Retinal Signals Research Articles

Normalization of Retinal Birefringence Scanning Signals.

Signal amplitudes obtained from retinal scanning depend on numerous factors. Working with polarized light to interrogate the retina, large parts of which are birefringent, is even more prone to artifacts. This article demonstrates the necessity of using normalization when working with retinal birefringence scanning signals in polarization-sensitive ophthalmic instruments. After discussing the pros and cons of employing a normalization signal obtained by means of added optoelectronic hardware, the study shifts over and focuses on a numerical normalization method based on merely the s- and p-polarization components without additional optical or electronic hardware. This minimizes the adverse effects of optical asymmetries, the presence of certain instrumental noise, device-to-device variability, pupil diameter, retinal reflectivity, subject-to-subject variations, the position of the eye in the exit pupil of the device, and even signal degradation by cataracts. Results were experimentally and numerically tested on human data from 15 test subjects and clearly demonstrated the signal standardization achieved by numerical normalization. This is expected to lead to substantial improvement in algorithms and decision-making software, especially in ophthalmic screening instruments for pediatric applications, without added hardware cost. The proposed normalization method is also applicable to other polarization-sensitive optical instruments.

Corrigendum to “Football-related concussions and head impacts are associated with changes in retinal structure and signaling” [Biomark. Neuropsychiatry 10 (2024) 100091

Corrigendum to “Football-related concussions and head impacts are associated with changes in retinal structure and signaling” [Biomark. Neuropsychiatry 10 (2024) 100091

Interplay Between Ocular Ischemia and Glaucoma: An Update.

Glaucoma is a main cause of irreversible blindness worldwide, with a high impact on productivity and quality of life. The mechanical and ischemic theories are currently the most recognized pathophysiological pathways that explain the neurodegeneration of retinal nerve fibers in glaucoma. In this narrative review, aspects of ischemia in glaucoma are discussed, including vascular dysregulation, retinal ischemia signaling pathways, roles of vascular endothelial growth factors, and future research and therapeutic directions. In conclusion, a better understanding of the ischemic processes in glaucoma may lead to innovative treatment options and improved management and follow-up of our patients.

Crosstalk between MIR-96 and IRS/PI3K/AKT/VEGF cascade in hRPE cells; A potential target for preventing diabetic retinopathy.

Regulation of visual system function demands precise gene regulation. Dysregulation of miRNAs, as key regulators of gene expression in retinal cells, contributes to different eye disorders such as diabetic retinopathy (DR), macular edema, and glaucoma. MIR-96, a member of the MIR-183 cluster family, is widely expressed in the retina, and its alteration is associated with neovascular eye diseases. MIR-96 regulates protein cascades in inflammatory and insulin signaling pathways, but further investigation is required to understand its potential effects on related genes. For this purpose, we identified a series of key target genes for MIR-96 based on gene and protein interaction networks and utilized text-mining resources. To examine the MIR-96 impact on candidate gene expression, we overexpressed MIR-96 via adeno-associated virus (AAV)-based plasmids in human retinal pigment epithelial (RPE) cells. Based on Real-Time PCR results, the relative expression of the selected genes responded differently to overexpressed MIR-96. While the expression levels of IRS2, FOXO1, and ERK2 (MAPK1) were significantly decreased, the SERPINF1 gene exhibited high expression simultaneously. pAAV-delivered MIR-96 had no adverse effect on the viability of human RPE cells. The data showed that changes in insulin receptor substrate-2 (IRS2) expression play a role in disrupted retinal insulin signaling and contribute to the development of diabetic complications. Considered collectively, our findings suggest that altered MIR-96 and its impact on IRS/PI3K/AKT/VEGF axis regulation contribute to DR progression. Therefore, further investigation of the IRS/PI3K/AKT/VEGF axis is recommended as a potential target for DR treatment.

Role of Elavl-like RNA-binding protein in retinal development and signal transduction.

