Ganglion Cell Layer Research Articles

Anatomy-driven segmentation of parafoveal optical coherence tomography (OCT) measures may improve associations with clinical outcomes in multiple sclerosis.

Previous investigations on optical coherence tomography (OCT) in multiple sclerosis (MS) focused on generalizable macular and peri-papillary regions without considering the anatomic variations of the retinal layer thickness. This study aimed to assess the utility of parafoveal retinal layer thickness measured by OCT, underscoring its relationships with clinical outcomes in MS. In this cross-sectional study, 214 people with MS (pwMS) and 57 age- and sex-matched healthy controls (HCs) were enrolled. Spectral domain OCT evaluation using 1, 3, 6mm Early Treatment Diabetic Retinopathy Study grid were conducted. The macular and parafoveal thickness (excluding the 1mm foveal/umbo contribution) of the retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), ganglion cell layer (GCL), inner plexiform layer (IPL), and the peri-papillary RNFL (pRNFL) were measured. Multivariable step-wise logistic, linear and generalized estimating equation (GEE) regression models were used to assess the association between the OCT parameters and clinical MS outcomes. The parafoveal RNFL thickness (d = 0.27, p = 0.023), GCL (d = 0.87, p < 0.001), IPL (d = 0.82, p < 0.001), and GCIPL (d = 0.85, p < 0.001) were all significantly lower in pwMS than HCs. Optic neuritis history [odds ratio (OR) = 0.84, p < 0.001] and progressive MS (PMS) status (OR = 0.92, p < 0.001) were bothbest predicted by parafoveal GCL. The Expanded Disability Status Scale (EDSS) was associated with the parafoveal thickness of GCL (standardized β = -0.472, p < 0.001) and pRNFL (standardized β = 0.187, p = 0.021). The parafoveal GCL thickness as predictor of MS disability was also confirmed by the GEE models. This investigation supports the potential use of parafoveal OCT segmentation as an alternative assessment method in detecting neuroinflammatory and neurodegenerative processes in MS. Averaging of the parafoveal retinal layer thickness into the OCT measures may increase the sensitivity of the standard macular OCT segmentation outcomes. Further studies should aim at exploring the reproducibility of this OCT outcome and its longitudinal responsiveness.

Unraveling the inflammation–degeneration tangle in early MS: preliminary insights from ferritin, neurogranin, TREM2, and retinal ganglion cell layer

BackgroundMultiple sclerosis (MS) involves a complex interplay between immune-mediated inflammation and neurodegeneration. Recent advances in biomarker research have provided new insights into the molecular underpinnings of MS, including ferritin, neurogranin, Triggering Receptor Expressed on Myeloid cells 2 (TREM2), and neurofilaments light chain.ObjectivesThis pilot study aims to investigate the levels of these biomarkers in the cerebrospinal fluid (CSF) of MS patients and explore their associations with clinical, cognitive, and optical coherence tomography (OCT) parameters.MethodsThis cross-sectional pilot study included 26 patients with relapsing MS (RMS) and 13 symptomatic controls (SCs). Clinical, cognitive, and OCT assessments were performed, and CSF samples were analyzed for ferritin, neurogranin, TREM2, and neurofilaments.ResultsNeurogranin levels were significantly higher in RMS patients compared to SCs (p = 0.04), and the receiver-operating characteristic (ROC) analysis indicated that neurogranin could be considered a disease biomarker (AUC = 0.733, p = 0.01). Ferritin and neurogranin showed a strong positive correlation (r = 0.690, p < 0.01), and both were inversely correlated with retinal ganglion cell layer (GCL) thickness. TREM2 was positively associated with baseline Expanded Disability Status Scale score.ConclusionThis pilot study suggests that neurogranin may be a potential biomarker at the time of MS diagnosis, and the interplay between ferritin, neurogranin, and TREM2 highlights the complex relationship between inflammation, oxidative stress, and neuronal damage in MS. The inverse association of ferritin and neurogranin with GCL thickness warrants further investigation into the role of iron metabolism and synaptic damage in the early stages of the disease.

Characterization of the Disorganization of the Inner Retinal Layers in Diabetics Using Increased Axial Resolution Optical Coherence Tomography.

