Population Of Retinal Ganglion Cells Research Articles

How We See Black and White: The Role of Midget Ganglion Cells.

According to classical opponent color theory, hue sensations are mediated by spectrally opponent neurons that are excited by some wavelengths of light and inhibited by others, while black-and-white sensations are mediated by spectrally non-opponent neurons that respond with the same sign to all wavelengths. However, careful consideration of the morphology and physiology of spectrally opponent L vs. M midget retinal ganglion cells (RGCs) in the primate retina indicates that they are ideally suited to mediate black-and-white sensations and poorly suited to mediate color. Here we present a computational model that demonstrates how the cortex could use unsupervised learning to efficiently separate the signals from L vs. M midget RGCs into distinct signals for black and white based only correlation of activity over time. The model also reveals why it is unlikely that these same ganglion cells could simultaneously mediate our perception of red and green, and shows how, in theory, a separate small population of midget RGCs with input from S, M, and L cones would be ideally suited to mediating hue perception.

Artificial Visual Information Produced by Retinal Prostheses.

Numerous retinal prosthetic systems have demonstrated somewhat useful vision can be restored to individuals who had lost their sight due to outer retinal degenerative diseases. Earlier prosthetic studies have mostly focused on the confinement of electrical stimulation for improved spatial resolution and/or the biased stimulation of specific retinal ganglion cell (RGC) types for selective activation of retinal ON/OFF pathway for enhanced visual percepts. To better replicate normal vision, it would be also crucial to consider information transmission by spiking activities arising in the RGC population since an incredible amount of visual information is transferred from the eye to the brain. In previous studies, however, it has not been well explored how much artificial visual information is created in response to electrical stimuli delivered by microelectrodes. In the present work, we discuss the importance of the neural information for high-quality artificial vision. First, we summarize the previous literatures which have computed information transmission rates from spiking activities of RGCs in response to visual stimuli. Second, we exemplify a couple of studies which computed the neural information from electrically evoked responses. Third, we briefly introduce how information rates can be computed in the representative two ways – direct method and reconstruction method. Fourth, we introduce in silico approaches modeling artificial retinal neural networks to explore the relationship between amount of information and the spiking patterns. Lastly, we conclude our review with clinical implications to emphasize the necessity of considering visual information transmission for further improvement of retinal prosthetics.

Improving the spatial resolution of artificial vision using midget retinal ganglion cell populations modeled at the human fovea

Objective. Retinal prostheses seek to create artificial vision by stimulating surviving retinal neurons of patients with profound vision impairment. Notwithstanding tremendous research efforts, the performance of all implants tested to date has remained rudimentary, incapable of overcoming the threshold for legal blindness. To maximize the perceptual efficacy of retinal prostheses, a device must be capable of controlling retinal neurons with greater spatiotemporal precision. Most studies of retinal stimulation were derived from either non-primate species or the peripheral primate retina. We investigated if artificial stimulation could leverage the high spatial resolution afforded by the neural substrates at the primate fovea and surrounding regions to achieve improved percept qualities. Approach. We began by developing a new computational model capable of generating anatomically accurate retinal ganglion cell (RGC) populations within the human central retina. Next, multiple RGC populations across the central retina were stimulated in-silico to compare clinical and recently proposed neurostimulation configurations based on their ability to improve perceptual efficacy and reduce activation thresholds. Main results. Our model uniquely upholds eccentricity-dependent characteristics such as RGC density and dendritic field diameter, whilst incorporating anatomically accurate features such as axon projection and three-dimensional (3D) RGC layering, features often forgone in favor of reduced computational complexity. Following epiretinal stimulation, the RGCs in our model produced response patterns in shapes akin to the complex and non-trivial percepts reported in clinical trials. Our results also demonstrated that even within the neuron-dense central retina, epiretinal stimulation using a multi-return hexapolar electrode arrangement could reliably achieve spatially focused RGC activation and could achieve single-cell excitation in 56% of all tested locations. Significance. This study establishes an anatomically accurate 3D model of RGC populations within the human central retina and demonstrates the potential for an epiretinal hexapolar configuration to achieve consistent, spatially confined retinal responses, even within the unique and neuron-dense foveal region. Our results and model promote the prospect and optimization of higher spatial resolution in future epiretinal implants.

