Explore the vast range of titles available.

The mature optic nerve cannot regenerate when injured, leaving victims of traumatic nerve damage or diseases such as glaucoma with irreversible visual losses. Recent studies have identified ways to stimulate retinal ganglion cells to regenerate axons part-way through the optic nerve, but it remains unknown whether mature axons can reenter the brain, navigate to appropriate target areas, or restore vision. We show here that with adequate stimulation, retinal ganglion cells are able to regenerate axons the full length of the visual pathway and on into the lateral geniculate nucleus, superior colliculus, and other visual centers. Regeneration partially restores the optomotor response, depth perception, and circadian photoentrainment, demonstrating the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals.

Visual evoked potentials (VEPs) can provide important diagnostic information regarding the functional integrity of the visual system. This document updates the ISCEV standard for clinical VEP testing and supersedes the 2009 standard. The main changes in this revision are the acknowledgment that pattern stimuli can be produced using a variety of technologies with an emphasis on the need for manufacturers to ensure that there is no luminance change during pattern reversal or pattern onset/offset. The document is also edited to bring the VEP standard into closer harmony with other ISCEV standards. The ISCEV standard VEP is based on a subset of stimulus and recording conditions that provide core clinical information and can be performed by most clinical electrophysiology laboratories throughout the world. These are: (1) Pattern-reversal VEPs elicited by checkerboard stimuli with large 1 degree (°) and small 0.25° checks. (2) Pattern onset/offset VEPs elicited by checkerboard stimuli with large 1° and small 0.25° checks. (3) Flash VEPs elicited by a flash (brief luminance increment) which subtends a visual field of at least 20°. The ISCEV standard VEP protocols are defined for a single recording channel with a midline occipital active electrode. These protocols are intended for assessment of the eye and/or optic nerves anterior to the optic chiasm. Extended, multi-channel protocols are required to evaluate postchiasmal lesions.

Failure of central nervous system (CNS) axons to regenerate after injury results in permanent disability. Several molecular neuro-protective and neuro-regenerative strategies have been proposed as potential treatments but do not provide the directional cues needed to direct target-specific axon regeneration. Here, we demonstrate that applying an external guidance cue in the form of electric field stimulation to adult rats after optic nerve crush injury was effective at directing long-distance, target-specific retinal ganglion cell (RGC) axon regeneration to native targets in the diencephalon. Stimulation was performed with asymmetric charged-balanced (ACB) waveforms that are safer than direct current and more effective than traditional, symmetric biphasic waveforms. In addition to partial anatomical restoration, ACB waveforms conferred partial restoration of visual function as measured by pattern electroretinogram recordings and local field potential recordings in the superior colliculus—and did so without the need for genetic manipulation. Our work suggests that exogenous electric field application can override cell-intrinsic and cell-extrinsic barriers to axon regeneration, and that electrical stimulation performed with specific ACB waveforms may be an effective strategy for directing anatomical and functional restoration after CNS injury.

Myelination speeds conduction of the nerve impulse, enhancing cognitive power. Changes of white matter structure contribute to learning, and are often assumed to reflect an altered number of myelin wraps. We now show that, in rat optic nerve and cerebral cortical axons, the node of Ranvier length varies over a 4.4-fold and 8.7-fold range respectively and that variation of the node length is much less along axons than between axons. Modelling predicts that these node length differences will alter conduction speed by ~20%, similar to the changes produced by altering the number of myelin wraps or the internode length. For a given change of conduction speed, the membrane area change needed at the node is >270-fold less than that needed in the myelin sheath. Thus, axon-specific adjustment of node of Ranvier length is potentially an energy-efficient and rapid mechanism for tuning the arrival time of information in the CNS. Information is transmitted around the nervous system as electrical signals passing along nerve cells. A fatty substance called myelin, which is wrapped around the nerve cells, increases the speed with which the signals travel along the nerve cells. This allows us to think and move faster than we would otherwise be able to do. The electrical signals start at small “nodes” between areas of myelin wrapping. Originally it was thought that we learn things mainly as a result of changes in the strength of connections between nerve cells, but recently it has been proposed that changes in myelin wrapping could also contribute to learning. Arancibia-Cárcamo, Ford, Cossell et al. investigated how much node structure varies in rat nerve cells, and whether differences in the length of nodes can fine-tune the activity of the nervous system. The experiments show that rat nerve cells do indeed have nodes with a range of different lengths. Calculations show that this could result in electrical signals moving at different speeds through different nerve cells. These findings raise the possibility that nerve cells actively alter the length of their nodes in order to alter their signal speed. The next step is to try to show experimentally that this happens during learning in animals.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases ( P  = 0.004) and surgical intervention in advanced disease ( P  = 3.6 × 10 − 6 ). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups. Multitrait genome-wide analysis of glaucoma and related phenotypes identifies new risk loci and enables development of a polygenic risk score to predict disease susceptibility and key clinical outcomes.

