models of other neurons where voltage clamp data are not available.

Diverse functions of DEAD-box proteins in oligodendrocyte development, differentiation, and homeostasis.

Oligodendrocytes, a type of glial cell in the central nervous system, have a critical role in the formation of myelin around axons, facilitating saltatory conduction, and maintaining the integrity of nerve axons. The dysregulation of oligodendrocyte differentiation and homeostasis have been implicated in a wide range of neurological diseases, including dysmyelinating disorders (e.g., Pelizaeus-Merzbacher disease), demyelinating diseases (e.g., multiple sclerosis), Alzheimer's disease, and psychiatric disorders. Therefore, unraveling the mechanisms of oligodendrocyte development, differentiation, and homeostasis is essential for understanding the pathogenesis of these diseases and the development of therapeutic interventions. Numerous studies have identified and analyzed the functions of transcription factors, RNA metabolic factors, translation control factors, and intracellular and extracellular signals involved in the series of processes from oligodendrocyte fate determination to terminal differentiation. DEAD-box proteins, multifunctional RNA helicases that regulate various intracellular processes, including transcription, RNA processing, and translation, are increasingly recognized for their diverse roles in various aspects of oligodendrocyte development, differentiation, and maintenance of homeostasis. This review introduces the latest insights into the regulatory networks of oligodendrocyte biology mediated by DEAD-box proteins.

A role of Lhx2 in the migration and axonal projection of cortical postmitotic neurons in the cortical upper layer of the mouse neocortex

The transcription factor LHX2 contains a LIM domain and plays an important role in the development of the vertebrate nervous system. Although much research has been conducted on the function of Lhx2 during cerebral development, its role in postmitotic neuron differentiation in the cerebral cortex remains unknown. Therefore, this study was conducted to determine the function of Lhx2 in dynamic and elaborate developmental processes, including neurogenesis. We first created and confirmed an Lhx2-BAC Gfp transgenic model to three-dimensionally confirm the spatiotemporal expression pattern of Lhx2 during brain development. On this basis, we used the bilateral in utero electroporation technique to express the dominant-negative form of LHX2. LHX2 was confirmed to be important for the migration and callosal projection of postmitotic neurons that form the upper layer of the cerebral cortex during neurogenesis. Additionally, transcriptome analysis confirmed that LHX2 affected the genes involved in neuronal migration and axonal projection. We demonstrated that Lhx2 is important for postmitotic neurons in the cerebral cortex, which migrate to normal positions and extend nerve axons. Taken together, our findings can provide important clues to understanding the relationship between human Lhx2 gene mutations and brain developmental diseases.

Current perspectives and concerns in corneal neurotization.

This study aimed to comprehensively explore the intricacies of corneal neurotization (CN) and the nuanced factors that set it apart from routine clinical practice, exerting a substantial influence on its success. A symbiotic relationship is evident between corneal innervation and ocular surface health. The loss of corneal innervation results in a potentially challenging corneal condition known as neurotrophic keratopathy (NK). The majority of treatments are primarily focused on preventing epithelial breakdown rather than addressing the underlying pathogenesis. Consequently, to address the impaired corneal sensation (underlying etiology), a novel surgical approach has emerged, namely CN, which involves transferring healthy sensory nerve axons to the affected cornea. This review offers valuable insights into the existing body of supporting evidence for CN, meticulously examining clinical studies, case reports, and experimental findings. The aim is to enhance our understanding of the effectiveness and potential outcomes associated with this innovative surgical technique. The exploration of innovative therapeutic avenues holds promise for revolutionizing the management of NK, offering a potentially permanent solution to a condition once deemed incurable and severely debilitating.

Association between aromatic amines and serum neurofilament light chain as a biomarker of neural damage: a cross-sectional study from NHANES.

Aromatic amines (AAs) are a group of compounds widely found in chemical industry, tobacco smoke, and during food processing, with established carcinogenic properties. To date, there have been no reports on the potential neurotoxic effects of adult exposure to AAs. Serum neurofilament light chain (sNfL) is a protein released into the bloodstream following nerve axon injury and has been validated as a reliable biomarker for various neurological diseases. However, there has been no research to investigate the relationship between AAs exposure and sNfL. In this study, we selected adults (aged ≥20 years) with data on both AAs and sNfL from the National Health and Nutrition Examination Survey (NHANES) conducted in 2013-2014. We used multivariable linear regression models to explore the correlation between urinary AAs and sNfL. In total, 510 adult participants with an average age of 43.58 ± 14.74 years were included in the study. Our findings indicate that, based on univariate linear regression and between-group comparative analyses, 1-Aminonaphthalene (1-AN), 2-Aminonaphthalene (2-AN), 4-Aminobiphenyl (4-AN) and o-Anisidine (o-ANI) showed a positive correlation with serum neurofilament light chain (P < 0.05). However, multiple linear regression analysis revealed that only 2-AN exhibited a positive correlation with serum neurofilament light chain (P < 0.05), while the correlations of other compounds with serum neurofilament light chain became non-significant. Although our cross-sectional study fails to establish causal relationships or determine clinical significance, the findings indicate a potential association between adult exposure to AAs, notably 2-AN, and nerve damage. Consequently, further research is needed to explore the connection between AAs exposure, sNfL, and neurological conditions in adults.

Pseudorabies Virus Glycoproteins E and B Application in Vaccine and Diagnosis Kit Development.

Background: Pseudorabies virus (PRV) is a highly infectious pathogen that affects a wide range of mammals and imposes a significant economic burden on the global pig industry. The viral envelope of PRV contains several glycoproteins, including glycoprotein E (gE) and glycoprotein B (gB), which play critical roles in immune recognition, vaccine development, and diagnostic procedures. Mutations in these glycoproteins may enhance virulence, highlighting the need for updated vaccines. Method: This review examines the functions of PRV gE and gB in vaccine development and diagnostics, focusing on their roles in viral replication, immune system interaction, and pathogenicity. Additionally, we explore recent findings on the importance of gE deletion in attenuated vaccines and the potential of gB to induce immunity. Results: Glycoprotein E (gE) is crucial for the virus's axonal transport and nerve invasion, facilitating transmission to the central nervous system. Deletion of gE is a successful strategy in vaccine development, enhancing the immune response. Glycoprotein B (gB) plays a central role in viral replication and membrane fusion, aiding viral spread. Mutations in these glycoproteins may increase PRV virulence, complicating vaccine efficacy. Conclusion: With PRV glycoproteins being essential to both vaccine development and diagnostic approaches, future research should focus on enhancing these components to address emerging PRV variants. Updated vaccines and diagnostic tools are critical for combating new, more virulent strains of PRV.

Controlled elevation of intraocular pressure in anesthetized mice

Our purpose was to develop a protocol for prolonged anesthesia in mice and evaluate optic nerve axon injury in response to 4 h of controlled elevation of intraocular pressure (CEI). During CEI, C57BL/6 male mice (3–5 months old) were anesthetized with 1.5% isoflurane with 100% oxygen for 4 h and placed on a warm platform, with expired gas and anesthetic actively evacuated. Lactated ringers (0.5 ml) with 5% dextrose was administered subcutaneously at the start and end of CEI. Physiological parameters (oxygen saturation = O2, heart rate = HR, systolic blood pressure = SBP, and temperature) were monitored throughout the 4-h CEI. One eye was cannulated with polyurethane tubing connected to a balanced salt solution reservoir and IOP elevated to 20 (N = 18), 30 (N = 13), 50 (N = 14), and 60 mmHg (N = 16). An additional group of 22 female mice was exposed to CEI of 60 mmHg. Fourteen days after CEI, optic nerves were assessed for axonal injury by masked observers that assigned a grade on a scale from 1 (normal) to 5 (>50% of axons degenerating). CEI optic nerve injury was compared to injury assessed in contralateral optic nerves (N = 84) and naïve optic nerves (N = 18) using a one-way ANOVA followed by Kruskal-Wallis test for multiple comparisons. The relationship between optic nerve injury, physiological parameters, and IOP were assessed by linear regression analyses. Physiologic parameters remained stable throughout CEI (O2 = 95 ± 9%; HR = 450 ± 39; SBP = 102 ± 15 mmHg, and temperature = 38 ± 0.7 °C) and were not statistically different between groups (all comparisons had P > 0.5). Mean optic nerve injury grades (±SD) for naïve optic nerves (1.01 ± 0.02) were not significantly different from fellow/contralateral optic nerves (1.03 ± 0.07, P > 0.99), or from CEI of 20 mmHg (1.04 ± 0.08, P > 0.99) or 30 mmHg (1.05 ± 0.06, P = 0.6). However, animals exposed to CEI of 50 mmHg (2.09 ± 1.43, P = 0.0005) and 60 mmHg (male: 2.86 ± 1.30, P < 0.0001, female: 1.63 ± 1.00, P = 0.0006) developed significant optic nerve injury relative to their fellow/contralateral optic nerves. Axonal injury grades following a CEI of 60 mmHg were not significantly different between male and female mice (P = 0.19). Optic nerve injury positively correlated (P < 0.0001) with IOP and not with physiological parameters, indicating that the optic nerve injury is IOP-related. In conclusion, prolonged anesthesia in mice requires careful attention to animal physiology. With this, a 4-h exposure to elevated IOP can produce significant optic nerve injury with IOPs equal to or greater than 50 mmHg. We provide detailed descriptions of methods and materials for producing prolonged elevations of IOP in mice while maintaining and monitoring their physiology, as well as a unique, cost-effective transducer system for monitoring pressure delivery.

Repeated intrathecal injections of peripheral nerve-derived stem cell spheroids improve outcomes in a rat model of traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a major cause of disability and mortality worldwide. However, existing treatments still face numerous clinical challenges. Building on our prior research showing peripheral nerve-derived stem cell (PNSC) spheroids with Schwann cell-like phenotypes can secrete neurotrophic factors to aid in neural tissue regeneration, we hypothesized that repeated intrathecal injections of PNSC spheroids would improve the delivery of neurotrophic factors, thereby facilitating the restoration of neurological function and brain tissue repair post-TBI.MethodsWe generated PNSC spheroids from human peripheral nerve tissue using suspension culture techniques. These spheroids were characterized using flow cytometry, immunofluorescence, and reverse-transcription polymerase chain reaction. The conditioned media were evaluated in SH-SY5Y and RAW264.7 cell lines to assess their effects on neurogenesis and inflammation. To simulate TBI, we established a controlled cortical impact (CCI) model in rats. The animals were administered intrathecal injections of PNSC spheroids on three occasions, with each injection spaced at a 3-day interval. Recovery of sensory and motor function was assessed using the modified neurological severity score (mNSS) and rotarod tests, while histological (hematoxylin and eosin, Luxol fast blue staining) and T2-weighted magnetic resonance imaging analyses, alongside immunofluorescence, were conducted to evaluate the recovery of neural structures and pathophysiology.ResultsPNSC spheroids expressed high levels of Schwann cell markers and neurotrophic factors, such as neurotrophin-3 and Ephrin B3. Their conditioned medium was found to promote neurite outgrowth, reduce reactive oxygen species-mediated cell death and inflammation, and influence M1-M2 macrophage polarization. In the CCI rat model, rats receiving repeated triple intrathecal injections of PNSC spheroids showed significant improvements in sensory and motor function, with considerable neural tissue recovery in damaged areas. Notably, this treatment promoted nerve regeneration, axon regrowth, and remyelination. It also reduced glial scar formation and inflammation, while encouraging angiogenesis.ConclusionOur findings suggest that repeated intrathecal injections of PNSC spheroids can significantly enhance neural recovery after TBI. This effect is mediated by the diverse neurotrophic factors secreted by PNSC spheroids. Thus, the strategy of combining therapeutic cell delivery with multiple intrathecal injections holds promise as a novel clinical treatment for TBI recovery.

Median nerve lesions in pediatric displaced supracondylar humerus fracture: A prospective neurological, electrodiagnostic and ultrasound characterization.

Supracondylar humerus fractures (SCHFs) are the most common elbow fractures in children. Traumatic median nerve injury and isolated lesions of its pure forearm motor branch, anterior interosseus nerve (AIN), have both been independently reported as complications of displaced SCHFs. Our main objectives were to characterize the neurological syndrome to distinguish median nerve from AIN lesions and to determine the prognosis of median nerve lesions after displaced SCHFs. Ten children were prospectively followed for an average of 11.6 months. Patients received a standardized clinical examination and high-resolution ultrasound of the median nerve every 1-3 months starting 1-2 months after trauma. Electrodiagnostic studies were performed within the first 4 months and after complete clinical recovery. All children shared a clinical syndrome with predominant but not exclusive affection of AIN innervated muscles. High-resolution ultrasound uniformly excluded persistent nerve entrapment and neurotmesis requiring revision surgery but visualized post-traumatic median nerve neuroma at the fracture site in all patients. Electrodiagnostic studies showed axonal motor and sensory median nerve neuropathy. All children achieved complete functional recovery under conservative management. Motor recovery required up to 11 months and differed between involved muscles. It was shown that neurological deficits of the median nerve in displaced SCHFs exceeded an isolated AIN lesion. Notably, detailed neurological follow-up examinations and sonographic exclusion of persistent nerve compression were able to guide conservative therapy in affected children. Under these conditions the prognosis of median nerve lesions was excellent despite severe initial deficits, development of neuroma and axonal injury.

Delayed Surgical Reversal of Optic Nerve Compression Leads to Exponential Degeneration of Optic Nerve Fibers and Selective Sparing of the Small Fibers.

To evaluate the effectiveness of surgical reversal of experimental optic nerve compression in treating persistent compressive optic neuropathy and to explore the relationship between surgical outcomes and the timing of the procedure. Surgical reversal procedures (decompression surgery) were conducted at five time intervals: 1, 3, and 7 days and 2 and 3 weeks following optic nerve compression in a rabbit model. The groups were labeled as DC-1d, DC-3d, DC-7d, DC-2w, and DC-3w, respectively. The study investigated changes in ganglion cell complex (GCC) thickness using spectral-domain optical coherence tomography and the percentage of surviving retinal ganglion cells (RGCs) through immunofluorescence staining and optic nerve axons stained with p-phenylenediamine at 4 weeks after decompression. Additionally, the area distribution of surviving axons was analyzed. The decline in GCC thickness was halted following decompression. The remaining thickness of the GCC in group DC-1d was found to be statistically significantly higher at 2, 3, and 4 weeks postonset compared to the no-decompression group. Similarly, GCC thickness in group DC-3d was significantly higher at 3 and 4 weeks postonset. The percentage of surviving RGCs and axons at 4 weeks postonset exhibited an exponential correlation with the onset time of decompression, with R2 values of 0.72 and 0.78, respectively. The surviving axon area declined following delayed decompression. Persistent substantial compression on the optic nerve leads to exponential degeneration of the optic nerve, initially affecting larger optic nerve fibers. Early intervention aimed at relieving the compression on the optic nerve may offer potential benefits in mitigating the degenerative effects and conserving visual function.

Electrical Stimulation: Enhancing Axonal Growth following Peripheral Nerve Injury.

Electrical stimulation has been integrated in recent decades into rehabilitation protocols following neuromuscular injuries. Existing literature supports the utilisation of prolonged or continuous stimulation generated by implantable or transcutaneous devices for chronic pain subsidence and muscle trophism maintenance, which improve outcomes following microsurgical interventions. Newer uses include brief electrical stimulation for peripheral nerve injury. Brief electrical stimulation has shown promise in expediting regeneration of both torn and crushed nerve axons in the murine model and has been incorporated into a limited number of clinical studies. Augmentation of the natural response of an injured peripheral nerve by electrical stimulation has the potential to accelerate regeneration, presumably leading to improved function and clinical outcomes. We review the existing literature on intraoperative utilisation of electrical stimulation to enhance regeneration, such as neural mechanisms of action and their microscopic effect in animal models, as well as results from initial human studies. Level of Evidence: Level V (Therapeutic).

The Role of Botulinum Toxin A Neuromodulator in the Management of Synkinesis in Facial Palsy.

Facial palsy describes the denervation of the facial nerve leading to difficulty in facial animation and expression. Facial synkinesis is the result of complex pathological nerve regeneration following damage to the facial nerve axons. Synkinesis in facial palsy can be managed using facial neuromuscular rehabilitation, botulinum toxin neuromodulators, and surgical treatment options. Botulinum toxin A can be used as an adjunct to other treatment options to manage synkinesis. This article will explore the role of botulinum toxin A in the management of synkinesis in facial palsy including the clinical assessment, injection location (muscles targeted), dosages, treatment interval, and long-term results. It will also include surgical management options.

Rotenone-Induced Optic Nerve Damage and Retinal Ganglion Cell Loss in Rats.

Rotenone is a mitochondrial complex I inhibitor that causes retinal degeneration. A study of a rat model of rotenone-induced retinal degeneration suggested that this model is caused by indirect postsynaptic N-methyl-D-aspartate (NMDA) stimulation triggered by oxidative stress-mediated presynaptic intracellular calcium signaling. To elucidate the mechanisms by which rotenone causes axonal degeneration, we investigated morphological changes in optic nerves and the change in retinal ganglion cell (RGC) number in rats. Optic nerves and retinas were collected 3 and 7 days after the intravitreal injection of rotenone. The cross-sections of the optic nerves were subjected to a morphological analysis with axon quantification. The axons and somas of RGCs were analyzed immunohistochemically in retinal flatmounts. In the optic nerve, rotenone induced axonal swelling and degeneration with the incidence of reactive gliosis. Rotenone also significantly reduced axon numbers in the optic nerve. Furthermore, rotenone caused axonal thinning, fragmentation, and beading in RGCs on flatmounts and decreased the number of RGC soma. In conclusion, the intravitreal injection of rotenone in rats induced morphological abnormities with a reduced number of optic nerve axons and RGC axons when the RGC somas were degenerated. These findings help elucidate the pathogenesis of optic neuropathy induced by mitochondrial dysfunction.

Mortality events associated with microsporidian, Spraguea sp., in White Trevally culture in Japan.

In 2021, White Trevally or Striped Jack cultured in the western part of Japan exhibited mild, but chronic mortalities from late September through early October. The cumulative mortality rate was approximately 0.02% per a net pen containing approximately 50,000 fish. Although the cumulative mortality rate was not high, most of the fish in net pens showed characteristic gross signs and an abnormal swimming behaviour. The body of diseased fish became pale and the yellow lines on the lateral sides of fish body became darken. In addition, silver lines along the dorsal fin became apparent. Loss of schooling behaviour was noted during the mortality event. In addition, affected fish became lethargic and failed to swim against current, or frequently stopped swimming and sank to the bottom of net pens after feeding. The goal of this study was to identify the cause of the mortality event. To achieve the goal, we used histopathology and metatranscriptome analysis. Histopathological examination revealed that xenoma of microsporidian were frequently observed in the nerve axon in the brain and spinal cord. Spores observed in the sections were stained with a fluorescent dye, Uvitex 2B, indicating those spores are microsporidian. The data from metatranscriptome analysis indicated that the microsporidian is Spraguea sp. The microsporidian was frequently detected from diseased fish with similar symptoms collected in the same region, suggesting that the microsporidian was highly associated with abnormal swimming behaviour of fish.

Serotonin neuromodulation directs optic nerve regeneration.

Optic nerve (ON) regeneration in mammalian systems is limited by an overshadowing dominance of inhibitory factors. This has severely hampered the identification of pro-regenerative pathways. Here, we take advantage of the regenerative capacity of larval zebrafish to identify pathways that promote ON regeneration. From a small molecule screen, we identified modulators of serotonin (5-HT) signaling that inhibit ON regeneration. We find several serotonin type-1 receptor genes are expressed in RGC neurons during regeneration and that inhibiting 5-HT1 receptors or components of the 5-HT pathway selectively impedes ON regeneration. We show that 5-HT1 receptor signaling is dispensable during ON development yet is critical for regenerating axons to emerge from the injury site. Blocking 5-HT receptors once ON axons have crossed the chiasm does not inhibit regeneration, suggesting a selective role for 5-HT receptor signaling early during ON regeneration. Finally, we show that agonist-mediated activation of 5-HT1 receptors leads to enhanced and ectopic axonal regrowth. Combined, our results provide evidence for mechanisms through which serotonin-dependent neuromodulation directs ON regeneration in vivo.