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ENeuro 2020Spike conduction velocity characteristically differs between myelinated and unmyelinated axons. Here we test whether spikes of myelinated and unmyelinated paths differ...
Spike conduction velocity characteristically differs between myelinated and unmyelinated axons. Here we test whether spikes of myelinated and unmyelinated paths differ in other respects by measuring rat retinal ganglion cell (RGC) spike duration in the intraretinal, unmyelinated nerve fiber layer and the extraretinal, myelinated optic nerve and optic chiasm. We find that rapid spike firing and illumination broaden spikes in intraretinal axons but not in extraretinal axons. RGC axons thus initiate spikes intraretinally and normalize spike duration extraretinally. Additionally, we analyze spikes that were recorded in a previous study of rhesus macaque retinogeniculate transmission and find that rapid spike firing does not broaden spikes in optic tract. The spike normalization we find reduces the number of spike properties that can change during RGC light responses. However, this is not because identical spikes fire in all axons. Instead, our recordings show that different subtypes of RGC generate axonal spikes of different durations and that the differences resemble spike duration increases that alter neurotransmitter release from other neurons. Moreover, previous studies have shown that RGC spikes of shorter duration can fire at higher maximum frequencies. These properties should facilitate signal transfer by different mechanisms at RGC synapses onto subcortical target neurons.
Topics: Animals; Axons; Macaca mulatta; Optic Chiasm; Optic Nerve; Rats; Retina; Retinal Ganglion Cells
PubMed: 32086286
DOI: 10.1523/ENEURO.0504-19.2020 -
Ocular Oncology and Pathology Nov 2018Optic nerve haemangioblastomas remain exceedingly rare extrinsic tumours of the optic nerve, often associated with von Hippel-Lindau disease. The authors report a...
Optic nerve haemangioblastomas remain exceedingly rare extrinsic tumours of the optic nerve, often associated with von Hippel-Lindau disease. The authors report a 25-year-old female with a slowly progressive unilateral optic nerve lesion, causing reduced vision and bilateral optic tract oedema. A diagnosis of optic nerve haemangioblastoma with piloid gliosis was made histologically after surgical resection. This is the first reported case of such dual pathology occurring in the optic nerve. The patient has been monitored without further adjuvant treatment, and has not had a recurrence to date, at 6 years of follow-up.
PubMed: 30574489
DOI: 10.1159/000486863 -
PloS One 2018Adult male C57BL/6J mice have previously been reported to have motor and memory deficits after experimental closed head traumatic brain injury (TBI), without associated...
Adult male C57BL/6J mice have previously been reported to have motor and memory deficits after experimental closed head traumatic brain injury (TBI), without associated gross pathologic damage or neuroimaging changes detectable by magnetic resonance imaging or diffusion tensor imaging protocols. The presence of neurologic deficits, however, suggests neural damage or dysfunction in these animals. Accordingly, we undertook a histologic analysis of mice after TBI. Gross pathology and histologic analysis using Nissl stain and NeuN immunohistochemistry demonstrated no obvious tissue damage or neuron loss. However, Luxol Fast Blue stain revealed myelin injury in the optic tract, while Fluoro Jade B and silver degeneration staining revealed evidence of axonal neurodegeneration in the optic tract as well as the lateral geniculate nucleus of the thalamus and superior colliculus (detectable at 7 days, but not 24 hours, after injury). Fluoro Jade B staining was not detectable in other white matter tracts, brain regions or in cell somata. In addition, there was increased GFAP staining in these optic tract, lateral geniculate, and superior colliculus 7 days post-injury, and morphologic changes in optic tract microglia that were detectable 24 hours after injury but were more prominent 7 days post-injury. Interestingly, there were no findings of degeneration or gliosis in the suprachiasmatic nucleus, which is also heavily innervated by the optic tract. Using micro-computed tomography imaging, we also found that the optic canal appears to decrease in diameter with a dorsal-ventral load on the skull, which suggests that the optic canal may be the site of injury. These results suggest that there is axonal degeneration in the optic tract and a subset of directly innervated areas, with associated neuroinflammation and astrocytosis, which develop within 7 days of injury, and also suggest that this weight drop injury may be a model for studying indirect traumatic optic neuropathy.