To compare a novel high-resolution optical coherence tomography (OCT) with improved axial resolution (High-Res OCT) with conventional spectral-domain OCT (SD-OCT) with regard to their capacity to characterize the disorganization of the retinal inner layers (DRIL) in diabetic maculopathy. Diabetic patients underwent multimodal retinal imaging (SD-OCT, High-Res OCT, and color fundus photography). Best-corrected visual acuity and diabetes characteristics were recorded. DR was graded using the international clinical diabetic retinopathy severity scale (DRSS). In each OCT B-scan, retinal layers were segmented and the loss of discernibility was annotated. DRIL areas were analyzed in en face projection using FIJI plugins. The Wilcoxon test and regression models were used for statistical analysis. In 93 eyes of 93 patients (mean age, 61.8 ± 12.9 years) DRIL was identified in 48 eyes. DRIL was most frequent in the central subfield (27%). In DRIL eyes, DRSS was significantly higher (4.43 ± 1.01 vs. 2.12 ± 1.66; P < 0.001), BCVA was significantly worse (0.34 ± 0.38 vs. 0.13 ± 0.22; P < 0.001), and the loss of discernibility of the individual inner retinal layers was significantly smaller in High-Res OCT compared with SD-OCT (0.21 ± 0.29 vs. 1.21 ± 1.21mm2; P < 0.001). The discernibility loss was greatest in the retinal nerve fiber layer and ganglion cell layer. DRIL occurs in eyes with advanced diabetic retinopathy, with a characteristic spread: from the inner toward the outer retina. High-Res OCT shows significantly smaller DRIL areas compared with SD-OCT, because of a more precise delineation of the inner retinal layers. Using OCT with increased axial resolution could enhance our understanding of DRIL development and progression, providing deeper insights into pathophysiological aspects, including malperfusion in the inner capillary plexus.

Establishing normal interocular symmetry range for macular optical coherence tomography parameters in healthy children.

The study aimed to evaluate the interocular symmetry of macular sublayer thickness among healthy children aged 6-12 years. The Shiraz Pediatric Eye Study included 500 randomly selected children who underwent SD-OCT of the macula and optical biometry using the IOLMaster-500. Exclusion criteria involved ocular abnormalities or axial lengths outside the 21.5-26.5 mm range. Software recorded total retinal thickness and sublayer thickness within each ETDRS subfield. The study included 862 eyes from 431 healthy children, with 254 girls (59%). The anticipated variation in total retinal thickness between eyes was below 13 µm in the fovea and under 7 µm in the inner or outer ring for 95% of the population. For nerve fiber layer and inner plexiform layer, the expected variation ranged from 2 to 4 µm, and for the ganglion-cell layer, it ranged from 2.5 to 5 µm. Intraclass correlation coefficient (ICC) rankings for retinal topography were highest in the outer ring, followed by the inner ring and fovea. The highest ICC for individual layers was found in overall retinal thickness, followed by inner retinal layers, outer-nuclear layer, inner plexiform layer, and inner nuclear layer. The study establishes a reliable reference range for interocular variances in macular sublayers, aiding clinical decision-making. The outer ring (3-6 mm) is most dependable for analysing most sublayers, while the inner ring is most suitable for examining the ganglion-cell layer.

Nitric oxide modulates contrast suppression in a subset of mouse retinal ganglion cells.

Neuromodulators have major influences on the regulation of neural circuit activity across the nervous system. Nitric oxide (NO) has been shown to be a prominent neuromodulator in many circuits and has been extensively studied in the retina. Here, it has been associated with the regulation of light adaptation, gain control, and gap junctional coupling, but its effect on the retinal output, specifically on the different types of retinal ganglion cells (RGCs), is still poorly understood. In this study, we used two-photon Ca2+ imaging and multi-electrode array (MEA) recordings to measure light-evoked activity of RGCs in the ganglion cell layer in the ex vivo mouse retina. This approach allowed us to investigate the neuromodulatory effects of NO on a cell type-level. Our findings reveal that NO selectively modulates the suppression of temporal responses in a distinct subset of contrast-suppressed RGC types, increasing their activity without altering the spatial properties of their receptive fields. Given that under photopic conditions, NO release is triggered by quick changes in light levels, we propose that these RGC types signal fast contrast changes to higher visual regions. Remarkably, we found that about one-third of the RGC types, recorded using two-photon Ca2+ imaging, exhibited consistent, cell type-specific adaptational response changes throughout an experiment, independent of NO. By employing a sequential-recording paradigm, we could disentangle those additional adaptational response changes from drug-induced modulations. Taken together, our research highlights the selective neuromodulatory effects of NO on RGCs and emphasizes the need of considering non-pharmacological activity changes, like adaptation, in such study designs.

