Human Ganglion Cells Research Articles

Morphology, Molecular Characterization, and Connections of Ganglion Cells in Primate Retina

The eye sends information about the visual world to the brain on over 20 parallel signal pathways, each specialized to signal features such as spectral reflection (color), edges, and motion of objects in the environment. Each pathway is formed by the axons of a separate type of retinal output neuron (retinal ganglion cell). In this review, we summarize what is known about the excitatory retinal inputs, brain targets, and gene expression patterns of ganglion cells in humans and nonhuman primates. We describe how most ganglion cell types receive their input from only one or two of the 11 types of cone bipolar cell and project selectively to only one or two target regions in the brain. We also highlight how genetic methods are providing tools to characterize ganglion cells and establish cross-species homologies.

Visual properties of human retinal ganglion cells.

The retinal output is the sole source of visual information for the brain. Studies in non-primate mammals estimate that this information is carried by several dozens of retinal ganglion cell types, each informing the brain about different aspects of a visual scene. Even though morphological studies of primate retina suggest a similar diversity of ganglion cell types, research has focused on the function of only a few cell types. In human retina, recordings from individual cells are anecdotal or focus on a small subset of identified types. Here, we present the first systematic ex-vivo recording of light responses from 342 ganglion cells in human retinas obtained from donors. We find a great variety in the human retinal output in terms of preferences for positive or negative contrast, spatio-temporal frequency encoding, contrast sensitivity, and speed tuning. Some human ganglion cells showed similar response behavior as known cell types in other primate retinas, while we also recorded light responses that have not been described previously. This first extensive description of the human retinal output should facilitate interpretation of primate data and comparison to other mammalian species, and it lays the basis for the use of ex-vivo human retina for in-vitro analysis of novel treatment approaches.

Literature Review on the Distribution of Spiral Ganglion Cell Bodies inside the Human Cochlear Central Modiolar Trunk.

This study aims to obtain a better understanding of the number and distribution of spiral ganglion cell bodies (SGCBs) in the central modiolar trunk of the human cochlea with normal hearing as well as with hearing loss due to various pathological conditions. A detailed PubMed search was performed using the key words "human spiral ganglion cell population," "analysis of spiral ganglion cell population," "survival of human spiral ganglion cells," "human Rosenthal's canal," "human ganglion cell counts," and "distribution of human spiral ganglion cells" to identify articles published between 1931 and 2019. The articles were included if the number of SGCBs in the four segments of the human cochlea and angular depth distribution of the SGCBs were mentioned. Out of the 237 articles that were initially identified, 20 articles met the inclusion criteria. The presence of SGCBs inside the Rosenthal's canal (RC) in the modiolar trunk extended to an angular depth of 630°-680°, which is close to the end of the second turn of the cochlea. SGCBs in Segment-IV of the cochlea account for approximately 25-30% of the entire SGCB population, regardless of the cochlear condition (normal vs. pathologic). In normal-hearing subjects, the total number of SGCB cases ranged between 23,910 and 33,702; in patients with hearing loss, the same was between 5,733 and 28,220. This literature review elaborates on the current state of knowledge regarding the number and distribution of SGCBs in the human cochlea.

Presence of the spiral ganglion cell bodies beyond the basal turn of the human cochlea

The purpose of this study was to obtain a better understanding of the number and distribution of spiral ganglion cell bodies (SGCB) in the central modiolus trunk of the human cochlea with normal hearing as well as with hearing loss due to various pathological conditions. A literature review was performed using the key words ‘human spiral ganglion cell population’, ‘analysis of spiral ganglion cell population’, ‘survival of human spiral ganglion cells’, ‘human Rosenthal’s canal’, ‘human ganglion cell counts’, and ‘distribution of human spiral ganglion cells’ to identify articles published between 1968 and 2018. Articles were included if the number of SGCB in the four segments of the human cochlea and angular depth distribution of the SGCB were stated. Of 236 articles initially identified, 19 articles met the inclusion criteria. SGCB inside the Rosenthal’s canal (RC) in the modiolus trunk extended to an angular depth of 630–680° which is near the end of the second turn of the cochlea. SGCBs in Segment IV of the cochlea account for approximately 25–30% of the entire SGCB population irrespective of the cochlear condition (normal vs. pathologic). In normal hearing subjects, the total number of SGCB ranged between 23,910 and 33,702 and in patients with hearing loss between 5733 and 28,220. This literature review elaborates on the current state of knowledge about the number and distribution of SGCB in the human cochlea.