Topics: Animals; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Gliosis; Head Injuries, Closed; Male; Mice, Inbred C57BL; Neurodegenerative Diseases; Optic Nerve Injuries; Optic Tract
PubMed: 29746557
DOI: 10.1371/journal.pone.0197346 -
Cells Apr 2021Traumatic brain injury (TBI) results in a number of impairments, often including visual symptoms. In some cases, visual impairments after head trauma are mediated by...
Traumatic brain injury (TBI) results in a number of impairments, often including visual symptoms. In some cases, visual impairments after head trauma are mediated by traumatic injury to the optic nerve, termed traumatic optic neuropathy (TON), which has few effective options for treatment. Using a murine closed-head weight-drop model of head trauma, we previously reported in adult mice that there is relatively selective injury to the optic tract and thalamic/brainstem projections of the visual system. In the current study, we performed blunt head trauma on adolescent C57BL/6 mice and investigated visual impairment in the primary visual system, now including the retina and using behavioral and histologic methods at new time points. After injury, mice displayed evidence of decreased optomotor responses illustrated by decreased optokinetic nystagmus. There did not appear to be a significant change in circadian locomotor behavior patterns, although there was an overall decrease in locomotor behavior in mice with head injury. There was evidence of axonal degeneration of optic nerve fibers with associated retinal ganglion cell death. There was also evidence of astrogliosis and microgliosis in major central targets of optic nerve projections. Further, there was elevated expression of endoplasmic reticulum (ER) stress markers in retinas of injured mice. Visual impairment, histologic markers of gliosis and neurodegeneration, and elevated ER stress marker expression persisted for at least 30 days after injury. The current results extend our previous findings in adult mice into adolescent mice, provide direct evidence of retinal ganglion cell injury after head trauma and suggest that axonal degeneration is associated with elevated ER stress in this model of TON.
Topics: Animals; Brain Injuries, Traumatic; Disease Models, Animal; Endoplasmic Reticulum Stress; Gliosis; Male; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Optic Nerve Injuries; Vision Disorders
PubMed: 33922788
DOI: 10.3390/cells10050996 -
The Journal of Neuroscience : the... Sep 2022The mouse retina encodes diverse visual features in the spike trains of >40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the >50...
The mouse retina encodes diverse visual features in the spike trains of >40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the >50 retinorecipient brain areas. Our catalog of RGC types and feature representations is nearing completion. Yet, we know little about where specific RGC types send their information. Furthermore, the developmental strategies by which RGC axons choose their targets and pattern their terminal arbors remain obscure. Here, we identify a genetic intersection ( and ) that selectively labels transient Suppressed-by-Contrast (tSbC) RGCs, a member of an evolutionarily conserved functionally mysterious RGC subclass. We find that tSbC RGCs selectively innervate the dorsolateral geniculate nucleus (dLGN) and ventrolateral geniculate nucleus (vLGN) of the thalamus, the superior colliculus (SC), and the nucleus of the optic tract (NOT) in mice of either sex. They binocularly innervate dLGN and vLGN but project only contralaterally to SC and NOT. In each target, tSbC RGC axons occupy a specific sublayer, suggesting that they restrict their input to specific circuits. The tSbC RGC axons span the length of the optic tract by birth and remain poised there until they simultaneously innervate their four targets around postnatal day 3. The tSbC RGC axons choose the right targets and establish mature stratification patterns from the outset. This precision is maintained in the absence of Brn3c. Our results provide the first map of SbC inputs to the brain, revealing a narrow target set, unexpected laminar organization, target-specific binocularity, and developmental precision. In recent years, we have learned a lot about the visual features encoded by RGCs, the output neurons of the eye. In contrast, we know little about where RGCs send their information and how RGC axons, which carry this information, target specific brain areas during development. Here, we develop an intersectional strategy to label a unique RGC type, the tSbC RGC, and map its projections. We find that tSbC RGC axons are highly selective. They innervate few retinal targets and restrict their arbors to specific sublayers within these targets. The selective tSbC RGC projection patterns develop synchronously and without trial and error, suggesting molecular determinism and coordination.
PubMed: 36002262
DOI: 10.1523/JNEUROSCI.2332-21.2022 -
Frontiers in Neuroscience 2021Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The...
Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades. We previously found that treatment with the CB2 inverse agonist SMM-189 after mild TBI in mice produced by focal cranial blast rescues visual deficits and the optic nerve axon loss that would otherwise result. We have further shown that raloxifene, which is Food and Drug Administration (FDA)-approved as an estrogen receptor modulator to treat osteoporosis, but also possesses CB2 inverse agonism, yields similar benefit in this TBI model through its modulation of microglia. As many different traumatic events produce TBI in humans, it is widely acknowledged that diverse animal models must be used in evaluating possible therapies. Here we examine the consequences of TBI created by blunt impact to the mouse head for visual function and associated pathologies and assess raloxifene benefit. We found that mice subjected to impact TBI exhibited decreases in contrast sensitivity and the B-wave of the electroretinogram, increases in light aversion and resting pupil diameter, and optic nerve axon loss, which were rescued by daily injection of raloxifene at 5 or 10 mg/ml for 2 weeks. Raloxifene treatment was associated with reduced M1 activation and/or enhanced M2 activation in retina, optic nerve, and optic tract after impact TBI. Our results suggest that the higher raloxifene dose, in particular, may be therapeutic for the optic nerve by enhancing the phagocytosis of axonal debris that would otherwise promote inflammation, thereby salvaging less damaged axons. Our current work, together with our prior studies, shows that microglial activation drives secondary injury processes after both impact and cranial blast TBI and raloxifene mitigates microglial activation and visual system injury in both cases. The results thus provide a strong basis for phase 2 human clinical trials evaluating raloxifene as a TBI therapy.
PubMed: 34776838
DOI: 10.3389/fnins.2021.701317 -
Frontiers in Endocrinology 2023Diabetic neuropathy and diabetic eye disease are well known complications of type 1 diabetes. We hypothesized that chronic hyperglycemia also damages the optic tract,...
INTRODUCTION
Diabetic neuropathy and diabetic eye disease are well known complications of type 1 diabetes. We hypothesized that chronic hyperglycemia also damages the optic tract, which can be measured using routine magnetic resonance imaging. Our aim was to compare morphological differences in the optic tract between individuals with type 1 diabetes and healthy control subjects. Associations between optic tract atrophy and metabolic measures, cerebrovascular and microvascular diabetic complications were further studied among individuals with type 1 diabetes.
METHODS
We included 188 subjects with type 1 diabetes and 30 healthy controls, all recruited as part of the Finnish Diabetic Nephropathy Study. All participants underwent a clinical examination, biochemical work-up, and brain magnetic resonance imaging (MRI). Two different raters manually measured the optic tract.
RESULTS
The coronal area of the optic chiasm was smaller among those with type 1 diabetes compared to non-diabetic controls (median area 24.7 [21.0-28.5] vs 30.0 [26.7-33.3] mm, p<0.001). In participants with type 1 diabetes, a smaller chiasmatic area was associated with duration of diabetes, glycated hemoglobin, and body mass index. Diabetic eye disease, kidney disease, neuropathy and the presence of cerebral microbleeds (CMBs) in brain MRI were associated with smaller chiasmatic size (p<0.05 for all).
CONCLUSION
Individuals with type 1 diabetes had smaller optic chiasms than healthy controls, suggesting that diabetic neurodegenerative changes extend to the optic nerve tract. This hypothesis was further supported by the association of smaller chiasm with chronic hyperglycemia, duration of diabetes, diabetic microvascular complications, as well as and CMBs in individuals with type 1 diabetes.
Topics: Humans; Optic Chiasm; Diabetes Mellitus, Type 1; Diabetes Complications; Chronic Disease; Atrophy; Hyperglycemia
PubMed: 37324273
DOI: 10.3389/fendo.2023.1134530 -
Advances in Ophthalmology Practice and... Dec 2021Magnetic resonance imaging (MRI) plays a significant role in assessing optic neuropathy and providing more detailed information about the lesion of the visual pathway to... (Review)
Review
BACKGROUND
Magnetic resonance imaging (MRI) plays a significant role in assessing optic neuropathy and providing more detailed information about the lesion of the visual pathway to help differentiate optic neuritis from other visual disorders. This study aims to systematically review the literature and verify if there is a real difference in lesion location among different demyelinating optic neuritis (DON) subtypes.