Müller glia in short- term dark adaptation of the Austrolebias charrua retina: cell proliferation and cytoarchitecture.

Fish with unique life cycles offer valuable insights into retinal plasticity, revealing mechanisms of environmental adaptation, cell proliferation, and thus, potentially regeneration. The variability of the environmental factors to which Austrolebias annual fishes are exposed has acted as a strong selective pressure shaping traits such as nervous system plasticity. This has contributed to adaptation to their extreme conditions including the decreased luminosity as ponds dry out. In particular, the retina of A. charrua has been shown to respond to 30 days of decreased luminosity by exacerbating cell proliferation Now, we aimed to determine the cellular component of the retina involved in shorter-term responses. To this end, we performed 5-bromo-2'-deoxyuridine (BrdU) experiments, exposing adult fish to a short period (11 days) of constant darkness. Strikingly, in control conditions, neurogenesis in the inner nuclear and ganglion cell layer in the differentiated retina was detected. In constant darkness, we observed an effect on inner nuclear layer cell proliferation and changes in retinal cytoarchitecture of the retina with cell clusters located in the inner plexiform layer. Additionally, increased BLBP (brain lipid-binding protein) presence was detected in darkness, which has been previously associated with immature and reactivated Müller glia. Thus, our results suggest that the A. charrua retina can respond to environmental changes via rapid activation of progenitor cells in the INL, namely the Müller glia This leads us to hypothesize, that cell proliferation and neurogenesis might contribute to the responses to the functional needs of organisms, potentially playing an adaptive role.

Hyperreflective retinal foci are associated with retinal degeneration after optic neuritis in neuromyelitis optica spectrum disorders and multiple sclerosis.

Hyperreflective retinal foci (HRF) visualized by optical coherence tomography (OCT) potentially represent clusters of microglia. We compared HRF frequencies and their association with retinal neurodegeneration between people with clinically isolated syndrome (pwCIS), multiple sclerosis (pwMS), aquaporin 4-IgG positive neuromyelitis optica spectrum disorder (pwNMOSD), and healthy controls (HC)-as well as between eyes with (ON+eyes) and without a history of optic neuritis (ON-eyes). Cross-sectional data of pwCIS, pwMS, and pwNMOSD with previous ON and HC were acquired at Charité-Universitätsmedizin Berlin. HRF analysis was performed manually on the central macular OCT scan. Semi-manual OCT segmentation was performed to acquire the combined ganglion cell and inner plexiform layer (GCIPL), inner nuclear layer (INL), and peripapillary retinal nerve fiber layer (pRNFL) thickness. Group comparisons were performed by linear mixed models. In total, 227 eyes from 88 patients (21 pwCIS, 32 pwMS, and 35 pwNMOSD) and 35 HCs were included. HRF in GCIPL and INL were more frequently detected in pwCIS, pwMS, and pwNMOSD than HCs (p < 0.001 for all comparisons) with pwCIS exhibiting the greatest numbers. ON+eyes of pwMS had less HRF in GCIPL than ON-eyes (p = 0.036), but no difference was seen in pwCIS and pwNMOSD. HRF GCIPL were correlated to GCIPL thickness in ON+eyes in pwMS (p = 0.040) and pwNMOSD (p = 0.031). HRF occur in ON+eyes and ON-eyes across neuroinflammatory diseases. In pwMS and pwNMOSD, HRF frequency was positively associated with GCIPL thickness indicating that HRF formation might be dependent on retinal ganglion cells.

Retinal organoid chip: engineering a physiomimetic oxygen gradient for optimizing long term culture of human retinal organoids.