Decoding natural signals from the peripheral retina

Ganglion cells in the peripheral retina have lower density and larger receptive fields than in the fovea. Consequently, the visual signals relayed from the periphery have substantially lower resolution than those relayed by the fovea. The information contained in peripheral ganglion cell responses can be quantified by how well they predict the foveal ganglion cell responses to the same stimulus. We constructed a model of human ganglion cell outputs by combining existing measurements of the optical transfer function with the receptive field properties and sampling densities of midget (P) ganglion cells. We then simulated a spatial population of P-cell responses to image patches sampled from a large collection of luminance-calibrated natural images. Finally, we characterized the population response to each image patch, at each eccentricity, with two parameters of the spatial power spectrum of the responses: the average response contrast (standard deviation of the response patch) and the falloff in power with spatial frequency. The primary finding is that the optimal estimate of response contrast in the fovea is dependent on both the response contrast and the steepness of the falloff observed in the periphery. Humans could exploit this information when decoding peripheral signals to estimate contrasts, estimate blur levels, or select the most informative locations for saccadic eye movements.

Decoding natural signals from the peripheral retina

Peripheral ganglion cells have lower density and larger receptive fields than the fovea. Consequently, the quality of the visual signals that they relay is reduced. The information contained in peripheral ganglion cell responses can be quantified by how well they predict the foveal ganglion cell responses to the same stimulus. Here, we developed a model of human ganglion cell outputs combining existing measurements of the optical transfer function with the receptive field properties and sampling densities of P ganglion cells. Next, we simulated a small spatial population of P-cell responses to 1° patches from a large sample of luminance-calibrated natural images. For each image patch we simulated population responses for retinal eccentricities ranging from 0°–15°. Spatial phase and orientation are largely preserved by circularly symmetric receptive fields. Therefore, we characterized the population of ganglion cell responses by their radially-averaged spatial power spectrum. A two parameter function adequately summarized these power spectra. One parameter describes the falloff of power with spatial frequency; the other describes the variance of the responses across cells in the population (power per ganglion cell). We found that the variance was constant with retinal eccentricity on average, but for a given patch the falloff parameter in the periphery was strongly predictive of the foveal variance. For example, at 15° eccentricity the percent error in the Bayes optimal prediction of foveal variance improved by a factor of 2 by taking into account both peripheral falloff and variance, as opposed to peripheral variance alone. Humans could exploit this information when decoding peripheral P-cell responses. Decoding in this way might facilitate various known perceptual constancies (e.g., contrast and blur constancy) creating the common percept of a sharp peripheral image. Further, it could reduce the number of eye movements necessary to encode the image.

The protective effects of ginkgo biloba extract on cultured human retinal ganglion cells

This study was designed to investigate the protective effects of ginkgo biloba extract (EGb) 761 on human retinal ganglion cells (RGC). It was an experimental study. Cultured human retinal cells were separated for four groups: control group, glutamate group, EGb761 group and EGb761+glutamate group. RGC survival rate was determined by immune Flow cytometry using Thy-1 as a special fluorescent antibody of RGC. RGC survival rate in Multi groups were analysed by repetitive measure analysis of variance (ANOVA), and the differences between groups were analysed by LSD t test. The effects of EGb761 on cultured human RGC were different under different interfere factors. The RGC survival rate was (61.94±7.75)% in control group, (44.59±4.19)% in glutamate group, (75.05±3.90)% in EGb761 group, and (63.19±9.44)% in EGb761+glutamate group. There were significant difference in different groups on survival rates of RGC (F=13.329, P<0.01). Compared with the control group, the survival rate of RGC in glutamate group was significantly decreased (P=0.010), while the EGb761 group was significantly increased (P=0.019), and the EGb761+glutamate group had no significant difference (P=0.801). Compared with the glutamate group, the survival rate of RGC in the EGb761 group and the EGb761+glutamate group was significantly increased (P=0.000, 0.020). There was no significant difference in the percentage of the large RGC in all groups. But compared with the control group (36.69±2.92)%, the percentage of large RGC in dead RGC in the EGb761 group (24.63±7.21)% and the EGb761+glutamate group (25.99±5.05)% was significantly decreased (P=0.001, 0.002). Compared with the glutamate group (40.78±3.34)%, the death rate of the large RGC in the EGb761 group and the EGb761+glutamate group was also significantly decreased (P=0.000, 0.000). EGb761 can protect RGC against glutamate induced neurotoxicity, and it has significant protective effect on cultured human RGC.