RNA-binding proteins (RBPs) play central roles in post-transcriptional gene regulation. However, the function of RBP in retinal progenitor cell differentiation and synaptic signal transmission are largely unexplored. Previously we have shown that Elavl2 regulates amacrine cell (AC) differentiation during retinogenesis, by directly binding to Nr4a2 and Barhl2. Elavl2 is expressed in early neuronal progenitors to mature neurons, and Elavl4 expression begins slightly later, during cortical neuron development as a paralog. Here, Retinal-specific Elavl2 and Elavl4 double knockout mice were made to further explore the role of Elavl2 and Elavl4 in retinal development and signal transduction. We disclose that Elavl4 binds to Satb1 to regulate Neurod1, then promoting retinal progenitor and amacrine cells differentiation. We were also surprised to find that Elavl2 interacted with GABAB receptors at the RNA and protein levels. In conclusion, Elavl2 and Elavl4 regulate amacrine cells differentiation through different pathways, leading to decreased scotopic vision. Our findings reveal the roles of Elavl2 and Elavl4 in retinal amacrine cells differentiation in modulating visual functions.

Fixational eye movements enhance the precision of visual information transmitted by the primate retina

Fixational eye movements alter the number and timing of spikes transmitted from the retina to the brain, but whether these changes enhance or degrade the retinal signal is unclear. To quantify this, we developed a Bayesian method for reconstructing natural images from the recorded spikes of hundreds of retinal ganglion cells (RGCs) in the macaque retina (male), combining a likelihood model for RGC light responses with the natural image prior implicitly embedded in an artificial neural network optimized for denoising. The method matched or surpassed the performance of previous reconstruction algorithms, and provides an interpretable framework for characterizing the retinal signal. Reconstructions were improved with artificial stimulus jitter that emulated fixational eye movements, even when the eye movement trajectory was assumed to be unknown and had to be inferred from retinal spikes. Reconstructions were degraded by small artificial perturbations of spike times, revealing more precise temporal encoding than suggested by previous studies. Finally, reconstructions were substantially degraded when derived from a model that ignored cell-to-cell interactions, indicating the importance of stimulus-evoked correlations. Thus, fixational eye movements enhance the precision of the retinal representation.

Efficacy of orthokeratology lens with the modified small treatment zone on myopia progression and visual quality: a randomized clinical trial

BackgroundTo evaluate the long-term effectiveness of orthokeratology (ortho-K) lenses with small treatment zone (STZ) or conventional treatment zone (CTZ) in controlling axial elongation in children with myopia as well as the impact on visual quality. We also sought to determine the effect of retinal visual signal quality on axial elongation.MethodsThis is a prospective randomized controlled study. A total of 140 participants (age ranging from 8 to 12 years) were randomly assigned to wear either STZ or CTZ ortho-K lenses. STZ ortho-K lenses design was achieved by changing the depth of reverse zone and the sagitta height of the optical zone. Using the IOL-Master 500, axial length (AL) was measured at baseline and after 6, 12 and 18 months of ortho-K treatment. Spherical aberration (SA) and corneal topographic parameters were obtained by the Pentacam anterior segment analyzer at baseline and the 1-month follow-up visit, and optical qualities were assessed by optical quality analysis system-II (OQAS-II) at baseline and after 1 month of lens wearing. Optical quality parameters mainly included the modulation transfer function (MTF) cutoff, Strehl ratio (SR), objective scattering index (OSI), and predicted visual acuity (PVA).ResultsA total of 131 participants completed the study, including 68 in the STZ group and 63 in the CTZ group. The STZ group had significantly reduced AL elongation compared to the CTZ group after treatment (12 months: 0.07 ± 0.11 mm vs. 0.14 ± 0.12 mm, P = 0.002; 18 months: 0.17 ± 0.15 mm vs. 0.26 ± 0.16 mm, P = 0.002). The topography in the STZ group showed a smaller treatment zone (TZ) diameter (2.50 ± 0.23 mm vs. 2.77 ± 0.18 mm, P < 0.001), a wider defocus ring width (2.45 ± 0.28 mm vs. 2.30 ± 0.30 mm, P = 0.006), and larger values of total amount of defocus (119.38 ± 63.71 D·mm2 vs. 91.40 ± 40.83 D·mm2, P = 0.003) and total SA (0.37 ± 0.25 μm vs. 0.25 ± 0.29 μm, P = 0.015), compared with the CTZ group. Objective visual quality decreased in both groups (P < 0.001). This was evidenced by a greater decrease in MTF cutoff (− 14.24 ± 10.48 vs. − 10.74 ± 9.46, P = 0.047) and SR values (− 0.09 ± 0.07 vs. − 0.06 ± 0.07, P = 0.026), and an increase in OSI value (0.84 ± 0.72 vs. 0.58 ± 0.53, P = 0.019). PVA9% decreased significantly in the STZ group but not the CTZ group. A statistically significant negative correlation was found between the changes in total SA and MTF cutoff values (r = − 0.202, P = 0.025). AL changes were associated with sex, change of MTF cutoff value, increment of total SA and TZ area.ConclusionsCompared with CTZ ortho-K lenses, STZ ortho-K lenses significantly inhibited axial elongation in children with myopia while moderately reducing their objective visual quality. Axial elongation was affected by retinal visual quality, and it may be a possible mechanism for ortho-K slowing myopia progression.Trial registration This trial is registered at Chinese Clinical Trial Registry on November 5, 2019 with trial registration number: ChiCTR1900027218. https://www.chictr.org.cn/showproj.html?proj=45380