An oxygen gradient across the retina plays a crucial role in its development and function. The inner retina resides in a hypoxic environment (2% O2) adjacent to the vitreous cavity. Oxygenation levels rapidly increase towards the outer retina (18% O2) at the choroid. In addition to retinal stratification, oxygen levels are critical for the health of retinal ganglion cells (RGCs), which relay visual information from the retina to the brain. Human stem cell derived retinal organoids are being engineered to mimic the structure and function of human retina for applications such as disease modeling, development of therapeutics, and cell replacement therapies. However, rapid degeneration of the retinal ganglion cell layers are a common limitation of human retinal organoid platforms. We report the design of a novel retinal organoid chip (ROC) that maintains a physiologically relevant oxygen gradient and allows the maturation of inner and outer retinal cell phenotypes for human retinal organoids. Our PDMS-free ROC holds 55 individual retinal organoids that were manually seeded, cultured for extended periods (over 150 days), imaged in situ, and retrieved. ROC was designed from first principles of liquid and gas mass transport, and fabricated from biologically- and chemically inert materials using rapid prototyping techniques such as micromachining, laser cutting, 3D printing and bonding. After computational and experimental validation of oxygen gradients, human induced pluripotent stem cell derived retinal organoids were transferred into the ROC, differentiated, cultured and imaged within the chip. ROCs that maintained active perfusion and stable oxygen gradients were successful in inducing higher viability of RGCs within retinal organoids than static controls, or ROC without oxygen gradients. Our physiologically relevant and higher-throughput retinal organoid culture system is well suited for applications in studying developmental perturbations to primate retinogenesis, including those driven by inherited traits, fetal environmental exposure to toxic agents, or acquired by genetic mutations, such as retinoblastoma.

Thioredoxin-interacting protein (TXNIP) inhibition promotes retinal ganglion cell survival and facilitates M1-like microglial transformation via the PI3K/Akt pathway in glaucoma

Abstract Background Glaucoma is a group of heterogeneous neurodegenerative diseases with abnormal energy metabolism and imbalanced neuroinflammation in the retina. Thioredoxin-interacting protein (TXNIP) is involved in glucose and lipid metabolism, and associated with oxidative stress and inflammation, however, not known whether to be involved in glaucoma neuropathy and its underlying mechanisms. Methods To establish the chronic ocular hypertension (COH) mice model. Western blot, RT-PCR, immunofluorescence and F-VEP were used to detect neuroinflammation level, glial activation and RGCs survival in retina of wild type, TXNIP knockout and MCC950 treatment COH mice. Microglia high-pressure cultured model was constructed. Western blot, RT-PCR and immunofluorescence were used to investigate the proinflammatory cytokines secretion, glucose uptake and phenotype transformation in wild type, TXNIP knockout and overexpressed microglia combined with IL-17A treatment. Finally, we explored the possible underlying mechanisms using relevant pathway inhibitor interventions. Results In this study, for the first time we reported that TXNIP expression was remarkably increased in experimental glaucomatous retina of chronic ocular hypertension (COH) mice, and it was mainly expressed in the ganglion cells layer (GCL). In addition, we found that ablation of TXNIP promoted retinal ganglion cells (RGCs) survival and alleviated visual function impairment in experimental glaucoma. Then, we explored the spatiotemporal consistency between glial activation and retinal inflammation levels in COH mice respectively with TXNIP-deficiency and under treatment of a thermo-containing protein domain 3 (NLRP3) inhibitor MCC950, and the results indicated that TXNIP probably mediated neuroinflammation in glaucomatous retina by activating microglia. Furthermore, upregulation of TXNIP was found in pressure-stimulated microglia, whereas silencing TXNIP facilitated microglial polarization trending towards M1 type and reduced glucose transporter-1 (Glut-1) expression on microglia under high pressure in vitro. Moreover, IL-17A was found to play a role in acting synergistically with TXNIP upon the regulation of microglia polarity transformation. Finally, knockout of TXNIP was revealed to promote PI3K phosphorylation, whereas inhibition of PI3K by LY294002 effectively suppressed Glut-1 expression, glucose uptake, and M1-like transformation tendency in microglia obtained from TXNIP-deficiency mice under high pressure stimulation. Conclusions TXNIP is significantly involved in the inflammation-related neuropathy of experimental glaucoma and probably facilitates M1-like microglial transformation via PI3K/Akt pathway.

Normative prospective data on automatically quantified retinal morphology correlated to retinal function in healthy ageing eyes by two microperimetry devices.