Correlated Activity in the Degenerate Retina Inhibits Focal Response to Electrical Stimulation.

Retinal prostheses have shown some clinical success in patients with retinitis pigmentosa and age-related macular degeneration. However, even after the implantation of a retinal prosthesis, the patient’s visual acuity is at best less than 20/420. Reduced visual acuity may be explained by a decrease in the signal-to-noise ratio due to the spontaneous hyperactivity of retinal ganglion cells (RGCs) found in degenerate retinas. Unfortunately, abnormal retinal rewiring, commonly observed in degenerate retinas, has rarely been considered for the development of retinal prostheses. The purpose of this study was to investigate the aberrant retinal network response to electrical stimulation in terms of the spatial distribution of the electrically evoked RGC population. An 8 × 8 multielectrode array was used to measure the spiking activity of the RGC population. RGC spikes were recorded in wild-type [C57BL/6J; P56 (postnatal day 56)], rd1 (P56), rd10 (P14 and P56) mice, and macaque [wild-type and drug-induced retinal degeneration (RD) model] retinas. First, we performed a spike correlation analysis between RGCs to determine RGC connectivity. No correlation was observed between RGCs in the control group, including wild-type mice, rd10 P14 mice, and wild-type macaque retinas. In contrast, for the RD group, including rd1, rd10 P56, and RD macaque retinas, RGCs, up to approximately 400–600 μm apart, were significantly correlated. Moreover, to investigate the RGC population response to electrical stimulation, the number of electrically evoked RGC spikes was measured as a function of the distance between the stimulation and recording electrodes. With an increase in the interelectrode distance, the number of electrically evoked RGC spikes decreased exponentially in the control group. In contrast, electrically evoked RGC spikes were observed throughout the retina in the RD group, regardless of the inter-electrode distance. Taken together, in the degenerate retina, a more strongly coupled retinal network resulted in the widespread distribution of electrically evoked RGC spikes. This finding could explain the low-resolution vision in prosthesis-implanted patients.

Influences of Glaucoma on the Structure and Function of Synapses in the Visual System.

Significance: Glaucoma is an age-related neurodegenerative disorder of the visual system associated with sensitivity to intraocular pressure (IOP). It is the leading irreversible cause of vision loss worldwide, and vision loss results from damage and dysfunction of the retinal output neurons known as retinal ganglion cells (RGCs). Recent Advances: Elevated IOP and optic nerve injury triggers pruning of RGC dendrites, altered morphology of excitatory inputs from presynaptic bipolar cells, and disrupted RGC synaptic function. Less is known about RGC outputs, although evidence to date indicates that glaucoma is associated with altered mitochondrial and synaptic structure and function in RGC-projection targets in the brain. These early functional changes likely contribute to vision loss and might be a window into early diagnosis and treatment. Critical Issues: Glaucoma affects different RGC populations to varying extents and along distinct time courses. The influence of glaucoma on RGC synaptic function as well as the mechanisms underlying these effects remain to be determined. Since RGCs are an especially energetically demanding population of neurons, altered intracellular axon transport of mitochondria and mitochondrial function might contribute to RGC synaptic dysfunction in the retina and brain as well as RGC vulnerability in glaucoma. Future Directions: The mechanisms underlying differential RGC vulnerability remain to be determined. Moreover, the timing and mechanisms of RGCs synaptic dysfunction and degeneration will provide valuable insight into the disease process in glaucoma. Future work will be able to capitalize on these findings to better design diagnostic and therapeutic approaches to detect disease and prevent vision loss. Antioxid. Redox Signal. 37, 842-861.

The Retinal Basis of Light Aversion in Neonatal Mice.