Dystroglycan-HSPG interactions provide synaptic plasticity and specificity.

This study examined the roles of the laminin and proteoglycan receptor dystroglycan (DG) in extracellular matrix stabilization and cellular mechanosensory processes conveyed through communication between the extracellular matrix (ECM) and cytoskeleton facilitated by DG. Specific functional attributes of HS-proteoglycans (HSPGs) are conveyed through interactions with DG and provide synaptic specificity through diverse interactions with an extensive range of cell attachment and adaptor proteins which convey synaptic plasticity. HSPG-DG interactions are important in phototransduction and neurotransduction and facilitate retinal bipolar-photoreceptor neuronal signaling in vision. Besides synaptic stabilization, HSPG-DG interactions also stabilize basement membranes and the ECM and have specific roles in the assembly and function of the neuromuscular junction. This provides neuromuscular control of muscle systems that control conscious body movement as well as essential autonomic control of diaphragm, intercostal and abdominal muscles and muscle systems in the face, mouth and pharynx which assist in breathing processes. DG is thus a multifunctional cell regulatory glycoprotein receptor and regulates a diverse range of biological and physiological processes throughout the human body. The unique glycosylation of the αDG domain is responsible for its diverse interactions with ECM components in cell-ECM signaling. Cytoskeletal cell regulatory switches assembled by the βDG domain in its role as a nuclear scaffolding protein respond to such ECM cues to regulate cellular behavior and tissue homeostasis thus DG has fascinating and diverse roles in health and disease.

Altered Functional Responses of the Retina in B6 Albino Tyrc/c Mice.

Mammals with albinism present low visual discrimination ability and different proportions of certain retinal cell subtypes. As the spatial resolution of the retina depends on the visual field sampling by retinal ganglion cells (RGCs) based on the convergence of upstream cell inputs, it could be affected in albinism and thus modify the RGC function. We used the Tyrc/c line, a mouse model of oculocutaneous albinism type 1 (OCA1), carrying a tyrosinase mutation, and previously characterized by a total absence of pigment and severe visual deficits. To assess their retinal function, we recorded the light responses of hundreds of RGCs ex vivo using multi-electrode array (MEA). We estimated the receptive field (RF)-center diameter of Tyr+/c and Tyrc/c RGCs using a checkerboard stimulation before simultaneously stimulating the center and surround of RGC RFs with full-field flashes. Following checkerboard stimulation, the RF-center diameters of RGCs were indistinguishable between Tyrc/c and Tyr+/c retinas. Nevertheless, RGCs from Tyrc/c retinas presented more OFF responses to full-field flashes than RGCs from Tyr+/c retinas. Unlike Tyr+/c retinas, very few OFF-center RGCs switched polarity to ON or ON-OFF responses after full-field flashes in Tyrc/c retinas, suggesting a different surround suppression in these retinas. The retinal output signal is affected in Tyrc/c retinas, despite intact RF-center diameters of their RGCs. Adaptive mechanisms during development are probably responsible for this change in RGC responses, related to the absence of ocular pigments.