The relationship between retinal morphology, as assessed by optical coherence tomography (OCT), and retinal function in microperimetry (MP) has not been well studied, despite its increasing importance as an essential functional endpoint for clinical trials and emerging therapies in retinal diseases. Normative databases of healthy ageing eyes are largely missing from literature. Healthy subjects above 50 years were examined using two MP devices, MP-3 (NIDEK) and MAIA (iCare). An identical grid, encompassing 45 stimuli was used for retinal sensitivity (RS) assessment. Deep-learning-based algorithms performed automated segmentation of ellipsoid zone (EZ), outer nuclear layer (ONL), ganglion cell layer (GCL) and retinal nerve fibre layer (RNFL) from OCT volumes (Spectralis, Heidelberg). Pointwise co-registration between each MP stimulus and corresponding location on OCT was performed via registration algorithm. Effect of age, eccentricity and layer thickness on RS was assessed by mixed effect models. Three thousand six hundred stimuli from twenty eyes of twenty patients were included. Mean patient age was 68.9 ± 10.9 years. Mean RS for the first exam was 28.65 ± 2.49 dB and 25.5 ± 2.81 dB for MP-3 and MAIA, respectively. Increased EZ thickness, ONL thickness and GCL thickness were significantly correlated with increased RS (all p < 0.001). Univariate models showed lower RS with advanced age and higher eccentricity (both p < 0.05). This work provides reference values for healthy age-related EZ and ONL-thicknesses without impairment of visual function and evidence for RS decrease with eccentricity and increasing age. This information is crucial for interpretation of future clinical trials in disease.

Histological analysis of retinal development and remodeling in the brown anole lizard (Anolis sagrei).

The fovea, a pit in the retina, is crucial for high-acuity vision in humans and is found in the eyes of other vertebrates, including certain primates, birds, lizards, and fish. Despite its importance for vision, our understanding of the mechanisms involved in fovea development remains limited. Widely used ocular research models lack a foveated retina, and studies on fovea development are mostly limited to histological and molecular studies in primates. As a first step toward elucidating fovea development in nonprimate vertebrates, we present a detailed histological atlas of retina and fovea development in the bifoveated Anolis sagrei lizard, a novel reptile model for fovea research. We test the hypothesis that retinal remodeling, leading to fovea formation and photoreceptor cell packing, is related to asymmetric changes in eye shape. Our findings show that anole retina development follows the typical spatiotemporal patterning observed in most vertebrates: retinal neurogenesis starts in the central retina, progresses through the temporal retina, and finishes in the nasal retina. However, the areas destined to become the central or temporal fovea differentiate earlier than the rest of the retina. We observe dynamic changes in retinal thickness during ocular elongation and retraction-thinning during elongation and thickening during retraction. Additionally, a transient localized thickening of the ganglion cell layer occurs in the temporal fovea region just before pit formation. Our data indicate that anole retina development is similar to that of humans, including the onset and progression of retinal neurogenesis, followed by changes in ocular shape and retinal remodeling leading to pit formation. We propose that anoles are an excellent model system for fovea development research.

Neuropathological correlates of vulnerability and resilience in the cerebellum in Alzheimer's disease.

We investigated whether the cerebellum develops neuropathology that correlates with well-accepted Alzheimer's disease (AD) neuropathological markers and cognitive status. We studied cerebellar cytoarchitecture in a cohort (N=30) of brain donors. In a larger cohort (N=605), we queried whether the weight of the contents of the posterior fossa (PF), which contains primarily cerebellum, correlated with dementia status. Although there was no granular layer (GL) cell loss, GL area was lower in AD cases, particularly in the lateral cerebellum. Lower numbers of mossy fiber synaptic terminals in the cerebellar GL of AD cases correlated with Braak stages IV-VI. PF content weight correlated with dementia independently of age, neuropathology, and education. In addition, we found that a measure of the relative size of the PF content weight to total brain weight correlated with less dementia. These results confirm that the cerebellum is not spared neuropathological damage in AD. Novel evidence of cerebellar atrophy in the granule cell layer of the lateral cerebellar cortex (or 'cognitive cerebellum'), and loss of a specific cerebellar synapse type in this region, the cerebellar glomerulus. Both correlated with dementia status and Braak stages IV through VI, in a cohort with complete neuropathological characterization. Although there have been recent brain imaging studies suggesting a role for cerebellum in Alzheimer's disease, we believe our study constitutes some of the most concrete neuropathological evidence to date of anatomic and synaptic substrates that are disrupted in AD. These changes in this cerebellar region may even play a role in the etiology of cognitive symptoms. Novel evidence that individuals with lower postmortem cerebellar weights showed more cognitive decline, independent of classical neuropathology markers such as Braak stage, Thal phase, or Corsortium to Establish a Registry for Alzheimer's Disease (CERAD) score, suggesting a role for this brain region in dementia, using advanced statistical analysis of a large unbiased population cohort (n=605), the Adult Changes in Thought (ACT) study. Conversely, a measure of how intact the cerebellum was correlated with less dementia, independent of classical neuropathology markers and cerebral cortical weight, again, in the ACT cohort of 605 brain donors. We believe that this novel finding has relevance and implications for the identification of resilience factors, which may protect against the development of dementia.