Spiral Ganglion Cell Loss Is Unrelated to Segmental Cochlear Sensory System Degeneration in Humans

To demonstrate that contrary to what occurs in animals, neuron loss in the human spiral ganglion is not in proportion to organ of Corti hair or supporting cell loss. Histopathological review of archival temporal bone histological sections. Nonprofit research facility. Four temporal bones, from an archival collection of 1,448 temporal bones, were found that had a total loss of hair and supporting cells limited to the basal segment of the cochlea and a hearing loss of 3 or more years (range, 3-28 yr). Cochlear reconstructions were conducted to demonstrate the populations of hair and supporting cells, peripheral processes (dendrites), spiral ganglion cells, and the amount of surviving stria vascularis in different cochlear segments. The total loss of hair and supporting cells of the organ of Corti in the base of the cochlea is not accompanied by a proportional loss of spiral ganglion cells in the modiolar base. A long-term loss of hearing in frequencies greater than 2 kHz, and corresponding hair cell loss, does not result in a subsequent loss of spiral ganglion cells in humans, in contrast to what has been reported in association with animals. These findings suggest that the poor performance of cochlear implant in patients after prolonged deafness is not caused by ongoing degeneration of ganglion cells.

The Effect of Organ of Corti Loss on Ganglion Cell Survival in Humans

Severe spiral ganglion cell loss does not necessarily follow loss of hair cells or supporting cells in humans. Despite some publications to the contrary, statements that loss of hair cells and/or supporting cells of the organ of Corti results in a severe loss of spiral ganglion cells in humans still appear in the literature, especially in respect to cochlear implants. This assumption is apparently based on studies in animals or cell culture and not from studies of human temporal bones. Morphological analysis of archival temporal bones with microscopic and statistical analysis of ganglion cell, hair cell, and supporting cell populations was performed in 33 ears with total hearing losses of varying causes and durations of deafness. None of the ears had remaining hair cells. Six ears had had cochlear implants. Ganglion cell counts ranging from 2,889 to 34,299 and the corresponding percentage of remaining ganglion cells based on age-normative data were not significantly related to the duration of hearing loss (r = -0.13 and 0.02, respectively, p > 0.05) or to remaining supporting cell populations (r's from 0.15 to 0.27, p > 0.05). More than half of ears (51.5%) had ganglion cell counts within two standard deviations of age-normative means. Mean ganglion cell counts and percentage of remaining ganglion cells of ears with surviving peripheral processes (dendrites) did not differ significantly from those of ears with no peripheral processes. The loss of hair and supporting cells in the organ of Corti in humans does not necessarily result in as significant a loss of spiral ganglion cells as has been reported animals. In fact, our results suggest that ganglion cell loss may be a primary concomitant loss due to the disease process.

Neural losses correlated with visual losses in clinical perimetry.

