Retinal Responses Research Articles

Longitudinal Morphological and Functional Assessment of RGC Neurodegeneration After Optic Nerve Crush in Mouse.

The mouse optic nerve crush (ONC) model has been widely used to study optic neuropathies and central nervous system (CNS) axon injury and repair. Previous histological studies of retinal ganglion cell (RGC) somata in retina and axons in ON demonstrate significant neurodegeneration after ONC, but longitudinal morphological and functional assessment of RGCs in living animals is lacking. It is essential to establish these assays to provide more clinically relevant information for early detection and monitoring the progression of CNS neurodegeneration. Here, we present in vivo data gathered by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and pattern electroretinogram (PERG) at different time points after ONC in mouse eyes and corresponding histological quantification of the RGC somata and axons. Not surprisingly, direct visualization of RGCs by SLO fundus imaging correlated best with histological quantification of RGC somata and axons. Unexpectedly, OCT did not detect obvious retinal thinning until late time points (14 and 28-days post ONC) and instead detected significant retinal swelling at early time points (1–5 days post-ONC), indicating a characteristic initial retinal response to ON injury. PERG also demonstrated an early RGC functional deficit in response to ONC, before significant RGC death, suggesting that it is highly sensitive to ONC. However, the limited progression of PERG deficits diminished its usefulness as a reliable indicator of RGC degeneration.

Issue Cover (May 2020)

Journal of NeurochemistryVolume 153, Issue 3 Issue CoverFree Access Issue Cover (May 2020) First published: 27 April 2020 https://doi.org/10.1111/jnc.14743 Read the full article: ‘VEGF-Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy’ by J. E. Rojo Arias, M. Economopoulou, D. A. Juárez López, A, Kurzbach, K. H. Au Yeung, V. Englmaier, M. Merdausl, M. Schaarschmidt, M. Ader, H. Morawietz, R. H. W. Funk, J. Jászai, (J. Neurochem. 2020, vol. 153 (3), pp. 390–412) on doi: 10.1111/jnc.14875 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Front cover: Ocular microvasculopathies compromise vision in diseases as retinopathy of prematurity and proliferative diabetic retinopathy. Using the oxygen induced retinopathy mouse model, we investigated the effects of aflibercept in modulating the aberrant retinal microvascular response to ischemia. Image content: In this image, a magnified view of a flat-mounted retina from a 17 day old mouse subjected to the oxygen-induced retinopathy protocol and subsequently treated with aflibercept is shown. FITC-labeled dextran (150 kDa) was injected intra-peritoneally to animals 2 hours prior to sacrifice and was detected in the retinal microvasculature residing primarily within the vascular lumen (green). By contrast, immunolabeling of the tissue with an anti-human IgG antibody (magenta) and visualization of cell nuclei with DAPI (white) revealed that Aflibercept is also detected in blood vessel walls, suggesting it can be transported across retinal endothelial cells under ischemic conditions. Albeit slow in nature, this controlled transport might be central to achieving the functional benefits in vision we report in our study. Read the full article ‘VEGF-Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy’ by J. E. Rojo Arias, M. Economopoulou, D. A. Juárez López, A, Kurzbach, K. H. Au Yeung, V. Englmaier, M. Merdausl, M. Schaarschmidt, M. Ader, H. Morawietz, R. H. W. Funk, J. Jászai, (J. Neurochem. 2020, vol. 153 (3), pp. 390–412) on doi: 10.1111/jnc.14875 Volume153, Issue3May 2020 RelatedInformation

The protective effect of Zhicao Tea Mixture on Müller cells and the expression of inflammatory factors in mice with diabetic retinopathy