METHODS
A systematic search was conducted including 8 electronic databases and related resources from the establishment of the database to August 25th, 2020. We classified DON into 5 subtypes and divided the visual pathways into five segments mainly comparing the differences in the involved visual pathway sites of different subtypes.
RESULTS
Fifty-five studies were included in the analysis, and the abnormal rate was as high as 92% during the acute phase (within 4 weeks of symptom onset). With respect to lesion location, the orbital segment of the optic nerve was the most frequently involved (87%), whereas optic tract involvement was very rare. Involvement of the orbital segment was more common in myelin oligodendrocyte glycoprotein antibody-related optic neuritis (MOG-ON) (78%) and chronic relapsing inflammatory optic neuropathy (CRION) (81%), while the lesion was found to be located more posteriorly in neuromyelitis optica spectrum disorder-related optic neuritis (NMOSD-ON). With respect to lesion length, approximately 77% of MOG-ON patients had lesions involving more than half of the optic nerve length.
CONCLUSIONS
MRI examination is recommended for DON patients in the acute phase. In MOG-ON, anterior involvement is more common and the involved length is mostly more than 1/2 of the optic nerve length, whereas posterior involvement, intracranial segment, optic chiasm, or optic tract, is more common in NMOSD-ON.
PROSPERO REGISTRATION NUMBER
CRD42020222430 (25-11-2020).
PubMed: 37846325
DOI: 10.1016/j.aopr.2021.100019 -
Investigative Ophthalmology & Visual... Aug 2021To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI).
PURPOSE
To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI).
METHODS
Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract.
RESULTS
Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls.
CONCLUSIONS
Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity.
Topics: Animals; Anisotropy; Cats; Diffusion Tensor Imaging; Disease Models, Animal; Glaucoma, Open-Angle; Gray Matter; Intraocular Pressure; Mice; Mice, Inbred DBA; Nerve Fibers; Optic Nerve; Rats; Rats, Sprague-Dawley; Visual Pathways
PubMed: 34410298
DOI: 10.1167/iovs.62.10.21 -
Scientific Reports Aug 2018Mouse models have shown that cerebral hypoperfusion causes white matter disruption and memory impairment relevant to the study of vascular cognitive impairment and...
Mouse models have shown that cerebral hypoperfusion causes white matter disruption and memory impairment relevant to the study of vascular cognitive impairment and dementia. The associated mechanisms include inflammation and oxidative stress are proposed to drive disruption of myelinated axons within hypoperfused white matter. The aim of this study was to determine if increased endogenous anti-oxidant and anti-inflammatory signalling in astrocytes was protective in a model of mild cerebral hypoperfusion. Transgenically altered mice overexpressing the transcription factor Nrf2 (GFAP-Nrf2) and wild type littermates were subjected to bilateral carotid artery stenosis or sham surgery. Behavioural alterations were assessed using the radial arm maze and tissue was collected for pathology and transcriptome analysis six weeks post-surgery. GFAP-Nrf2 mice showed less pronounced behavioural impairments compared to wild types following hypoperfusion, paralleled by reduced optic tract white matter disruption and astrogliosis. There was no effect of hypoperfusion on anti-oxidant gene alterations albeit the levels were increased in GFAP-Nrf2 mice. Instead, pro-inflammatory gene expression was determined to be significantly upregulated in the optic tract of hypoperfused wild type mice but differentially affected in GFAP-Nrf2 mice. In particular, complement components (C4 and C1q) were increased in wild type hypoperfused mice but expressed at levels similar to controls in hypoperfused GFAP-Nrf2 mice. This study provides evidence that overexpression of Nrf2 in astrocytes exerts beneficial effects through repression of inflammation and supports the potential use of Nrf2-activators in the amelioration of cerebrovascular-related inflammation and white matter degeneration.
Topics: Amino Acid Transport System y+; Animals; Astrocytes; Behavior, Animal; Carotid Stenosis; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognitive Dysfunction; Disease Models, Animal; Gene Expression; Glutamate-Cysteine Ligase; Maze Learning; Mice, Inbred C57BL; Mice, Transgenic; NF-E2-Related Factor 2; Optic Tract; White Matter
PubMed: 30135571
DOI: 10.1038/s41598-018-30675-4