The validity of clinical perimetry for evaluation of the pathology of glaucoma is based on correlated losses in retinal ganglion cells and visual sensitivity, but procedures to quantify neural losses from visual field defects have not been developed. The purpose of the present study was to investigate the neural and sensitivity losses from experimental glaucoma to establish the framework for a quantitative model for the structure-function relationships of standard clinical perimetry. Perimetry, by behavioral testing, and retinal histology data were obtained from rhesus monkeys with significant visual field defects caused by experimental glaucoma. Ganglion cell densities were obtained from sections of retina that corresponded to 16 perimetry test locations. Perimetry sensitivity as a function of ganglion cell density at corresponding retina/visual field locations was analyzed. The structure-function relationships were linear on log-log coordinates, with parameters that varied systematically with eccentricity. The slope value varied from 1.25 dB/dB at 4.2 degrees from fixation to a value of 2.32 dB/dB at 24 degrees from fixation, whereas the intercept value varied from -25.2 dB to -55.7 dB over the same range of eccentricities. The structure-function relationships produced a model to predict the ganglion cell density underlying a given level of visual sensitivity and location in the visual field. The model, with no free parameters, produced an accurate and relatively precise quantification of retinal ganglion cell losses caused by experimental glaucoma in monkeys. However, because the early detection of glaucoma is limited by intersubject variability, ganglion cell losses of 40% to 50% were necessary before visual sensitivity losses exceeded the normal 95% confidence limits. With retinal eccentricity as a factor, the neural losses from glaucoma are predictable from visual sensitivity measurements by clinical perimetry. The relationships derived from experimental glaucoma in monkeys also accurately predict the rate of age-related losses of retinal ganglion cells in humans, based on the normative perimetry data for age-related reductions in visual sensitivity. The success of the model in this study suggested that it is potentially applicable to the clinical interpretation of the state of glaucomatous optic neuropathy.

Nasotemporal overlap of retinal ganglion cells in humans: a functional study.

A zone of overlap along the vertical retinal meridian where ipsi- and contralaterally projecting ganglion cells intermingle has been demonstrated histologically in nonhuman primates. The widening of the zone of overlap in the foveal region was thought to produce a foveal sparing extending 1.5 degrees in the blind hemifield in human hemianopia. The functional relevance of the nasotemporal overlap is still unclear and cannot be shown definitely by conventional perimetry, because of insufficient spatial accuracy, light-scattering effects, and insufficient fixation control. Therefore, this study was undertaken to investigate the vertical field border by a perimetric method that does not have these shortcomings. A scanning laser ophthalmoscope (SLO) was used to scan vertical triplets of dots along the vertical field border in 20 patients (36 eyes) with homonymous hemianopia without macular sparing. Stimuli and fundus were imaged simultaneously for fixation monitoring. None of the patients showed a field border that coincided exactly with the vertical midline. In 34 eyes, the seeing area extended from the vertical meridian into the blind hemifield and formed a vertical strip of perception. None of the patients showed additional foveal sparing. Twenty-two eyes showed a concave shape of the seeing area within the foveal region of the blind hemifield. Our results show that the nasotemporal overlap exists in humans. It consists of a strip of intact perception reaching into the blind hemifield. The concave shape can be explained by the size and distribution of the receptive fields of the retinal ganglion cells.

Analysis of Second-order Kernel Response Components of Multifocal Electroretinograms Elicited from Normal Subjects

Purpose: It has been reported that the second-order kernel response components of multifocal electroretinograms (mERGs) reflect the electrical activity of the inner retinal layers. In this study, we have investigated whether the amplitudes of the second-order kernel response components correlate with the spatial distribution of human retinal ganglion cells. Methods: Multifocal electroretinograms were recorded using the Veris III™ system from 5 healthy subjects with different stimulus and recording parameters. The mERGs were analyzed using the Veris Science™ software programs. The stimuli consisted of densely arranged arrays of 103, 61, 37 or 19 hexagonal elements. Four minutes were required to record one set of mERG responses using 8 sessions, and 8 minutes using 16 sessions. The second-order kernel response components were extracted and analyzed using the Veris Science™ program. Results: The signal-to-noise ratio of the first-order kernel response components was improved considerably by the summation of the nine reproducible responses from the same subject but the second-order kernel response components were not. The summation of the nine reproducible responses was insufficient to identify an array of the second-order kernel response components. Both the first- and second-order kernel response components were larger when fewer hexagonal elements were used. There was no significant difference in the individual responses between the 4-minute and the 8-minute recordings. A response density analysis revealed a weak correlation between the amplitude distribution of the second-order kernel response components and the spatial distribution of human retinal ganglion cells. Conclusions: The distribution of the amplitudes of the second-order kernel response components of the mERGs elicited from normal subjects did not correlate with the distribution of human ganglion cells. This suggests that the theory that second-order kernel response components arise from the activity of retinal ganglion cells should be reconsidered.