Fixational Eye Movements Enhance the Precision of Visual Information Transmitted by the Primate Retina.

Fixational eye movements alter the number and timing of spikes transmitted from the retina to the brain, but whether these changes enhance or degrade the retinal signal is unclear. To quantify this, we developed a Bayesian method for reconstructing natural images from the recorded spikes of hundreds of retinal ganglion cells (RGCs) in the macaque retina (male), combining a likelihood model for RGC light responses with the natural image prior implicitly embedded in an artificial neural network optimized for denoising. The method matched or surpassed the performance of previous reconstruction algorithms, and provides an interpretable framework for characterizing the retinal signal. Reconstructions were improved with artificial stimulus jitter that emulated fixational eye movements, even when the eye movement trajectory was assumed to be unknown and had to be inferred from retinal spikes. Reconstructions were degraded by small artificial perturbations of spike times, revealing more precise temporal encoding than suggested by previous studies. Finally, reconstructions were substantially degraded when derived from a model that ignored cell-to-cell interactions, indicating the importance of stimulus-evoked correlations. Thus, fixational eye movements enhance the precision of the retinal representation.

Retinal Input Is Required for the Maintenance of Neuronal Laminae in the Ventrolateral Geniculate Nucleus.

Retinal ganglion cell (RGC) axons provide direct input into several brain regions, including the dorsal lateral geniculate nucleus (dLGN), which is important for image-forming vision, and the ventrolateral geniculate nucleus (vLGN), which is associated with nonimage-forming vision. Through both activity- and morphogen-dependent mechanisms, retinal inputs play important roles in the development of dLGN, including the refinement of retinal projections, morphological development of thalamocortical relay cells (TRCs), timing of corticogeniculate innervation, and recruitment and distribution of inhibitory interneurons. In contrast, little is known about the role of retinal inputs in the development of vLGN. Grossly, vLGN is divided into two domains, the retinorecipient external vLGN (vLGNe) and nonretinorecipient internal vLGN (vLGNi). Studies previously found that vLGNe consists of transcriptionally distinct GABAergic subtypes distributed into at least four adjacent laminae. At present, it remains unclear whether retinal inputs influence the development of these cell-type-specific neuronal laminae in vLGNe. Here, we elucidated the developmental timeline for these laminae in the mouse vLGNe, and results indicate that these laminae are specified at or before birth. We observed that mutant mice without retinal inputs have a normal laminar distribution of GABAergic cells at birth; however, after the first week of postnatal development, these mutants exhibited a dramatic disruption in the laminar organization of inhibitory neurons and clear boundaries between vLGNe and vLGNi. Overall, our results show that while the formation of cell-type-specific layers in mouse vLGNe does not depend on RGC inputs, retinal signals are critical for their maintenance.