Objective To observe the protective effect of Zhicao Tea Mixture on Muller cells and the expression of inflammatory factors in mice with diabetic retinopathy. Methods Seventy-five C57BL/6J mice were randomly divided into the normal control group, diabetes mellitus (DM) group, low concentrations group, medium concentrations group and high concentrations group, with 16 mice in each group. The diabetes model of mice in all groups except the normal control group were established by intraperitoneal injection of STZ (60 mg/kg). Four weeks after the successful modeling, the Zhicao Tea Mixture with low (30 ml/kg), medium (60 ml/kg) and high concentrations (120 ml/kg) were respectively administered by gavage. Weight and blood glucose of mice in each group were measured every two weeks. After 8 weeks, Western blot method was used to detect the mice retina Muller cells activation marker gelatinous fibrous acidic protein (GFAP). Immunofluorescence was performed to detect the expression GFAP and glutamine synthetase (GS). Real-time quantitative PCR (RT- qPCR) and ELISA were used to determine the mRNA and protein expression levels of mouse retinal VEGF, TNF-α, IL-1β and IL-6 respectively. Results The weight of mice in the DM group was lower than that of the normal control group, and the blood glucose was increased. Zhicao Tea Mixture had no effect on the weight of DM mice, but had a significant hypoglycemic effect. The GFAP expression (t=38.318, P<0.001) in the retina of mice in the DM group was increased and GS expression (t=29.737, P<0.001) was decreased compared with the control group. The GFAP expression (t=13.677, 19.387, 16.305; P<0.05) in the retina of mice in the low, medium and high concentrations group were decreased and GS expression (t=5.170, 19.399, 6.705; P<0.05) were increased compared with the DM group. The expressions of retinal inflammatory factors VEGF, TNF-α, IL-1β and IL-6 in DM group all increased, while the expressions of the above-mentioned inflammatory factors in the retina of mice decreased in the low, medium and high concentrations group. Conclusion Zhicao Tea Mixture can decrease the blood glucose of DM mice and reduces the diabetic retinal inflammatory response. Key words: Diabetic retinopathy/physiopathology; Inflammation; Muller cells; Zhicao Tea Mixture

Dopamine and Early Retinal Dysfunction in Diabetes: Insights From a Phase 1 Study.

Diabetes is a rapidly growing chronic disease worldwide, and one of its common complications, diabetic retinopathy (DR), is a leading cause of blindness in middle-aged people (1). Classically, DR has been identified by its microvascular phenotype on fundus examination in the eye clinic, which includes microaneurysms, retinal nerve-fiber layer infarcts, intraretinal hemorrhages, retinal exudation, and abnormal blood vessel growth (2). However, insights from the ever-growing body of literature on this blinding retinal disease have shown that DR effects the entire neurovascular unit that encompasses the intimate relationships between the neurons, glia, and vasculature of the retina (2). To this end, studies have demonstrated retinal dysfunction and alterations in retinal structure prior to the detection of the above described vascular abnormalities (3–6). Furthermore, by time the microvascular complications of DR are apparent, impairment in visual function and vision loss is typically already present (7). Therefore, being able to reliably detect retinal deficits prior to observable vascular changes may identify a window where interventions can be administered to slow or halt DR and prevent irreversible visual loss. The electroretinogram (ERG) measures the electrical activity of the retina in response to a light stimulus. ERGs require trained personnel, dilation of the pupils, placement of electrodes on the cornea, and patient cooperation to limit eye movements, limiting its practicality as a screening test in retinal disorders. The ERG response that is recorded has many different components. Oscillatory potentials (OPs) are one of …

Associations of Arterial Stiffness With Cognitive Performance, and the Role of Microvascular Dysfunction: The Maastricht Study.

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, -0.018 SD [95% CI, -0.036 to -0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, -0.089 SD [95% CI, -0.124 to -0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction.

Homeostatic Plasticity Shapes the Retinal Response to Photoreceptor Degeneration.