Prevalence and ultrastructural morphology of axosomatic synapses on spiral ganglion cells in humans of different ages

Axosomatic synapses were found on human spiral ganglion cells (HSGCs). Ultrastructural characterization and calculation of the prevalence of these synapses were performed by electron microscopic semi-serial sections of both type I and type II HSGCs, in specimens from subjects of ages 1 day, 14 days, 21 years and 51 years. Synapses on type I HSGCs were extremely rare. In contrast, axosomatic synapses were present on approximately 50% of type II HSGCs of a young adult. This prevalence seemed to vary by age. Thus, no synapses were found in a 1-day old neonate, few in a 14-day old, and on approximately 15% of the type II SGCs from a 51-year old specimen. The origin of the nerve fibers synapsing on the type II HSGCs could not be determined. In view of the fact that some of the fibers projected from the intraganglionic spiral bundle, which is known to contain olivocochlear efferents, these fibers may represent an efferent pathway to the spiral ganglion. However, since there was morphological evidence of more than one type of nerve fiber synapsing on type II HSGCs, other neural origins must be considered. Although the physiological function of these synapses is unknown, they may mediate pre-synaptic neural modulation of the type II HSGCs at the level of the spiral ganglion.

The excitotoxicity theory of glaucoma

Glaucoma can be defined as a disease in which one of the pathophysiological consequences of raised intra-ocular pressure is damage of the optic nerve, and subsequently the loss of retinal ganglion cells (RGCs). One of the main aims of modern glaucoma therapy is to alter the intraocular pressure, either surgically or pharmacologically. Recently it was shown that the vitreous of glaucoma patients contains increased levels of glutamate (27 microM as compared to 11 microM in controls). This concentration of glutamate is sufficient to induce retinal ganglion cell death. The rise in intraocular pressure is probably the initial insult, which enhances the increase or release of glutamate. Although the increase in intravitreal glutamate levels is an accompanying feature of glaucoma, it could contribute to the loss of retinal ganglion cells in humans itself. Therefore, despite efficient control of intra-ocular pressure, RGC's loss will continue resulting in further visual impairment, if the toxic effect of glutamate is not blocked. If it would be possible to understand the mechanism leading to excessive vitreous levels of glutamate in glaucoma or to block its toxic effects, then the resulting visual loss could be retarded. This review discusses various proposed mechanisms leading to intraocular glutamate toxicity and the role of neuroprotection in this disease. (Literature search by Medline).

Quantitative evaluation of cochlear neurons and computer-aided three-dimensional reconstruction of spiral ganglion cells in humans with a peripheral loss of nerve fibres

Quantitative data on human cochlear neuronal elements were collected from various regions in five patients with high-tone hearing loss due to presbycusis and in two patients with normal hearing. The number of nerve fibres was assessed in the spiral lamina and in the inner acoustic meatus together with counts of spiral ganglion cells. The results show that the number of neurons decreased peripherally, i.e., with increasing distance from the central nervous system in patients with high-tone hearing loss due to presbycusis. In two patients with normal hearing no significant difference in the number of neurons was found in the lamina spiralis as compared to the inner acoustic canal. Computer-aided 3-dimensional reconstruction of the human spiral ganglion displayed large bipolar neurons (type I cells), but also large ganglion cells with one missing axon. The results may indicate that a slow retrograde degeneration occurs from the periphery towards the spiral ganglion in presbycusis. Transmission electron microscopy analysis of freshly fixed human spiral ganglions displayed interneural connections. It is speculated whether a trophic supply from other neurons at the level of the spiral ganglion can prevent or delay further degeneration of the central axon.

Nerve fibre interaction with large ganglion cells in the human spiral ganglion: A TEM study

A TEM study was performed on freshly fixed human spiral ganglions (HSG) biopsied during skull base surgery. Well preserved tissue specimens were obtained for ultrastructural analysis. The investigation revealed that nerve fibres frequently form contacts with the large ganglion cells (type I cells). In the areas of contact, membrane specializations occurred, consisting of symmetric or asymmetric densities often alternating from one cell to the other with a reduced intercellular distance ( ~ 10 nm). High power TEM showed the intercellular cleft to contain an extra dense line resulting in a pentalaminar structure. The dense line appeared on the side of the membrane protein concentration. Protein densities jutted into the cytoplasm along the intracellular face spreading into a diffuse cytoplasmic web physically related to accumulating mitochondria. This indicated a concentration of oxygen-dependant metabolic activity in these regions. It is believed that the nerve junctions are involved in electric transmission between type I ganglion cells. The neural junctions were morphologically different from synaptic contacts between small human ganglion cells (type II cells) and nerve fibres which have been suspected of sharing the olivocochlear bundle as their origin.

T Cell–mediated ganglionitis associated with acute sensory neuronopathy

A 67-year-old man presented with acute painful sensory loss, areflexia, ataxia, urinary retention, and severe constipation and became unable to walk within 2 weeks. He died suddenly 5 weeks after the onset of symptoms. Autopsy revealed widespread inflammation of sensory and autonomic ganglia with immunocytochemical evidence of a CD8+ T cell-mediated cytotoxic attack against ganglion neurons. This observation suggests a novel pathogenetic mechanism of immune-mediated human ganglion cell damage comparable to mechanisms operating in polymyositis.

Very large neurons of the inner retina of humans and other mammals.

Large ganglion cells, called parasol cells, are known to occur in the Golgi-stained, human retina. This report describes a population of much larger cells that is not stained by Golgi technique. These cells may be located in the human ganglion cell layer using Nomarski differential interference contrast optics and unstained, flatmounted tissue. These cells are regularly distributed in young and old adults in a Gaussian fashion along the radii that extend from the perimacula toward the far periphery. The author did not find the cells in the central retina. The most frequent (J-type) cells have soma diameters between 26 and 40 microns. Rare (S-type) cells measure up to 55 microns in diameter. Many cells have processes that appear to be axons or dendrites. These cell types may be especially sensitive to damage early in diseases of the inner retina.

Functional differentiation of a human ganglion cell derived neuroblastoma cell line SH-SY5Y induced by a phorbol ester (TPA)

When the human neuroblastoma cell line SH-SY5Y is exposed to 12- o-tetradecanoyl-phorbol-13-acetate (TPA) the cells grow long processes indicative of neural differentiation. Concomitantly there is an increase in the resting membrane potential from −44 ± 2 mV found in untreated cells to −63 ± 4 mV after induction. The TPA treated cells are depolarized when the external potassium concentration is increased to 46 mM and upon addition of veratridine. In contrast to the untreated cells depolarization in differentiated cells leads to an increase in the rate of Ca 2+ influx. This increase in Ca 2+ influx is blocked by the Ca 2+ channel antagonist, verapamil, while the Na + channel blocker tetrodotoxin only marginally inhibits the K + depolarization-induced Ca 2+ influx. The results suggest that the induction of morphological differentiation in this cell line is associated with the appearance of features of excitable cells.

Limited transcription of the herpes simplex virus genome when latent in human sensory ganglia.

Human paravertebral ganglia were examined for the presence of specific sequences of viral RNA by in situ cytological hybridization, using as probes individual fragments of herpes simplex virus type 2 DNA. Ganglia were obtained at autopsy from 40 patients, and 14 were positive for herpes simplex virus RNA. Transcripts from the left-hand 30% of the viral genome were detected in all of the herpes simplex virus-positive cases. RNA homologous to other sequences from the L component were present less frequently, and no RNA from the S component was detected. These results argue that specific transcription of the herpes simplex virus genome occurs in latently infected human ganglion cells.