Melanopsin in the human and chicken choroid

The choroid embedded in between retina and sclera is essential for retinal photoreceptor nourishment, but is also a source of growth factors in the process of emmetropization that converts retinal visual signals into scleral growth signals. Still, the exact control mechanisms behind those functions are enigmatic while circadian rhythms are involved. These rhythms are attributed to daylight influences that are melanopsin (OPN4) driven. Recently, OPN4-mRNA has been detected in the choroid, and while its origin is unknown we here seek to identify the underlying structures using morphological methods.Human and chicken choroids were prepared for single- and double-immunohistochemistry of OPN4, vasoactive intestinal peptide (VIP), substance P (SP), CD68, and α-smooth muscle actin (ASMA). For documentation, light-, fluorescence-, and confocal laser scanning microscopy was applied. Retinal controls proved the reliability of the OPN4 antibody in both species.In humans, OPN4 immunoreactivity (OPN4-IR) was detected in nerve fibers of the choroid and adjacent ciliary nerve fibers. OPN4+ choroidal nerve fibers lacked VIP, but were co-localized with SP. OPN4-immunoreactivity was further detected in VIP+/SP + intrinsic choroidal neurons, in a hitherto unclassified CD68-negative choroidal cell population thus not representing macrophages, as well as in a subset of choroidal melanocytes. In chicken, choroidal nerve fibers were OPN4+, and further OPN4-IR was detected in clustered suprachoroidal structures that were not co-localized with ASMA and therefore do not represent non-vascular smooth-muscle cells. In the choroidal stroma, numerous cells displayed OPN4-IR, the majority of which was VIP-, while a few of those co-localized with VIP and were therefore classified as avian intrinsic choroidal neurons. OPN4-immunoreactivity was absent in choroidal blood vessels of both species.In summary, OPN4-IR was detected in both species in nerve fibers and cells, some of which could be identified (ICN, melanocytes in human), while others could not be classified yet. Nevertheless, the OPN4+ structures described here might be involved in developmental, light-, thermally-driven or nociceptive mechanisms, as known from other systems, but with respect to choroidal control this needs to be proven in upcoming studies.

To Assess The Retinal Nerve Fibre Layer (RNFL) Thickness And Signal Strength Before And After Phacoemulsification Cataract Surgery

To Assess The Retinal Nerve Fibre Layer (RNFL) Thickness And Signal Strength Before And After Phacoemulsification Cataract Surgery

Visual imagery vividness correlates with afterimage conscious perception.

Afterimages are illusory, visual conscious perceptions. A widely accepted theory is that afterimages are caused by retinal signaling that continues after the physical disappearance of a light stimulus. However, afterimages have been reported without preceding visual, sensory stimulation (e.g. conditioned afterimages and afterimages induced by illusory vision). These observations suggest the role of top-down brain mechanisms in afterimage conscious perception. Therefore, some afterimages may share perceptual features with sensory-independent conscious perceptions (e.g. imagery, hallucinations, and dreams) that occur without bottom-up sensory input. In the current investigation, we tested for a link between the vividness of visual imagery and afterimage conscious perception. Participants reported their vividness of visual imagery and perceived sharpness, contrast, and duration of negative afterimages. The afterimage perceptual features were acquired using perception matching paradigms that were validated on image stimuli. Relating these perceptual reports revealed that the vividness of visual imagery positively correlated with afterimage contrast and sharpness. These behavioral results support shared neural mechanisms between visual imagery and afterimages. However, we cannot exclude alternative explanations, including demand characteristics and afterimage perception reporting inaccuracy. This study encourages future research combining neurophysiology recording methods and afterimage paradigms to directly examine the neural mechanisms of afterimage conscious perception.

A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy

Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-3399-270 could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3′-mRNA sequencing and signaling studies indicated that IL-3399-270 and IL-33109-270 were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-3399–270 and IL-33109–270, significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33–/– mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies.

Impaired dopamine signaling in early diabetic retina: Insights from D1R and D4R agonist effects on whole retina responses

The retina has low dopamine levels early in diabetes. To determine how low dopamine levels affected dopamine signaling, the effects of dopamine receptor agonists and mRNA localization were measured after 6 weeks of diabetes. Whole retina ex vivo electroretinogram (ERG) recordings were used to analyze how dopamine type 1 receptor (D1R) and type 4 (D4R) agonists change the light-evoked retinal responses of non-diabetic and 6-week diabetic (STZ injected) mouse retinas. Fluorescence in situ hybridization was utilized to analyze D4R and D1R mRNA locations and expression levels. D4R activation reduced A- and B-wave ERG amplitudes and increased B-wave implicit time and rise-time in the non-diabetic group without a corresponding change in the diabetic group. D1R activation increased B-wave rise-time and oscillatory potential peak time in the non-diabetic group also with no change in the diabetic group. The lack of responsivity to D1R or D4R agonists shows an impairment of dopamine signaling in the diabetic retina. D4R mRNA was found primarily in the outer nuclear layer where photoreceptor cell bodies reside. D1R mRNA was found in the inner nuclear layer and ganglion cell layer that contain bipolar, amacrine, horizontal and ganglion cells. There was no change in D4R or D1R mRNA expression between the non-diabetic and diabetic retinas. This suggests that the significant dopamine signaling changes observed were not from lower receptor expression levels but could be due to changes in dopamine receptor activity or protein levels. These studies show that changes in retinal dopamine signaling could be an important mechanism of diabetic retinal dysfunction.