Aversive responses to bright light (photoaversion) require signaling from the eye to the brain. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) encode absolute light intensity and are thought to provide the light signals for photoaversion. Consistent with this, neonatal mice exhibit photoaversion before the developmental onset of image vision, and melanopsin deletion abolishes photoaversion in neonates. It is not well understood how the population of ipRGCs, which constitutes multiple physiologically distinct types (denoted M1-M6 in mouse), encodes light stimuli to produce an aversive response. Here, we provide several lines of evidence that M1 ipRGCs that lack the Brn3b transcription factor drive photoaversion in neonatal mice. First, neonatal mice lacking TRPC6 and TRPC7 ion channels failed to turn away from bright light, while two photon Ca2+ imaging of their acutely isolated retinas revealed reduced photosensitivity in M1 ipRGCs, but not other ipRGC types. Second, mice in which all ipRGC types except for Brn3b-negative M1 ipRGCs are ablated exhibited normal photoaversion. Third, pharmacological blockade or genetic knockout of gap junction channels expressed by ipRGCs, which reduces the light sensitivity of M2-M6 ipRGCs in the neonatal retina, had small effects on photoaversion only at the brightest light intensities. Finally, M1s were not strongly depolarized by spontaneous retinal waves, a robust source of activity in the developing retina that depolarizes all other ipRGC types. M1s therefore constitute a separate information channel between the neonatal retina and brain that could ensure behavioral responses to light but not spontaneous retinal waves.SIGNIFICANCE STATEMENT At an early stage of development, before the maturation of photoreceptor input to the retina, neonatal mice exhibit photoaversion. On exposure to bright light, they turn away and emit ultrasonic vocalizations, a cue to their parents to return them to the nest. Neonatal photoaversion is mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs), a small percentage of the retinal ganglion cell population that express the photopigment melanopsin and depolarize directly in response to light. This study shows that photoaversion is mediated by a subset of ipRGCs, called M1-ipRGCs. Moreover, M1-ipRGCs have reduced responses to retinal waves, providing a mechanism by which the mouse distinguishes light stimulation from developmental patterns of spontaneous activity.

An in-silico analysis of electrically evoked responses of midget and parasol retinal ganglion cells in different retinal regions

Objective. Visual outcomes provided by present retinal prostheses that primarily target retinal ganglion cells (RGCs) through epiretinal stimulation remain rudimentary, partly due to the limited knowledge of retinal responses under electrical stimulation. Better understanding of how different retinal regions can be quantitatively controlled with high spatial accuracy, will be beneficial to the design of micro-electrode arrays and stimulation strategies for next-generation wide-view, high-resolution epiretinal implants. Approach. A computational model was developed to assess neural activity at different eccentricities (2 mm and 5 mm) within the human retina. This model included midget and parasol RGCs with anatomically accurate cell distribution and cell-specific morphological information. We then performed in silico investigations of region-specific RGC responses to epiretinal electrical stimulation using varied electrode sizes (5–210 µm diameter), emulating both commercialized retinal implants and recently developed prototype devices. Main results. Our model of epiretinal stimulation predicted RGC population excitation analogous to the complex percepts reported in human subjects. Following this, our simulations suggest that midget and parasol RGCs have characteristic regional differences in excitation under preferred electrode sizes. Relatively central (2 mm) regions demonstrated higher number of excited RGCs but lower overall activated receptive field (RF) areas under the same stimulus amplitudes (two-way analysis of variance (ANOVA), p < 0.05). Furthermore, the activated RGC numbers per unit active RF area (number-RF ratio) were significantly higher in central than in peripheral regions, and higher in the midget than in the parasol population under all tested electrode sizes (two-way ANOVA, p < 0.05). Our simulations also suggested that smaller electrodes exhibit a higher range of controllable stimulation parameters to achieve pre-defined performance of RGC excitation. An empirical model: I = a · exp (b · D) + c of the stimulus amplitude (I)–electrode diameter (D) relationship was constructed to achieve the pre-defined objective function values in different retinal regions, indicating the ability of controlling retinal outputs by fine-tuning the stimulation amplitude with different electrode sizes. Finally, our multielectrode simulations predicted differential neural crosstalk between adjacent electrodes in central temporal and peripheral temporal regions, providing insights towards establishing a non-uniformly distributed multielectrode array geometry for wide-view retinal implants. Significance. Stimulus–response properties in central and peripheral retina can provide useful information to estimate electrode parameters for region-specific activation by retinal stimulation. Our findings support the possibility of improving the performance of epiretinal prostheses by exploring the influence of electrode array geometry on activation of different retinal regions.

Differential effects of experimental glaucoma on intrinsically photosensitive retinal ganglion cells in mice.

Glaucoma is a group of eye diseases characterized by retinal ganglion cell (RGC) loss and optic nerve damage. Studies, including this study, support that RGCs degenerate and die in a type-specific manner following the disease insult. Here we specifically examined one RGC type, the intrinsically photosensitive retinal ganglion cell (ipRGC), and its associated functional deficits in a mouse model of experimental glaucoma. We induced chronic ocular hypertension (OHT) by laser photocoagulation and then characterized the survival of ipRGC subtypes. We found that ipRGCs suffer significant loss, similar to the general RGC population, but ipRGC subtypes are differentially affected following chronic OHT. M4 ipRGCs, which are involved in pattern vision, are susceptible to chronic OHT. Correspondingly, mice with chronic OHT experience reduced contrast sensitivity and visual acuity. By comparison, M1 ipRGCs, which project to the suprachiasmatic nuclei to regulate circadian rhythmicity, exhibit almost no cell loss following chronic OHT. Accordingly, we observed that circadian re-entrainment and circadian rhythmicity are largely not disrupted in OHT mice. Our study demonstrates the link between subtype-specific ipRGC survival and behavioral deficits in glaucomatous mice. These findings provide insight into glaucoma-induced visual behavioral deficits and their underlying mechanisms.

Effect of systemic immunosuppression and BM‐MSC allotransplantation in retinal functionality and RGC population

AbstractPurposeBone marrow mesenchymal stem cell (BM‐MSC) transplant is widely studied in preclinical models because of their potential neuroprotective properties. In the clinic, allotransplants are combined with systemic immunosuppressive treatments to improve transplantation outcomes. We purposed to carry out a comparative functional and histological study to find out the role of immunosuppression after BM‐MSC allotransplantation in retina.Methods20,000 BM‐MSC from donor eGFP‐C57BL/6J mice were intravitreally injected into recipient BALB/c mice. Animals were divided in two groups (n=5/each). One group was immunosuppressed right after the BM‐MSC injection with oral cyclosporine in water (100 mg/ml) and a daily intraperitoneal injection of cortisone (1.6 mg/kg), whereas the other group was kept w/o immunosuppression as control. Electroretinograms were performed before and 5 days and 21 days after the BM‐MSC graft. Animals were perfused, and flat mounted retinas analyzed at 21 days. Brn3a+ retinal ganglion cells (RGC) were automatically quantified, and their spatial distribution analyzed with isodensity maps.ResultsBM‐MSC allotransplant alone causes a significant decrease (40%) of the positive scotopic threshold response (pSTR, RGC function) at 21 days compared to baseline. In the immunosuppressed group, retinal functionality was further impaired as most of the electroretinogram waves (pSTR, rod response, a and b waves, and photopic wave) drastically decreased at 5 days compared to allotransplant alone. This functionality was partially recovered at 21 days. In spite of the functional impairment, the population of RGC was not affected in any group.ConclusionsIn allogeneic BM‐MSC transplants, immunosuppression has a negative effect on retinal function.

Morphological and distributional properties of SMI-32 immunoreactive ganglion cells in the rat retina.

SMI‐32 is widely used to identify entire populations of alpha retinal ganglion cells (RGCs), and several SMI‐32+ RGC subsets have been studied thoroughly in rodents. However, due to the thick cover of SMI‐32+ neurofilaments, the morphology of SMI‐32+ RGCs in the central retinal region is obscured and rarely described. Moreover, SMI‐32 labels more than one morphological RGC type and the full morphological characteristics and distribution of SMI‐32+ RGCs have yet to be discovered. Here, using intracellular neurobiotin injections combined with SMI‐32 antibody staining, we investigated morphological and distributional properties of the entire SMI‐32+ RGCs population in the rat retina. We found that SMI‐32+ RGCs were evenly distributed throughout the rat retina. We compared the morphological features of SMI‐32+ ON and OFF cells in the central, middle, and peripheral retinal regions. We found that SMI‐32+ RGCs in different regions have distinct characteristics, such as the soma area and the dendritic field area, and Sholl analysis of ON cells and OFF cells revealed significant differences between each region. We classified SMI‐32+ RGCs into five clusters based on morphological features and found that a majority of SMI‐32+ RGCs belong to alpha‐like cells; however, a small proportion of SMI‐32+ RGCs had small soma and small dendritic fields. Together, we present a full description of the morphology and distribution of SMI‐32 immunoreactive RGCs in the rat retina.

Melanopsin phototransduction: beyond canonical cascades.

ABSTRACTMelanopsin is a visual pigment that is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). It is involved in regulating non-image forming visual behaviors, such as circadian photoentrainment and the pupillary light reflex, while also playing a role in many aspects of image-forming vision, such as contrast sensitivity. Melanopsin was initially discovered in the melanophores of the skin of the frog Xenopus, and subsequently found in a subset of ganglion cells in rat, mouse and primate retinas. ipRGCs were initially thought to be a single retinal ganglion cell population, and melanopsin was thought to activate a single, invertebrate-like Gq/transient receptor potential canonical (TRPC)-based phototransduction cascade within these cells. However, in the 20 years since the discovery of melanopsin, our knowledge of this visual pigment and ipRGCs has expanded dramatically. Six ipRGC subtypes have now been identified in the mouse, each with unique morphological, physiological and functional properties. Multiple subtypes have also been identified in other species, suggesting that this cell type diversity is a general feature of the ipRGC system. This diversity has led to a renewed interest in melanopsin phototransduction that may not follow the canonical Gq/TRPC cascade in the mouse or in the plethora of other organisms that express the melanopsin photopigment. In this Review, we discuss recent findings and discoveries that have challenged the prevailing view of melanopsin phototransduction as a single pathway that influences solely non-image forming functions.

Identification of long noncoding RNAs in injury-resilient and injury-susceptible mouse retinal ganglion cells

BackgroundEmerging evidence indicates that long noncoding RNAs (lncRNAs) are important regulators of various biological processes, and their expression can be altered following certain pathological conditions, including central nervous system injury. Retinal ganglion cells (RGCs), whose axons form the optic nerve, are a heterogeneous population of neurons with more than 40 molecularly distinct subtypes in mouse. While most RGCs, including the ON-OFF direction-selective RGCs (ooDSGCs), are vulnerable to axonal injury, a small population of RGCs, including the intrinsically photosensitive RGCs (ipRGCs), are more resilient.ResultsBy performing systematic analyses on RNA-sequencing data, here we identify lncRNAs that are expressed in ooDSGCs and ipRGCs with and without axonal injury. Our results reveal a repertoire of different classes of lncRNAs, including long intergenic noncoding RNAs and antisense ncRNAs that are differentially expressed between these RGC types. Strikingly, we also found dozens of lncRNAs whose expressions are altered markedly in response to axonal injury, some of which are expressed exclusively in either one of the types. Moreover, analyses into these lncRNAs unraveled their neighboring coding genes, many of which encode transcription factors and signaling molecules, suggesting that these lncRNAs may act in cis to regulate important biological processes in these neurons. Lastly, guilt-by-association analysis showed that lncRNAs are correlated with apoptosis associated genes, suggesting potential roles for these lncRNAs in RGC survival.ConclusionsOverall, the results of this study reveal RGC type-specific expression of lncRNAs and provide a foundation for future investigation of the function of lncRNAs in regulating neuronal type specification and survival.

Dim light in the evening causes coordinated realignment of circadian rhythms, sleep, and short-term memory

Light provides the primary signal for entraining circadian rhythms to the day/night cycle. In addition to rods and cones, the retina contains a small population of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). Concerns have been raised that exposure to dim artificial lighting in the evening (DLE) may perturb circadian rhythms and sleep patterns, and OPN4 is presumed to mediate these effects. Here, we examine the effects of 4-h, 20-lux DLE on circadian physiology and behavior in mice and the role of OPN4 in these responses. We show that 2 wk of DLE induces a phase delay of ∼2 to 3 h in mice, comparable to that reported in humans. DLE-induced phase shifts are unaffected in Opn4-/- mice, indicating that rods and cones are capable of driving these responses in the absence of melanopsin. DLE delays molecular clock rhythms in the heart, liver, adrenal gland, and dorsal hippocampus. It also reverses short-term recognition memory performance, which is associated with changes in preceding sleep history. In addition, DLE modifies patterns of hypothalamic and cortical cFos signals, a molecular correlate of recent neuronal activity. Together, our data show that DLE causes coordinated realignment of circadian rhythms, sleep patterns, and short-term memory process in mice. These effects are particularly relevant as DLE conditions-due to artificial light exposure-are experienced by the majority of the populace on a daily basis.

Systemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats

PurposeTo analyze responses of different RGC populations to left intraorbital optic nerve transection (IONT) and intraperitoneal (i.p.) treatment with 7,8-Dihydroxyflavone (DHF), a potent selective TrkB agonist. MethodsAdult albino Sprague-Dawley rats received, following IONT, daily i.p. injections of vehicle (1%DMSO in 0.9%NaCl) or DHF. Group-1 (n = 58) assessed at 7days (d) the optimal DHF amount (1–25 mg/kg). Group-2, using freshly dissected naïve or treated retinas (n = 28), investigated if DHF treatment was associated with TrkB activation using Western-blotting at 1, 3 or 7d. Group-3 (n = 98) explored persistence of protection and was analyzed at survival intervals from 7 to 60d after IONT. Groups 2–3 received daily i.p. vehicle or DHF (5 mg/kg). Retinal wholemounts were immunolabelled for Brn3a and melanopsin to identify Brn3a+RGCs and m+RGCs, respectively. ResultsOptimal neuroprotection was achieved with 5 mg/kg DHF and resulted in TrkB phosphorylation. The percentage of surviving Brn3a+RGCs in vehicle treated rats was 60, 28, 18, 13, 12 or 8% of the original value at 7, 10, 14, 21, 30 or 60d, respectively, while in DHF treated retinas was 94, 70, 64, 17, 10 or 9% at the same time intervals. The percentages of m+RGCs diminished by 7d–13%, and recovered by 14d–38% in vehicle-treated and to 48% in DHF-treated retinas, without further variations. ConclusionsDHF neuroprotects Brn3a + RGCs and m + RGCs; its protective effects for Brn3a+RGCs are maximal at 7 days but still significant at 21d, whereas for m+RGCs neuroprotection was significant at 14d and permanent.

Age Related Response of Neonatal Rat Retinal Ganglion Cells to Reduced TrkB Signaling in vitro and in vivo.

During development of retinofugal pathways there is naturally occurring cell death of at least 50% of retinal ganglion cells (RGCs). In rats, RGC death occurs over a protracted pre- and early postnatal period, the timing linked to the onset of axonal ingrowth into central visual targets. Gene expression studies suggest that developing RGCs switch from local to target-derived neurotrophic support during this innervation phase. Here we investigated, in vitro and in vivo, how RGC birthdate affects the timing of the transition from intra-retinal to target-derived neurotrophin dependence. RGCs were pre-labeled with 5-Bromo-2′-Deoxyuridine (BrdU) at embryonic (E) day 15 or 18. For in vitro studies, RGCs were purified from postnatal day 1 (P1) rat pups and cultured with or without: (i) brain derived neurotrophic factor (BDNF), (ii) blocking antibodies to BDNF and neurotrophin 4/5 (NT-4/5), or (iii) a tropomyosin receptor kinase B fusion protein (TrkB-Fc). RGC viability was quantified 24 and 48 h after plating. By 48 h, the survival of purified βIII-tubulin immunopositive E15 but not E18 RGCs was dependent on addition of BDNF to the culture medium. For E18 RGCs, in the absence of exogenous BDNF, addition of blocking antibodies or TrkB-Fc reduced RGC viability at both 24 and 48 h by 25–40%. While this decrease was not significant due to high variance, importantly, each blocking method also consistently reduced complex process expression in surviving RGCs. In vivo, survival of BrdU and Brn3a co-labeled E15 or E18 RGCs was quantified in rats 24 h after P1 or P5 injection into the eye or contralateral superior colliculus (SC) of BDNF and NT-4/5 antibodies, or serum vehicle. The density of E15 RGCs 24 h after P1 or P5 injection of blocking antibodies was reduced after SC but not intraretinal injection. Antibody injections into either site had little obvious impact on viability of the substantially smaller population of E18 RGCs. In summary, most early postnatal RGC death in the rat involves the elimination of early-born RGCs with their survival primarily dependent upon the availability of target derived BDNF during this time. In contrast, late-born RGC survival may be influenced by additional factors, suggesting an association between RGC birthdate and developmental death mechanisms.

Retinal Ganglion Cells-Diversity of Cell Types and Clinical Relevance.

Retinal ganglion cells (RGCs) are the bridging neurons that connect the retinal input to the visual processing centres within the central nervous system. There is a remarkable diversity of RGCs and the various subtypes have unique morphological features, distinct functions, and characteristic pathways linking the inner retina to the relevant brain areas. A number of psychophysical and electrophysiological tests have been refined to investigate this large and varied population of RGCs. Technological advances, such as high-resolution optical coherence tomography imaging, have provided additional tools to define the pattern of RGC involvement and the chronological sequence of events in both inherited and acquired optic neuropathies. The mechanistic insights gained from these studies, in particular the selective vulnerability and relative resilience of particular RGC subtypes, are of fundamental importance as they are directly relevant to the development of targeted therapies for these invariably progressive blinding diseases. This review provides a comprehensive description of the various types of RGCs, the developments in proposed methods of classification, and the current gaps in our knowledge of how these RGCs are differentially affected depending on the underlying aetiology. The synthesis of the current body of knowledge on the diversity of RGCs and the pathways that are potentially amenable to therapeutic modulation will hopefully lead to much needed effective treatments for patients with optic neuropathies.

Electric Stimulation Elicits Heterogeneous Responses in ON but Not OFF Retinal Ganglion Cells to Transmit Rich Neural Information.

Retinal implants electrically stimulate surviving retinal neurons to restore vision in people blinded by outer retinal degeneration. Although the healthy retina is known to transmit a vast amount of visual information to the brain, it has not been studied whether prosthetic vision contains a similar amount of information. Here, we assessed the neural information transmitted by population responses arising in brisk transient (BT) and brisk sustained (BS) subtypes of ON and OFF retinal ganglion cells (RGCs) in the rabbit retina. To correlate the response heterogeneity and the information transmission, we first quantified the cell-to-cell heterogeneity by calculating the spike time tiling coefficient (STTC) across spiking patterns of RGCs in each type. Then, we computed the neural information encoded by the RGC population in a given type. In responses to light stimulation, spiking activities were more heterogeneous in OFF than ON RGCs (STTCAVG = 0.36, 0.45, 0.77 and 0.55 for OFF BT, OFF BS, ON BT, and ON BS, respectively). Interestingly, however, in responses to electric stimulation, both BT and BS subtypes of OFF RGCs showed remarkably homogeneous spiking patterns across cells (STTCAVG = 0.93 and 0.82 for BT and BS, respectively), whereas the two subtypes of ON RGCs showed slightly increased populational heterogeneity compared to light-evoked responses (STTCAVG = 0.71 and 0.63 for BT and BS, respectively). Consequently, the neural information encoded by the electrically-evoked responses of a population of 15 RGCs was substantially lower in the OFF than the ON pathway: OFF BT and BS cells transmit only ~23% and ~53% of the neural information transmitted by their ON counterparts. Together with previously-reported natural spiking activities in ON RGCs, the higher neural information may make ON responses more recognizable, eliciting the biased percepts of bright phosphenes.

Dynamic changes in cell size and corresponding cell fate after optic nerve injury

Identifying disease-specific patterns of retinal cell loss in pathological conditions has been highlighted by the emergence of techniques such as Detection of Apoptotic Retinal Cells and Adaptive Optics confocal Scanning Laser Ophthalmoscopy which have enabled single-cell visualisation in vivo. Cell size has previously been used to stratify Retinal Ganglion Cell (RGC) populations in histological samples of optic neuropathies, and early work in this field suggested that larger RGCs are more susceptible to early loss than smaller RGCs. More recently, however, it has been proposed that RGC soma and axon size may be dynamic and change in response to injury. To address this unresolved controversy, we applied recent advances in maximising information extraction from RGC populations in retinal whole mounts to evaluate the changes in RGC size distribution over time, using three well-established rodent models of optic nerve injury. In contrast to previous studies based on sampling approaches, we examined the whole Brn3a-positive RGC population at multiple time points over the natural history of these models. The morphology of over 4 million RGCs was thus assessed to glean novel insights from this dataset. RGC subpopulations were found to both increase and decrease in size over time, supporting the notion that RGC cell size is dynamic in response to injury. However, this study presents compelling evidence that smaller RGCs are lost more rapidly than larger RGCs despite the dynamism. Finally, using a bootstrap approach, the data strongly suggests that disease-associated changes in RGC spatial distribution and morphology could have potential as novel diagnostic indicators.

Photosensitive ganglion cells: A diminutive, yet essential population.

Our visual system has evolved to provide us with an image of the scene that surrounds us, informing us of its texture, colour, movement, and depth with an enormous spatial and temporal resolution, and for this purpose, the image formation (IF) dedicates the vast majority of our retinal ganglion cell (RGC) population and much of our cerebral cortex. On the other hand, a minuscule proportion of RGCs, in addition to receiving information from classic cone and rod photoreceptors, express melanopsin and are intrinsically photosensitive (ipRGC). These ipRGC are dedicated to non-image-forming (NIF) visual functions, of which we are unaware, but which are essential for aspects related to our daily physiology, such as the timing of our circadian rhythms and our pupillary light reflex, among many others. Before the discovery of ipRGCs, it was thought that the IF and NIF functions were distinct compartments regulated by different RGCs, but this concept has evolved in recent years with the discovery of new types of ipRGCs that innervate subcortical IF regions, and therefore have IF visual functions. Six different types of ipRGCs are currently known. These are termed M1-M6, and differ in their morphological, functional, molecular properties, central projections, and visual behaviour responsibilities. A review is presented on the melanopsin visual system, the most active field of research in vision, for which knowledge has grown exponentially during the last two decades, when RGCs giving rise to this pathway were first discovered.

Projections of ipRGCs and conventional RGCs to retinorecipient brain nuclei.

Retinal ganglion cells (RGCs), the output neurons of the retina, allow us to perceive our visual environment. RGCs respond to rod/cone input through the retinal circuitry, however, a small population of RGCs are in addition intrinsically photosensitive (ipRGCs) and project to unique targets in the brain to modulate a broad range of subconscious visual behaviors such as pupil constriction and circadian photoentrainment. Despite the discovery of ipRGCs nearly two decades ago, there is still little information about how or if conventional RGCs (non-ipRGCs) target ipRGC-recipient nuclei to influence subconscious visual behavior. Using a dual recombinase fluorescent reporter strategy, we showed that conventional RGCs innervate many subconscious ipRGC-recipient nuclei, apart from the suprachiasmatic nucleus. We revealed previously unrecognized stratification patterns of retinal innervation from ipRGCs and conventional RGCs in the ventral portion of the lateral geniculate nucleus. Further, we found that the percent innervation of ipRGCs and conventional RGCs across ipsi- and contralateral nuclei differ. Our data provide a blueprint to understand how conventional RGCs and ipRGCs innervate different brain regions to influence subconscious visual behaviors.