Homeostatic plasticity stabilizes input and activity levels during neural development, but whether it can restore connectivity and preserve circuit function during neurodegeneration is unknown. Photoreceptor degeneration is the most common cause of blindness in the industrialized world. Visual deficits are dominated by cone loss, which progresses slowly, leaving a window during which rewiring of second-order neurons (i.e., bipolar cells) could preserve function. Here we establish a transgenic model to induce cone degeneration with precise control and analyze bipolar cell responses and their effects on vision through anatomical reconstructions, invivo electrophysiology, and behavioral assays. In young retinas, we find that three bipolar cell types precisely restore input synapse numbers when 50% of cones degenerate but one does not. Of the three bipolar cell types that rewire, two contact new cones within stable dendritic territories, whereas one expands its dendrite arbors to reach new partners. In mature retinas, only one of four bipolar cell types rewires homeostatically. This steep decline in homeostatic plasticity is accompanied by reduced light responses of bipolar cells and deficits in visual behaviors. By contrast, light responses and behavioral performance are preserved when cones degenerate in young mice. Our results reveal unexpected cell type specificity and a steep maturational decline of homeostatic plasticity. The effect of homeostatic plasticity on functional outcomes identify it as a promising therapeutic target for retinal and other neurodegenerative diseases.

Outcomes of 25-gauge vitrectomy with air tamponade for idiopathic macular hole repair surgery

AIM: To evaluate the anatomic and visual outcomes of 25-gauge vitrectomy combined with air tamponade for the treatment of idiopathic macular hole (IMH). METHODS: Thirty eyes of 27 patients with IMH were included in this prospective interventional study. All patients underwent 25-gauge pars plana vitrectomy (PPV) combined with phacoemulsification and air tamponade. Best corrected visual acuity [BCVA; logarithm of the minimum angle of resolution (logMAR)], perimetry and multifocal electroretinography (mfERG) were conducted before and after the operation. Anatomical changes were evaluated with optical coherence tomography (OCT). RESULTS: The macular holes closed successfully in 28 eyes after the primary vitrectomy. The mean BCVA improved from 0.72±0.22 logMAR preoperatively to 0.29±0.18 logMAR postoperatively (P&lt;0.001). In the visual field of central 10°, the average mean deviation (MD) decreased from -3.59±1.83 dB preoperatively to -2.51±1.36 dB postoperatively (P&lt;0.001) and the average pattern standard deviation (PSD) decreased from 1.86±0.68 dB preoperatively to 1.33±0.32 dB postoperatively (P=0.001). The retinal response densities of mfERG in the foveal and perifoveal area increased significantly, and implicit times of rings 4-6 prolonged significantly too (P&lt;0.05). The symptom duration and baseline N1 amplitude densities at ring 1 had a significant impact on postoperative BCVA (P&lt;0.001, P=0.001, respectively). CONCLUSION: The 25-gauge PPV and air tamponade with 1d prone positioning produced favorable anatomic and functional outcomes.

MAdCAM-1 mediates retinal neuron degeneration in experimental colitis through recruiting gut-homing CD4+ T cells.

Extra-intestinal manifestations (EIMs) of the eyes are found in IBD patients, but the underlying pathogenesis remains unknown. To investigate the pathogenesis of IBD-associated retinal dysfunction, chronic colitis was induced in mice by oral administration of dextran sodium sulfate (DSS). Electroretinography (ERG) was performed to evaluate retinal function. Retinal neuron degeneration was analyzed by immunohistochemistry. Colitic mice displayed aberrant amplitudes of ERG a-, b-wave and oscillatory potentials (OP). Importantly, we observed severe degeneration of bipolar and ganglion cells. In contrast, outer retinal neurons (mainly photoreceptor cells) are mildly affected by colitis. Moreover, retinal inflammatory responses were significantly upregulated during colitis, including microglia activation, lymphocyte infiltration and cytokine/chemokine production. Notably, mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was upregulated in retinal microvessels, especially the superficial and deep plexuses, and recruited gut-homing CD4+ T cells to be co-localized with bipolar and ganglion cells during colitis. Expectedly, in vivo depletion of CD4+ T cells or blockade of MAdCAM-1 greatly alleviated colitis-induced retinal inflammatory responses and neuron degeneration. Therefore, our data provide novel insight into the pathogenesis of IBD-associated retinal dysfunction, and targeted immune therapy directly against MAdCAM-1 might provide a novel approach in the management of eye EIM of IBD.