Polarization-resolved analysis of outer retinal bands: investigating ballistic and multiply scattered photons using full-field swept-source optical coherence tomography.

Precise interpretation of the anatomical origins of outer retinal optical coherence tomography (OCT) presents technical challenges owing to the delicate nature of the retina. To address this challenge, our study introduces a novel polarization-sensitive full-field swept-source OCT (FF-SS-OCT) that provides parallel-polarization and cross-polarization OCT measurements, predominantly capturing ballistically reflected photons and multiply scattered photons, respectively. Notably, parallel-polarization OCT unveils layer-like structures more effectively, including the inner plexiform layer (IPL) sub-layers, outer plexiform layer (OPL) sub-layers (in rod-dominant regions), and rod/cone outer segment (OS) tips, compared to cross-polarization OCT, where such sub-layers are not visible. Through a comparative analysis of parallel-polarization and cross-polarization OCT images of the outer retina, we discovered that the 2nd outer retinal OCT band results from contributions from both the ellipsoid zone (EZ) and the inner segment/outer segment (IS/OS) junction. Similarly, the 3rd outer retinal OCT band appears to reflect contributions from both the interdigitation zone (IZ) and photoreceptor OS tips. This polarization-sensitive approach advances our understanding of the origins of outer retinal OCT signals and proposes potential new biomarkers for assessing retinal health and diseases.

The effects of time restricted feeding on age-related changes in the mouse retina

Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of intermittent fasting, the amount of time for food intake is regulated without restricting the caloric intake. TRF is beneficial for the central nervous system to support brain health in the context of aging. Therefore, we here ask whether TRF also exerts beneficial effects in the aged retina. We compared aged mice (24 months) on a TRF paradigm (access to food for six hours per day) for either 6 or 12 months against young control mice (8 months) and aged control mice on an ad libitum diet. We examined changes in the retina at the functional (electroretinography), structural (histology and fluorescein angiograms) and molecular (gene expression) level. TRF treatment showed amelioration of age-related reductions in both scotopic and photopic b-wave amplitudes suggesting benefits for retinal interneuron signaling. TRF did not affect age-related signs of retinal inflammation or microglial activation at either the molecular or histological level. Our data indicate that TRF helps preserve some aspects of retinal function that are decreased with aging, adding to our understanding of the health benefits that altered feeding patterns may confer.

Electrophysiological Analysis of Retinal Organoid Development Using 3D Microelectrodes of Liquid Metals.

Despite of the substantial potential of human-derived retinal organoids, the degeneration of retinal ganglion cells (RGCs) during maturation limits their utility in assessing the functionality of later-born retinal cell subtypes. Additionally, conventional analyses primarily rely on fluorescent emissions, which limits the detection of actual cell functionality while risking damage to the 3D cytoarchitecture of organoids. Here, an electrophysiological analysis is presented to monitor RGC development in early to mid-stage retinal organoids, and compare distinct features with fully-mature mouse retina. This approach utilizes high-resolution 3D printing of liquid-metal microelectrodes, enabling precise targeting of specific inner retinal layers within organoids. The adaptable distribution and softness of these microelectrodes facilitate the spatiotemporal recording of inner retinal signals. This study not only demonstrates the functional properties of RGCs in retinal organoid development but also provides insights into their synaptic connectivity, reminiscent of fetal native retinas. Further comparison with fully-mature mouse retina in vivo verifies the organoid features, highlighting the potential of early-stage retinal organoids in biomedical research.

Dopamine enhances GABAA receptor-mediated current amplitude in a subset of intrinsically photosensitive retinal ganglion cells.

Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions.NEW & NOTEWORTHY Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions.