John B. Troy

Steady discharges of X and Y retinal ganglion cells of cat under photopic illuminance

The discharges of ON- and OFF-center X and Y retinal ganglion cells in the presence of stationary patterns or of a uniform field of photopic luminance were recorded from urethane-anesthetized adult cats. The interval statistics and power spectra of these discharges were determined from these discharge records. The patterned stimuli were selected and positioned with respect to a cells receptive field so as to generate steady discharges that were different in mean discharge rate from that cells discharge for the diffuse field. The interval statistics of discharges recorded for diffuse or patterned illumination for all cell types can be modeled, approximately, as coming from renewal processes with gamma-distributed intervals. The gamma order of the interval distributions was found to be nearly proportional to the mean discharge rate for X cells, but not for Y cells. Typical values for the gamma orders and their dependence on mean rate for different cell types are given. The same model of a renewal process with gamma-distributed intervals is used to model the measured power spectra and performs well. When the gamma order is proportional to mean rate, the power spectral density at low temporal frequencies is independent of discharge rate. Gamma order was proportional to mean rate for X cells but not for Y cells. Nonetheless, the power spectral densities of both cell types at low frequencies were approximately independent of discharge rate. Hence, noise in this band of frequencies can be considered additive. The consequences of departures from the renewal process and of the gamma order not being proportional to mean rate are considered. The significance of different rates of discharge for signaling is discussed.

Y-cell receptive field and collicular projection of parasol ganglion cells in macaque monkey retina.

The distinctive parasol ganglion cell of the primate retina transmits a transient, spectrally nonopponent signal to the magnocellular layers of the lateral geniculate nucleus. Parasol cells show well-recognized parallels with the α-Y cell of other mammals, yet two key α-Y cell properties, a collateral projection to the superior colliculus and nonlinear spatial summation, have not been clearly established for parasol cells. Here, we show by retrograde photodynamic staining that parasol cells project to the superior colliculus. Photostained dendritic trees formed characteristic spatial mosaics and afforded unequivocal identification of the parasol cells among diverse collicular-projecting cell types. Loose-patch recordings were used to demonstrate for all parasol cells a distinct Y-cell receptive field “signature” marked by a nonlinear mechanism that responded to contrast-reversing gratings at twice the stimulus temporal frequency [second Fourier harmonic (F2)] independent of stimulus spatial phase. The F2 component showed high contrast gain and temporal sensitivity and appeared to originate from a region coextensive with that of the linear receptive field center. The F2 spatial frequency response peaked well beyond the resolution limit of the linear receptive field center, showing a Gaussian center radius of ∼15 μm. Blocking inner retinal inhibition elevated the F2 response, suggesting that amacrine circuitry does not generate this nonlinearity. Our data are consistent with a pooled-subunit model of the parasol Y-cell receptive field in which summation from an array of transient, partially rectifying cone bipolar cells accounts for both linear and nonlinear components of the receptive field.

Incorporation of the electrode-electrolyte interface into finite-element models of metal microelectrodes

An accurate description of the electrode-electrolyte interfacial impedance is critical to the development of computational models of neural recording and stimulation that aim to improve understanding of neuro-electric interfaces and to expedite electrode design. This work examines the effect that the electrode-electrolyte interfacial impedance has upon the solutions generated from time-harmonic finite-element models of cone- and disk-shaped platinum microelectrodes submerged in physiological saline. A thin-layer approximation is utilized to incorporate a platinum-saline interfacial impedance into the finite-element models. This approximation is easy to implement and is not computationally costly. Using an iterative nonlinear solver, solutions were obtained for systems in which the electrode was driven at ac potentials with amplitudes from 10 mV to 500 mV and frequencies from 100 Hz to 100 kHz. The results of these simulations indicate that, under certain conditions, incorporation of the interface may strongly affect the solutions obtained. This effect, however, is dependent upon the amplitude of the driving potential and, to a lesser extent, its frequency. The solutions are most strongly affected at low amplitudes where the impedance of the interface is large. Here, the current density distribution that is calculated from models incorporating the interface is much more uniform than the current density distribution generated by models that neglect the interface. At higher potential amplitudes, however, the impedance of the interface decreases, and its effect on the solutions obtained is attenuated.

Sustained ocular hypertension induces dendritic degeneration of mouse retinal ganglion cells that depends on cell type and location.