Optical coherence tomography: implications for neurology.

This article explores the role of optical coherence tomography (OCT) in neurology practice, particularly in diagnosing and monitoring conditions such as papilledema, optic neuritis, and retinal artery occlusion. OCT has been increasingly utilized as a noninvasive and effective tool for detecting and monitoring neuroaxonal damage in the visual pathway, which is important for early intervention and improved patient outcomes across a variety of neurologic conditions. OCT as an imaging modality continues to demonstrate its utility in quantifying optic nerve and retinal changes reflecting neuroaxonal injury, including, peripapillary retinal nerve fiber layer (pRNFL) thickness and macular ganglion cell layer thickness (or volume). This review focuses on recent evidence regarding the utilization of this modality in diagnosing, monitoring, and quantifying treatment responses in patients with papilledema, optic neuritis, and retinal artery occlusion. Advances in OCT technology, including deep learning algorithms, continue to enhance the diagnostic accuracy and predictive capabilities in the field of neuro-ophthalmology. In recent years, OCT has become an essential tool in neuro-ophthalmic assessment, offering precise structural and anatomical assessments that support diagnosis, treatment planning, and monitoring of conditions affecting the visual pathway. Ongoing advances in OCT technology are expected to further enhance its clinical utility.

The Relationship between Retinal and Ganglion Layer Thickness and Perfusion in Patients with Type 2 Diabetes: A Cross-Sectional Study in Indonesia

The Relationship between Retinal and Ganglion Layer Thickness and Perfusion in Patients with Type 2 Diabetes: A Cross-Sectional Study in Indonesia

Balance Performance in Aged Mice is Dependent on Unipolar Brush Cells.

The vestibular processing regions of the cerebellum integrate vestibular information with other sensory modalities and motor signals to regulate balance, gaze stability, and spatial orientation. A class of excitatory glutamatergic interneurons known as unipolar brush cells (UBCs) are highly concentrated within the granule cell layer of these regions. UBCs receive vestibular signals directly from primary vestibular afferents and indirectly from mossy fibers. Each UBC excites numerous granule cells and could contribute to computations necessary for balance-related motor function. Prior research has implicated UBCs in motor function, but their influence on balance performance remains unclear, especially in aged mice that have age-related impairment. Here we tested whether UBCs contribute to motor coordination and balance by disrupting their activity with chemogenetics in aged and young mice. Age-related balance deficits were apparent in mice > 6 months old. Disrupting the activity of a subpopulation of UBCs caused aged mice to fall off a balance beam more frequently and altered swimming behaviors that are sensitive to vestibular dysfunction. These effects were not seen in young (7-week-old) mice. Thus, disrupting the activity of UBCs impairs mice with age-related balance issues and suggest that UBCs are essential for balance and vestibular function in aged mice.

Evaluation of optical coherence tomography and optical coherence tomography angiography findings of fibromyalgia.

To execute comprehensive study about optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) findings in fibromyalgia (FM) to elaborate macula, optic disk changes. A total of 84 participants comprising 44 FM patients and 40 healthy controls were included. Macular full thickness, retinal nerve fiber layer (RNFL), ganglion cell layer (GCL)+, GCL++, superficial vessel density (SVD), deep vessel density (DVD), foveal avascular zone (FAZ), circumpapillary vessel density (cpVD), RNFL measurements were evaluated using OCT/OCTA. Each FM patient completed Fibromyalgia Impact Questionnaire (FIQ), Short Form-36 (SF-36), Widespread Pain Index (WPI), Symptom Severity Scale (SSS). OCT/OCTA parameters were compared between controls and FM patients. Correlation between FIQ, SF-36, WPI, SSS and OCT/OCTA were evaluated. Logistic regression analysis were performed to analyze associated parameters. Macular full thickness parafoveal nasal, temporal, superior, inferior, perifoveal temporal, superior, GCL+ parafoveal nasal, temporal, superior, inferior, GCL+ perifoveal temporal, GCL++ parafoveal nasal, temporal, superior, inferior, GCL++ perifoveal nasal were lower in FM patients. Difference was not found in SVD, DVD or FAZ measurements. cpVD in nasal, superior, inferior were higher in FM patients. RNFL temporal was lower in FM patients. Weak correlations were observed between FIQ, SF-36, WPI, SSS scores and OCT/OCTA parameters. Superior cpVD was associated with FM due to logistic regression analysis. OCT/OCTA can provide objective supplementary measurements in the assessment of FM. Changes in measurements like RNFL, macula GCL, cpVD are important to evaluate the neuroretinal changes in FM.

Mossy Fiber Sprouting in Temporal Lobe Epilepsy: The Impact of Netrin-1, DCC, and Gene Expression Changes.

Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy, often associated with hippocampal sclerosis (HS), which involves selective neuronal loss in the Cornu Ammonis subregion 1 CA1 and CA4 regions of the hippocampus. Granule cells show migration and mossy fiber sprouting, though the mechanisms remain unclear. Microglia play a role in neurogenesis and synaptic modulation, suggesting they may contribute to epilepsy. This study examines the role of microglia and axonal guidance molecules in neuronal reorganization in TLE. Nineteen hippocampal samples from patients with TLE undergoing epilepsy surgery were analyzed. Microglial activity (M1/M2-like microglia) and neuronal guidance molecules were assessed using microscopy and semi-automated techniques. Gene expression was evaluated using the nCounter Expression Profiling method. Neuronal cell loss was correlated with decreased activity of the M1 microglial phenotype. In the CA2 region, neuronal preservation was linked to increased mossy fiber sprouting and microglial presence. Neuronal markers such as Deleted in Colorectal Cancer (DCC) and Synaptopodin were reduced in areas of cell death, while Netrin-1 was elevated in the granule cell layer, potentially influencing mossy fiber sprouting. The nCounter analysis revealed downregulation of genes involved in neuronal activity (e.g., NPAS4, BCL-2, GRIA1) and upregulation of IκB, indicating reduced neuroinflammation. This study suggests reduced neuroinflammation in areas of neuronal loss, while regions with preserved neurons showed mossy fiber sprouting associated with microglia, Netrin-1, and DCC.

Fluorescent identification of axons, dendrites and soma of neuronal retinal ganglion cells with a genetic marker as a tool for facilitating the study of neurodegeneration.

This study characterizes a fluorescent Slc17a6-tdTomato neuronal reporter mouse line with strong labeling of axons throughout the optic nerve, of retinal ganglion cell (RGC) soma in the ganglion cell layer (GCL), and of RGC dendrites in the inner plexiform layer (IPL). The model facilitated assessment of RGC loss in models of degeneration and of RGC detection in mixed neural/glial cultures. The tdTomato signal showed strong overlap with >98% cells immunolabeled with RGC markers RBPMS or BRN3A, consistent with the ubiquitous presence of the vesicular glutamate transporter 2 (VGUT2, SLC17A6) in all RGC subtypes. There was no cross-labeling of ChAT-positive displaced amacrine cells in the GCL, although some signal emanated from the outer plexiform layer, consistent with horizontal cells. The fluorescence allowed rapid screening of RGC loss following optic nerve crush and intraocular pressure (IOP) elevation. The bright fluorescence also enabled non-invasive monitoring of extensive neurite networks and neuron/astrocyte interactions in culture. Robust Ca2+ responses to P2X7R agonist BzATP were detected from fluorescent RGCs using Ca2+-indicator Fura-2. Fluorescence from axons and soma was detected invivo with a confocal scanning laser ophthalmoscope (cSLO); automatic RGC soma counts enhanced through machine learning approached the numbers found in retinal wholemounts. Controls indicated no impact of Slc17a6-tdTomato expression on light-dependent neuronal function as measured with a microelectrode array (MEA), or on retinal structure as measured with optical coherence tomography (OCT). In summary, the bright fluorescence in axons, dendrites and soma of ~all RGCs in the Slc17a6-tdTomato reporter mouse may facilitate the study of RGCs.