A combination of increased neural activity, induced by visual stimulation or using chemogenetics, and increasing mTOR signaling promotes retinal ganglion cell axon regeneration and partial recovery of visual behaviors after injury. Axons in the mammalian CNS fail to regenerate after injury. Here we show that if the activity of mouse retinal ganglion cells (RGCs) is increased by visual stimulation or using chemogenetics, their axons regenerate. We also show that if enhancement of neural activity is combined with elevation of the cell-growth-promoting pathway involving mammalian target of rapamycin (mTOR), RGC axons regenerate long distances and re-innervate the brain. Analysis of genetically labeled RGCs revealed that this regrowth can be target specific: RGC axons navigated back to their correct visual targets and avoided targets incorrect for their function. Moreover, these regenerated connections were successful in partially rescuing a subset of visual behaviors. Our findings indicate that combining neural activity with activation of mTOR can serve as powerful tool for enhancing axon regeneration, and they highlight the remarkable capacity of CNS neurons to re-establish accurate circuit connections in adulthood.

Damage to the axons of the adult mammalian central nervous system (CNS) from traumatic injury or neurodegenerative diseases often results in permanent loss of function due to failure of axons to regenerate. Zebrafish, however, can express regeneration-associated genes to revert CNS neurons to a growth-competent state and regenerate damaged axons to functionality. An established model for CNS axon regeneration is optic nerve injury in zebrafish, where it was previously shown that thousands of genes are temporally expressed during the regeneration time course. It is likely that hubs of key transcription factors, rather than individual factors regulate the temporal clusters of expression after injury to facilitate cell survival, regrowth, and synaptic targeting in the brain. One transcription factor of interest in orchestrating CNS axon regeneration is jun . However, it remains unclear if CNS regeneration can progress without Jun. To test this, a transgenic zebrafish line was developed to express a heat-shock inducible dominant negative Jun. Induction of dominant negative Jun downregulated endogenous jun expression and larvae with functional jun knockdown demonstrated impaired retinal ganglion cell axon regeneration. Analysis of select putative Jun target genes, previously shown to be upregulated in adult zebrafish optic nerve regeneration, demonstrated that with functional Jun knockdown, atf3 and ascl1a were significantly downregulated, and sox11a was upregulated at distinct time points. These results position jun as a key regulator for successful optic nerve regeneration, further distinguish the regeneration program from development, and advance our knowledge for the formation of future therapies to treat CNS damage.

Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAP -CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAP -CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAP -CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAP -CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.

Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors Deleted in Colorectal Cancer (DCC) and Neogenin or repulsion through binding the DCC/Uncoordinated (Unc5) A–D receptor complex. The crystal structures of Netrin-1/receptor complexes have recently been revealed. These studies have provided a structure based explanation of Netrin-1 bi-functionality. Netrin-1 and its receptor are continuously expressed in the adult nervous system and are differentially regulated after nerve injury. In the adult spinal cord and optic nerve, Netrin-1 has been considered as an inhibitor that contributes to axon regeneration failure after injury. In the peripheral nervous system, Netrin-1 receptors are expressed in Schwann cells, the cell bodies of sensory neurons and the axons of both motor and sensory neurons. Netrin-1 is expressed in Schwann cells and its expression is up-regulated after peripheral nerve transection injury. Recent studies indicated that Netrin-1 plays a positive role in promoting peripheral nerve regeneration, Schwann cell proliferation and migration. Targeting of the Netrin-1 signaling pathway could develop novel therapeutic strategies to promote peripheral nerve regeneration and functional recovery.

In this work, we develop a robust, extensible tool to automatically and accurately count retinal ganglion cell axons in optic nerve (ON) tissue images from various animal models of glaucoma. We adapted deep learning to regress pixelwise axon count density estimates, which were then integrated over the image area to determine axon counts. The tool, termed AxoNet, was trained and evaluated using a dataset containing images of ON regions randomly selected from whole cross sections of both control and damaged rat ONs and manually annotated for axon count and location. This rat-trained network was then applied to a separate dataset of non-human primate (NHP) ON images. AxoNet was compared to two existing automated axon counting tools, AxonMaster and AxonJ, using both datasets. AxoNet outperformed the existing tools on both the rat and NHP ON datasets as judged by mean absolute error, R 2 values when regressing automated vs. manual counts, and Bland-Altman analysis. AxoNet does not rely on hand-crafted image features for axon recognition and is robust to variations in the extent of ON tissue damage, image quality, and species of mammal. Therefore, AxoNet is not species-specific and can be extended to quantify additional ON characteristics in glaucoma and potentially other neurodegenerative diseases.