PURPOSE Glaucoma is characterized by retinal ganglion cell (RGC) death and frequently associated with elevated IOP. How RGCs degenerate before death is little understood, so we sought to investigate RGC degeneration in a mouse model of ocular hypertension. METHODS A laser-induced mouse model of chronic ocular hypertension mimicked human high-tension glaucoma. Immunohistochemistry was used to characterize overall RGC loss and an optomotor behavioral test to measure corresponding changes in visual capacity. Changes in RGC functional properties were characterized by a large-scale multielectrode array (MEA). The transgenic Thy-1-YFP mouse line, in which a small number of RGCs are labeled with yellow fluorescent protein (YFP), permitted investigation of whether subtypes of RGCs or RGCs from particular retinal areas were differentially vulnerable to elevated IOP. RESULTS Sustained IOP elevation in mice was achieved by laser photocoagulation. We confirmed RGC loss and decreased visual acuity in ocular hypertensive mice. Furthermore, these mice had fewer visually responsive cells with smaller receptive field sizes compared to controls. We demonstrated that RGC dendritic shrinkage started from the vertical axis of hypertensive eyes and that mono-laminated ON cells were more susceptible to IOP elevation than bi-laminated ON-OFF cells. Moreover, a subgroup of ON RGCs labeled by the SMI-32 antibody exhibited significant dendritic atrophy in the superior quadrant of the hypertensive eyes. CONCLUSIONS RGC degeneration depends on subtype and location in hypertensive eyes. This study introduces a valuable model to investigate how the structural and functional degeneration of RGCs leads to visual impairments.

Orientation sensitivity of ganglion cells in primate retina

The two-dimensional shape of the receptive field center of macaque retinal ganglion cells was determined by measuring responses to drifting sinusoidal gratings of different spatial frequency and orientation. The responses of most cells to high spatial frequencies depended on grating orientation, indicating that their centers were not circularly symmetric. In general, center shape was well described by an ellipse. The major axis of the ellipse tended to point towards the fovea or perpendicular to this. Parvocellular pathway cells had greater center ellipticity than magnocellular pathway cells; the median ratio of the major-to-minor axis was 1.72 and 1.38, respectively. Parvocellular pathway cells also had centers that were often bimodal in shape, suggesting that they received patchy cone/bipolar cell input. We conclude that most ganglion cells in primate retina have elongated receptive field centers and thus show orientation sensitivity.

Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse

We performed genome-wide chemical mutagenesis of C57BL/6J mice using N-ethyl-N-nitrosourea (ENU). Electroretinographic screening of the third generation offspring revealed two G3 individuals from one G1 family with a normal a-wave but lacking the b-wave that we named nob4. The mutation was transmitted with a recessive mode of inheritance and mapped to chromosome 11 in a region containing the Grm6 gene, which encodes a metabotropic glutamate receptor protein, mGluR6. Sequencing confirmed a single nucleotide substitution from T to C in the Grm6 gene. The mutation is predicted to result in substitution of Pro for Ser at position 185 within the extracellular, ligand-binding domain and oocytes expressing the homologous mutation in mGluR6 did not display robust glutamate-induced currents. Retinal mRNA levels for Grm6 were not significantly reduced, but no immunoreactivity for mGluR6 protein was found. Histological and fundus evaluations of nob4 showed normal retinal morphology. In contrast, the mutation has severe consequences for visual function. In nob4 mice, fewer retinal ganglion cells (RGCs) responded to the onset (ON) of a bright full field stimulus. When ON responses could be evoked, their onset was significantly delayed. Visual acuity and contrast sensitivity, measured with optomotor responses, were reduced under both photopic and scotopic conditions. This mutant will be useful because its phenotype is similar to that of human patients with congenital stationary night blindness and will provide a tool for understanding retinal circuitry and the role of ganglion cell encoding of visual information.

Visual responses of ganglion cells of a New‐World primate, the capuchin monkey, Cebus apella

1 The genetic basis of colour vision in New‐World primates differs from that in humans and other Old‐World primates. Most New‐World primate species show a polymorphism; all males are dichromats and most females trichromats. 2 In the retina of Old‐World primates such as the macaque, the physiological correlates of trichromacy are well established. Comparison of the retinae in New‐ and Old‐World species may help constrain hypotheses as to the evolution of colour vision and the pathways associated with it. 3 Ganglion cell behaviour was recorded from trichromatic and dichromatic members of a New‐World species (the capuchin monkey, Cebus apella) and compared with macaque data. Despite some differences in quantitative detail (such as a temporal response extended to higher frequencies), results from trichromatic animals strongly resembled those from the macaque. 4 In particular, cells of the parvocellular (PC) pathway showed characteristic frequency‐dependent changes in responsivity to luminance and chromatic modulation, cells of the magnocellular (MC) pathway showed frequency‐doubled responses to chromatic modulation, and the surround of MC cells received a chromatic input revealed on changing the phase of heterochromatically modulated lights. 5 Ganglion cells of dichromats were colour‐blind versions of those of trichromats. 6 This strong physiological homology is consistent with a common origin of trichromacy in New‐ and Old‐World monkeys; in the New‐World primate the presence of two pigments in the middle‐to‐long wavelength range permits full expression of the retinal mechanisms of trichromatic vision.

Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses.

An electroretinogram (ERG) screen identified a mouse with a normal a‐wave but lacking a b‐wave, and as such it was designated no b‐wave3 (nob3). The nob3 phenotype mapped to chromosome 11 in a region containing the metabotropic glutamate receptor 6 gene (Grm6). Sequence analyses of cDNA identified a splicing error in Grm6, introducing an insertion and an early stop codon into the mRNA of affected mice (designated Grm6nob3). Immunohistochemistry of the Grm6nob3 retina showed that GRM6 was absent. The ERG and visual behaviour abnormalities of Grm6nob3 mice are similar to Grm6nob4 animals, and similar deficits were seen in compound heterozygotes (Grm6nob4/nob3), indicating that Grm6nob3 is allelic to Grm6nob4. Visual responses of Grm6nob3 retinal ganglion cells (RGCs) to light onset were abnormal. Grm6nob3 ON RGCs were rarely recorded, but when they were, had ill‐defined receptive field (RF) centres and delayed onset latencies. When Grm6nob3 OFF‐centre RGC responses were evoked by full‐field stimulation, significantly fewer converted that response to OFF/ON compared to Grm6nob4 RGCs. Grm6nob4/nob3 RGC responses verified the conclusion that the two mutants are allelic. We propose that Grm6nob3 is a new model of human autosomal recessive congenital stationary night blindness. However, an allelic difference between Grm6nob3 and Grm6nob4 creates a disparity in inner retinal processing. Because the localization of GRM6 is limited to bipolar cells in the On pathway, the observed difference between RGCs in these mutants is likely to arise from differences in their inputs.

The Smooth Monostratified Ganglion Cell: Evidence for Spatial Diversity in the Y-Cell Pathway to the Lateral Geniculate Nucleus and Superior Colliculus in the Macaque Monkey

In the primate visual system approximately 20 morphologically distinct pathways originate from retinal ganglion cells and project in parallel to the lateral geniculate nucleus (LGN) and/or the superior colliculus. Understanding of the properties of these pathways and the significance of such extreme early pathway diversity for later visual processing is limited. In a companion study we found that the magnocellular LGN-projecting parasol ganglion cells also projected to the superior colliculus and showed Y-cell receptive field structure supporting the hypothesis that the parasol cells are analogous to the well studied alpha-Y cell of the cats retina. We here identify a novel ganglion cell class, the smooth monostratified cells, that share many properties with the parasol cells. Smooth cells were retrogradely stained from tracer injections made into either the LGN or superior colliculus and formed inner-ON and outer-OFF populations with narrowly monostratified dendritic trees that surprisingly appeared to perfectly costratify with the dendrites of parasol cells. Also like parasol cells, smooth cells summed input from L- and M-cones, lacked measurable S-cone input, showed high spike discharge rates, high contrast and temporal sensitivity, and a Y-cell type nonlinear spatial summation. Smooth cells were distinguished from parasol cells however by smaller cell body and axon diameters but ∼2 times larger dendritic tree and receptive field diameters that formed a regular but lower density mosaic organization. We suggest that the smooth and parasol populations may sample a common presynaptic circuitry but give rise to distinct, parallel achromatic spatial channels in the primate retinogeniculate pathway.

Responses to sinusoidal gratings of two types of very nonlinear retinal ganglion cells of cat

Perhaps 35% of all of the ganglion cells of the cat do not have classical center-surround organized receptive fields. This paper describes, quantitatively, the responses of two such cell types to stimulation with sinusoidal luminance gratings, whose spatial frequency, mean luminance, contrast, and temporal frequency were varied independently. The patterns were well-focused on the retina of the anesthetized and paralyzed cat. In one type of cell, the maintained discharge was depressed or completely suppressed when a contrast pattern was imaged onto the receptive field (suppressed-by-contrast cell). In the other type of cell, the introduction of a pattern elicited a burst of spikes (impressed-by-contrast cell). When stimulated with drifting gratings, the cells mean rate of discharge was reduced (suppressed-by-contrast cell) or elevated (impressed-by-contrast cell) over a limited band of spatial frequencies. There was no significant modulated component of response. The reduction in mean rate of suppressed-by-contrast cells caused by drifting gratings had a monotonic dependence on contrast, a relatively low-pass temporal-frequency characteristic and was greater under photopic than mesopic illuminance. If grating of spatial frequency, that when drifted evoked a response from these cells, were instead held stationary and contrast-reversed, the mean rate of a suppressed-by-contrast cell was also reduced and that of an impressed-by-contrast cell increased. But, for contrast-reversed gratings, the discharge contained substantial modulation at even harmonic frequencies, the largest being the second harmonic. The amplitude of this second harmonic did not depend on the spatial phase of the grating, and its dependence on spatial frequency, at least for suppressed-by-contrast cells, was similar to that of the reduction in mean rate of discharge. Our results suggest that the receptive fields of suppressed-by-contrast and impressed-by-contrast cells can be modeled with the general form of the nonlinear subunit components of Hochstein and Shapleys (1976) Y cell model.