Inhibition of acetylcholinesterase attenuated retinal inflammation via suppressing NF-κB activation

Elevated inflammatory cytokines contribute to the pathogenesis of various retinal diseases such as diabetic retinopathy, retinal vasculitis and retinitis. However, the underlying mechanism of retinal inflammation remains largely unknown. Recent studies demonstrated that acetylcholinesterase (ACHE) is an inflammatory indicator in central neural system. This study was aimed to dissect the role of ACHE in retinal inflammation, and its mechanism of action. Retinal inflammation was induced by intravitreal injection of tumor necrosis factor-α (TNF-α) in heterozygous ACHE knockdown mice (ACHE+/-) and wild type mice (ACHE+/+). Donepezil, a well-known ACHE inhibitor, was administrated by daily gavage. Expression of ACHE and intercellular adherent molecule-1 (ICAM-1), infiltration of CD11b+ inflammatory cells, retinal leukostasis and vascular leakage was determined in both ACHE+/- and ACHE+/+ mice. ARPE-19 cells, a human retinal pigment epithelial cell line, were cultured for in vitro assay. Knockdown of ACHE was achieved by lipofectamine-mediated siRNA transfection and pharmaceutical suppression of ACHE was manipulated by donepezil. Cellular expression and distribution of ACHE, ICAM-1, and phosphorylation of NF-κB, IκB and IKKα/β were detected by western-blot analysis or immunocytochemistry. Retinal expression of ACHE was dramatically upregulated, in parallel with increased ICAM-1 expression, enhanced leukostasis and augmented CD11b+ inflammatory cell infiltration as well as vascular hyperpermeability in ACHE+/+ mice injected with TNF-α. However, TNF-α-injected ACHE+/- mice showed lower level of ICAM-1, less leukostasis and fewer infiltrated CD11b+ cells. Moreover, TNF-α-induced retinal vascular leakage was significantly reduced in ACHE+/- mice. Similarly, TNF-α-induced retinal inflammatory response were also attenuated by donepezil intervention. In addition, TNF-α treatment resulted in significant induction of ACHE, upregulation of ICAM-1 and nuclear translocation of NF-κB, phosphorylation of IκB and IKKα/β in ARPE-19 cells. However, inhibition of ACHE reduced TNF-α-induced phosphorylation of NF-κB, IκB and IKKα/β in ARPE-19 cells. The present study reveals a pivotal role of ACHE in retinal inflammation. Inhibition of ACHE attenuates retinal inflammation and retinal leakage likely through suppressing NF-κB signaling activation.

Effects of age on retinal macrophage responses to acute elevation of intraocular pressure

There is accumulating evidence that aging shifts the central nervous system milieu towards a proinflammatory state, with increased reactivity of microglia in the aging eye and brain having been implicated in the development of age-related neurodegenerative conditions. Indeed, alterations to microglial morphology and function have been recognized as a part of normal aging. Here, we sought to assess the effects of age on the retinal microglial and macrophage response to acute intraocular pressure (IOP) elevation. Further, we performed experiments whereby bone marrow from young or middle-aged mice was used to reconstitute the bone marrow of whole-body irradiated 12 month old mice. Bone marrow chimeric mice then underwent cannulation and IOP elevation 8 weeks after whole-body irradiation and bone marrow transplantation in order to determine whether the age of bone marrow alters the macrophage response to retinal injury. Our data show retinal macrophage reactivity and microglial morphological changes were enhanced in older mice when compared to younger mice in response to injury. When IOP elevation was performed after whole-body irradiation and bone marrow rescue, we noted subretinal macrophage accumulation and glial reactivity was reduced compared to non-irradiated mice that had also undergone IOP elevation. This effect was evident in both groups of chimeric mice that had received either young or middle-aged bone marrow, suggesting irradiation itself may alter the macrophage and glial response to injury rather than the age of bone marrow.

Challenging a Myth and Misconception: Red-Light Vision in Rats.

Simple SummaryLight substantially influences animal physiology and behavior. Thus, it is a prerequisite to house laboratory animals under optimal light conditions. Different species possess different sets of photoreceptors, resulting in differential perception of the visible-light spectrum. While humans are trichromats with red-, green- and blue-sensitive cones, rats and mice are dichromats possessing ultraviolet- and green-sensitive cones. This led to the common assumption that red light is invisible to rodents and therefore red lights are commonly used in husbandry and experiments to observe animals during their dark phase. The retinal sensitivity of rats to red light though has never been assessed under scotopic conditions (dark-adapted) even though this mimics the setting red observation lights are being used. We examined the sensitivity to far-red light of the dark- and light-adapted rat retina. Our study demonstrates that the rat retina responds to far-red light under both conditions with great sensitivity, indicating that rats are not red-light blind. This should be taken into consideration when using red light to keep the effects of light on the retina and physiology to a minimum and will improve animal well-being and lead to better quality data by decreasing the variable light.Due to the lack of L-cones in the rodent retina, it is generally assumed that red light is invisible to rodents. Thus, red lights and red filter foils are widely used in rodent husbandry and experimentation allowing researchers to observe animals in an environment that is thought to appear dark to the animals. To better understand red-light vision in rodents, we assessed retinal sensitivity of pigmented and albino rats to far-red light by electroretinogram. We examined the sensitivity to red light not only on the light- but also dark-adapted retina, as red observation lights in husbandry are used during the dark phase of the light cycle. Intriguingly, both rods and cones of pigmented as well as albino rats show a retinal response to red light, with a high sensitivity of the dark-adapted retina and large electroretinogram responses in the mesopic range. Our results challenge the misconception of rodents being red-light blind. Researchers and housing facilities should rethink the use of red observation lights at night.

High resolution optical coherence elastography of retina under prosthetic electrode

Quantitatively investigating the biomechanics of retina with a retinal prosthetic electrode, we explored the effects of the prosthetic electrode on the retina, and further supplemented data for a potential clinical trial. Biomechanical properties were assessed with a high resolution optical coherence tomography (OCT) based elastography (OCE) system. A shaker was used to initiate elastic waves and an OCT system was used to track axial displacement along with wave propagation. Rabbits received surgery to implant the retinal prosthetic electrode, and elastic wave speed was measured before and after implantation; anatomical B-mode images were also acquired. Spatial-temporal maps of each layer in retina with and without prosthetic electrodes were acquired. Elastic wave speed of nerve fiber to inner plexiform layer, inner nuclear to outer nuclear layer, retinal pigmented epithelium layer and choroid to sclera layer without prosthetic electrode were found to be 3.66±0.36, 5.33±0.07, 6.85±0.37, and 9.69±0.24 m/s, respectively. With prosthetic electrode, the elastic wave speed was found to be 4.09±0.26, 5.14±0.11, 6.88±0.70, and 9.99±0.73 m/s, respectively in each layer. Our results show that the elastic wave speed in each layer of retina is slightly faster with the retinal electrode, and further demonstrate that the retinal prosthetic electrode does not affect biomechanical properties significantly. In the future, we expect OCE technology to be used by clinicians where it could become part of routine testing and evaluation of the biomechanical properties of the retina in response to long term use of prosthetic electrodes in patients.

Targeting Neurovascular Interaction in Retinal Disorders.

The tightly structured neural retina has a unique vascular network comprised of three interconnected plexuses in the inner retina (and choroid for outer retina), which provide oxygen and nutrients to neurons to maintain normal function. Clinical and experimental evidence suggests that neuronal metabolic needs control both normal retinal vascular development and pathological aberrant vascular growth. Particularly, photoreceptors, with the highest density of mitochondria in the body, regulate retinal vascular development by modulating angiogenic and inflammatory factors. Photoreceptor metabolic dysfunction, oxidative stress, and inflammation may cause adaptive but ultimately pathological retinal vascular responses, leading to blindness. Here we focus on the factors involved in neurovascular interactions, which are potential therapeutic targets to decrease energy demand and/or to increase energy production for neovascular retinal disorders.

Ring analysis of multifocal oscillatory potentials (mfOPs) in cCSNB suggests near-normal ON-OFF pathways at the fovea only.

To investigate the center-periphery distribution of ON and OFF retinal responses in complete congenital stationary night blindness (cCSNB). Photopic full-field flash ERGs (photopic ffERGs) and OPs (photopic ffOPs) and slow m-sequence (to enhance OP prominence) mfERGs (and filtered mfOPs) evoked by a 37 hexagon stimulus array were recorded from normal subjects and cCSNB patients. Discrete wavelet transform (DWT) analysis of photopic ffERGs and mfERGs was also performed in order to assess the contribution of the ON and OFF retinal pathways (i.e., OFF-to-ON ratio) in both cohorts. As expected, the photopic ffERG (and ffOPs) responses in cCSNB were devoid of the first two of the three OPs (i.e., OP2 and OP3 and OP4) normally seen on the ascending limb of the b-wave. A similar finding was also noted in the mfERGs (and mfOPs) of ring 4. In contrast, the mfERGs (and mfOPs) of ring 1 included all three OPs. DWT analysis revealed that while in normal subjects, the OFF-to-ON ratio of mfERGs slightly increased from rings 1 to 4 (from 0.61 ± 0.03 to 0.78 ± 0.04; p < 0.05; median: from 0.62 to 0.79; p < 0.05), in cCSNB this ratio increased significantly more [from 0.73 ± 0.13 (ring 1) to 1.18 ± 0.17 (ring 4); p < 0.05; median: 0.78 to 1.22; p < 0.05], hence from a normal ON-dominated ratio (central ring) to an OFF-dominated ratio (peripheral ring). Our results show a clear discrepancy of ON and OFF mfOP components in cCSNB. Responses originating from the most central ring (i.e., ring 1) disclosed a near-normal electrophysiological contribution (as revealed with the presence of OP2, OP3 and OP4 as well as with the DWT OFF-to-ON ratio) of the retinal ON and OFF pathways in mfERG (and mfOPs) responses compared to responses from the more peripheral ring (and ffOP) which are devoid of the ON OPs (i.e., OP2 and OP3).

Integrin CD11b Deficiency Aggravates Retinal Microglial Activation and RGCs Degeneration After Acute Optic Nerve Injury.

Neuroinflammation plays a vital role in the process of a variety of retinal ganglion cells (RGCs) degenerative diseases including traumatic optic neuropathy (TON). Retinal microglial activation is believed as a harbinger of TON, and robust microglial activation can aggravate trauma-induced RGCs degeneration, which ultimately leads to RGCs loss. Toll like receptor 4 (TLR4)-triggered inflammation is of great importance in retinal inflammatory response after optic nerve injury. CD11b on macrophage and brain microglia can inhibit TLR4-triggered inflammation. However, the functional role of CD11b in retinal microglia is not well understood. Here, using an optic nerve crush model and CD11b gene deficient mice, we found that CD11b protein expression was mainly on retinal microglia, significantly increased after optic nerve injury, and still maintained at a high level till at least 28days post crush. Compared with wild type mice, following acute optic nerve injury, CD11b deficient retinae exhibited more exacerbated microglial activation, accelerated RGCs degeneration, less growth associated protein-43 expression, as well as more proinflammatory cytokines such as interleukin-6 and tumor necrosis factor α while less anti-inflammatory factors such as arginase-1 and interleukin-10 production. We conclude that CD11b is essential in regulating retinal microglial activation and neuroinflammatory responses after acute optic nerve injury, which is critical for subsequent RGCs degeneration and loss.

Nonlinear retinal response modeling for future neuromorphic instrumentation

The development of a bio-inspired image sensor that can match the functionality of the vertebrate retina in terms of image resolution, power dissipation and dynamic resolution demands an extremely challenging standard in terms of efficiency and performance [1]–[4]. At present, functional biological image processing possesses extremely high temporal resolution by asynchronously optimizing the sampling rate of a scene but suffers from low spatial resolution, noise, and an inability to process low frequency content [5]. Regardless, the use of dynamic vision sensors that emulate biological retina behaviors are important in performing classification tasks using high-speed motion detection at low-power requirements [6]–[9]. The difficulty in pushing image sensor performance to meet the specifications of the retina lies in the biological complexities of the underlying neural networks. Therefore, a prerequisite for hardware mapping of biological vision systems is understanding the bioprocessing between various retina cells. Here, we present a biologically plausible cellular network retina simulator, where light stimuli are accepted at the front-end array of photoreceptor cells, and pass through a system of nonlinear integral equations derived from experimental voltage- and current-clamp data used to calculate the response of each sequential retina cell. It was shown in [10], [11] that integrating the system improves performance when compared with conventional numerical solvers. We expect that by placing our simulator in the hands of interdisciplinary researchers, especially computational neuroscientists, mathematical scientists and machine learning practitioners, it will foster the development of more efficient representations of visual inputs in deep learning applications.

Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity.

Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation. A2 deletion also has been shown to be protective against retinal inflammation in models of ischemic retinopathy and multiple sclerosis. We investigated the effect of A2 deletion on western diet-induced retinopathy. Wild-type mice fed a high-fat, high-sucrose western diet for 16 weeks exhibited elevated retinal expression of A2, markers of the inflammasome pathway, oxidative stress, and activation of microglia/macrophages. Western diet feeding induced exaggerated retinal light responses without affecting visual acuity or retinal morphology. These effects were reduced or absent in mice with global A2 deletion. Exposure of retinal endothelial cells to palmitate and high glucose, a mimic of the obese state, increased expression of A2 and inflammatory mediators and induced cell death. These effects, except for A2, were prevented by pretreatment with an arginase inhibitor. Collectively, our study demonstrated a substantial role of A2 in early manifestations of diabetic retinopathy.

Retinal neurovascular responses to transcorneal electrical stimulation measured with optical coherence tomography.

Noninvasive transcorneal electrical stimulation (TES) has emerged as a potential strategy to facilitate visual restoration and promote retinal cell survival for certain retinal and optic nerve diseases owing to its neuroprotective effects. However, the neurovascular responses of retinal neurons evoked by TES have not been completely determined. To investigate this issue, we utilized a custom-designed spectral-domain optical coherence tomography (SD-OCT) to record the retinal neural and vascular responses under TES in vivo simultaneously. Significant increases of both positive and negative intrinsic optical signal (IOS) changes were recorded in all three segmented retinal layers, which mainly related to neural activities. However, the changes of TES-induced retinal vascular responses, including blood velocity, cross-sectional area of vessel, and blood flow, were not significant. It suggests that TES mainly elicited neural responses in retina, while no significant vascular responses were evoked. Our results provide experimental evidence to the mechanism of retinal neurovascular coupling under TES. Additionally, the present study also suggests that SD-OCT could be utilized as a promoting method to explore neurovascular responses under retinal stimulation in clinical treatment and technology. Impact statement Noninvasive transcorneal electrical stimulation (TES) has emerged as an effective treatment for certain retinal and optic nerve diseases owing to its neuroprotective effects. However, the retinal neurovascular responses evoked by TES have not been completely determined. To investigate this issue, we utilized a custom-designed spectral-domain optical coherence tomography (SD-OCT) to record the retinal neural and vascular responses evoked by TES in vivo simultaneously. The present study suggested that TES mainly elicited neural responses in retina, while no significant vascular responses were evoked. Our results provide experimental evidence to the mechanism of retinal neurovascular coupling evoked by TES. Additionally, the present study also suggests that SD-OCT could be utilized as a promoting method to explore neurovascular responses under retinal electrical stimulation.