N-Methyl-d-Aspartate-Induced Excitotoxicity and Its Impact on the Renin-Angiotensin System in Retinal Tissue.

Purpose: Renin-angiotensin system (RAS) is expressed in neuronal tissue and plays a role in neurodegenerative diseases involving excitotoxicity as a pathophysiological mechanism. In retina, excessive excitatory neurotransmission via N-methyl-d-aspartate (NMDA) receptors underlies neuronal apoptosis in conditions like glaucoma. However, it is not known if NMDA-mediated excitotoxicity alters retinal RAS expression. Hence, this study investigated the effect of NMDA exposure on the expression of RAS in rat retinas. Methods: Two groups of Sprague-Dawley rats received either phosphate buffer saline or NMDA (160 nmol). On day 7 posttreatment, retinal expression of RAS components including renin, angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II (Ang II), Ang 1-7, Ang 1-9, MAS receptor, angiotensin II type 1 receptor (AT1R), ACE2, and aldosterone was measured using enzyme-linked immunosorbent assay and polymerase chain reaction. Morphometric studies were done to assess morphological alterations. Results: Following the exposure to NMDA, an upregulation of ACE expression was noted at both the protein (2.03-folds; P < 0.001) and mRNA (1.86-folds; P < 0.01) levels in rat retinas. AT1R protein and mRNA expression were greater by 1.73 (P < 0.0001) and 2.28-folds (P < 0.0001), respectively. However, mRNA expression for ACE2, Ang 1-7, and Ang 1-9, showed a 1.51-(P < 0.05), 2.41-(P < 0.001), and 2.37-(P < 0.0001) fold decrease. Ganglion cell layer (GCL) thickness and linear cell density in GCL were significantly lower in the NMDA-treated group (P < 0.05). Conclusions: NMDA exposure increases expression of the classical RAS and suppresses that of alternate RAS in rat retinas. These alterations are associated with retinal morphological changes indicating significant loss of neuronal cells in the GCL of rat retinas.

GlyT2-positive interneurons regulate timing and variability of information transfer in a cerebellar-behavioural loop.

GlyT2-positive interneurons, Golgi and Lugaro cells, reside in the input layer of the cerebellar cortex in a key position to influence information processing. Here, we examine the contribution of GlyT2-positive interneurons to network dynamics in Crus 1 of mouse lateral cerebellar cortex during free whisking. We recorded neuronal population activity using NeuroPixels probes before and after chemogenetic downregulation of GlyT2-positive interneurons in male and female mice. Under resting conditions, cerebellar population activity reliably encoded whisker movements. Reductions in the activity of GlyT2-positive cells produced mild increases in neural activity which did not significantly impair these sensorimotor representations. However, reduced Golgi and Lugaro cell inhibition did increase the temporal alignment of local population network activity at the initiation of movement. These network alterations had variable impacts on behaviour, producing both increases and decreases in whisking velocity. Our results suggest that inhibition mediated by GlyT2-positive interneurons primarily governs the temporal patterning of population activity, which in turn is required to support downstream cerebellar dynamics and behavioural coordination.Significance statement The cerebellum has a simple and conserved structure which has tantalised neurobiologists wishing to understand its function. Here we look at the role of granule cell layer inhibitory interneurons, Golgi and Lugaro cells, in the cerebellar cortex. We selectively turned down the activity of these cells in the awake cerebellum to characterise their influence on network activity and behaviour. We show that downregulation of Golgi and Lugaro cells has very little influence on sensorimotor representations in the cerebellum (i.e., what is represented), but instead modulates the timing of cortical population activity (i.e., when information is represented). Our results indicate that inhibitory interneurons in the granule cell layer are necessary to appropriately pace changes in cerebellar activity to match ongoing behaviour.