Luo Tong formula attenuates retinal inflammation in diabetic rats via inhibition of the p38MAPK/NF-\u03baB pathway

BackgroundDiabetic retinopathy (DR) is a serious microvascular complication of diabetes and remains the leading cause of blindness in adults. Retinal inflammation is playing a crucial role in the development of DR, and targeting inflammatory mediators is a promising strategy for controlling DR. Here, we investigated compound Chinese medicine Luo Tong formula (LTF) alleviated retinal inflammatory responses in a STZ-induced diabetic rat model.MethodsSprague–Dawley rats were divided into four groups: control, streptozotocin-induced diabetic, LTF-treated diabetic, and calcium dobesilate (CaD)-treated diabetic rats. Blood samples were collected for blood glucose examination. Hematoxylin–eosin and periodic acid-Schiff staining were conducted for light microscopy observations. Retinal cell apoptosis was detected using the TUNEL assay. Proteins expression was quantified by Western blotting and/or immunohistochemistry, and gene expression was assessed by real-time PCR.ResultsDiabetic rats showed significant increases in the expression of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), nuclear factor-κB (NF-κB), and the phospho-p38 mitogen-activated protein kinase (p-p38-MAPK)/p38 MAPK ratio compared to control rats. LTF treatment significantly improved both retinal and pancreatic pathological injury, LTF treatment also inhibited inducible the p-p38 MAPK/p38 MAPK ratio and NF-κB activation and decreased the subsequent induction of the retinal expression of proinflammatory mediators TNF-α, IL-1β, MCP-1 and ICAM-1 compared to diabetic rats. LTF also exhibited a protective effect on islet function.ConclusionsLTF before the onset of DR can alleviate retinal pathological injury, LTF may play an anti-inflammatory role by inhibiting p38-MAPK and then inhibiting NF-κB pathway. But further studies are needed to confirm this conclusion.Trial registration This is an animal experiment, trial registration is not necessary.

A multifocal electroretinography study to evaluate risk of developing macular hole in the fellow eye of patients suffering with unilateral macular hole.

Background:Visual outcome of eyes has often been found to be unsatisfactory even after successful closure of a macular hole, owing to factors like persistent metamorphopsia, scotoma, and reduced sensitivity. Therefore, it becomes critical to evaluate and study the probability and risk of developing a macular hole in the fellow eyes of the patient. This study analyzed the multifocal electroretinographic responses to help predict the risk of macular hole development in fellow eyes.Methods:In total 26 fellow eyes, 26 eyes with macular hole, and 50 eyes of 25 controls were enrolled prospectively. The retinal responses from the different rings were compared in the three groups. Optical coherence tomography was done to rule out macular pathology or vitreomacular traction in the fellow eyes.Results:All the fellow eyes under observation showed significantly reduced mean amplitudes of retinal response densities, in all rings as compared with controls (31.45 ± 10.38 versus 48.87 ± 7.55, p = 0.00). Three of the fellow eyes developed a macular hole during the 24 months observation period. The prevalence of fellow eye involvement was 11.5%. Relative risk of developing macular hole in the fellow eye ranged from 25 to 75.Conclusion:All the fellow eyes, including those that did not develop a macular hole, showed significantly reduced responses on multifocal electroretinogram. This indicates that macular hole may not be a focal disease. It may have widespread functional deficit which is bilateral in nature and suggestive of a degenerative or ischemic insult.