The macaque visual cortex is exquisitely organized into columns, modules, and streams, much of which can be correlated with its metabolic organization revealed by cytochrome oxidase (CO). Plasticity in the adult primate visual system has also been documented by changes in CO activity. Yet, the molecular mechanism of regulating this enzyme remains not well understood. Being one of only four bigenomic enzymes in mammalian cells, the transcriptional regulation of this enzyme necessitates a potential bigenomic coordinator. Nuclear respiratory factor 2 (NRF-2) or GA-binding protein is a transcription factor that may serve such a critical role. The goal of the present study was to determine if the two major subunits of NRF-2, 2α and 2β, had distinct subcellular distribution in neurons of the rat and monkey visual cortex, if major metabolic neuronal types in the macaque exhibited different levels of the two subunits, and if they would respond differently to monocular impulse blockade. Quantitative immuno-electron microscopy was used. In both rats and monkeys, nuclear labeling of α and β subunits was mainly over euchromatin rather than heterochromatin, consistent with their active participation in transcriptional activity. Cytoplasmic labeling was over free ribosomes, the Golgi apparatus, and occasionally the nuclear envelope, signifying sites of synthesis and possible posttranslational modifications. The density of both subunits was much higher in the nucleus than in the cytoplasm for all neurons examined, again indicating that their major sites of cellular action is in the nucleus. In both layer IVC and supragranular puffs of the macaque visual cortex, the expression of both NRF-2α and β was higher in medium-sized, non-pyramidal (type C and C-like) cells previously shown to have higher CO activity than small, type A and A-like cells with low CO activity. Pyramidal, type B cells in puffs had intermediate levels of CO as well as NRF-2α and β labeling. Monocular impulse blockade induced a greater reduction of NRF-2 labeling in type C/C-like than type A/A-like cells. These results substantiate and extend our previous findings that NRF-2 is constitutively active in adult primate and rat visual cortical neurons, that it is expressed more strongly in metabolically more active neurons, and that its level is directly regulated by neuronal activity, the blockade of which imposes a greater down-regulation of this transcription factor in metabolically more active than less active neurons.

Phosducin (Pd) is a 28-kD phosphoprotein whose expression in retina appears limited to photoreceptor cells. Pd binds to the β,γ subunits of transducin (Gt). Their binding affinity is markedly diminished by Pd phosphorylation. While Pd has long been regarded as a candidate for the regulation of Gt, the molecular details of Pd function remain unclear. This gap in understanding is due in part to a lack of precise information concerning the total amount and subcellular localization of rod Pd. While earlier studies suggested that Pd was a rod outer segment (ROS) protein, recent findings have demonstrated that Pd is distributed throughout the rod. In this report, the subcellular distribution and amounts of rat Pd are quantified with immunogold electron microscopy. After light or dark adaptation, retinal tissues were fixed in situ and prepared for ultrathin sectioning and immunogold labeling. Pd concentrations were analyzed over the entire length of the rod. The highest Pd labeling densities were found in the rod synapse. Less intense Pd staining was observed in the ellipsoid and myoid regions, while minimal labeling densities were found in the ROS and the rod nucleus. In contrast with rod Gt, no evidence was found for light-dependent movement of Pd between inner and outer segments. There is a relative paucity of Pd in the ROS as compared with the large amounts of Gt found there. This does not support the earlier idea that Pd could modulate Gt activity by controlling its concentration. On the other hand, the presence of Pd in the nucleus is consistent with its possible role as a regulator of transcription. The functions of Pd in the ellipsoid and myoid regions remain unclear. The highest concentration of Pd was found at the rod synapse, consistent with a suggested role for Pd in the regulation of synaptic function.

Brain-derived neurotrophic factor (BDNF) is a preferred ligand for a member of the tropomyosin-related receptor family, trkB. Activation of trkB is implicated in various activity-independent as well as activity-dependent growth processes in many developing and mature neural systems. In the subcortical visual system, where electrical activity has been implicated in normal development, both differential survival, as well as remodeling of axonal arbors, have been suggested to contribute to eye-specific segregation of retinal ganglion cell inputs. Here, we tested whether BDNF is required for eye-specific segregation of visual inputs to the lateral geniculate nucleus and the superior colliculus, and two other major subcortical target fields in mice. We report that eye-specific patterning is normal in two mutants that lack BDNF expression during the segregation period: a germ-line knockout for BDNF, and a conditional mutant in which BDNF expression is absent or greatly reduced in the central nervous system. We conclude that the availability of BDNF is not necessary for eye-specific segregation in subcortical visual nuclei.

In the Royal College of Surgeons, rat photoreceptor degeneration occurs over the first several months of life, causing deterioration of visual cortical responsiveness seen as greater numbers of cells being nonresponsive to visual stimulation, poor tuning of those cells that do respond, and an overall tendency for domination by the contralateral visual input. If the progress of degeneration in one eye is slowed by intraretinal cell transplantation, cortical responses to stimulation of the remaining, untreated, eye are much stronger, better tuned and histograms of ocular dominance resemble more those in normal rats. This suggests that the rescued eye is able to enhance performance in the untreated eye by some form of postsynaptic mechanism.

Multifocal VEP (mfVEP) responses were obtained from 13 normal human subjects for nine test conditions, covering three viewing conditions (dichoptic and left and right monocular), and three different temporal stimulation forms (rapid contrast reversal, rapid pattern pulse presentation, and slow pattern pulse presentation). The rapid contrast reversal stimulus had pseudorandomized reversals of checkerboards in each visual field region at a mean rate of 25 reversals/s, similar to most mfVEP studies to date. The rapid pattern pulse presentation had pseudorandomized presentations of a checkerboard for one frame, interspersed with uniform grey frames, with a mean rate of 25 presentations/s per region per eye. The slow pattern pulse stimulus had six presentations/s per region per eye. Recording time was 5.3 min/condition. For dichoptic presentation slow pattern pulse responses were 4.6 times larger in amplitude than the contrast reversal responses. Binocular suppression was greatest for the contrast reversal stimulus. Consideration of the signal-to-noise ratios indicated that to achieve a given level of reliability, slow pattern pulse stimuli would require half the recording time of contrast reversal stimuli for monocular viewing, and 0.4 times the recording time for dichoptically presented stimuli. About half the responses to the slow pattern pulse stimuli had peak value exceeding five times their estimated standard error. Responses were about 20% smaller in the upper visual field locations. Space–time decomposition showed that responses to slow pattern pulse were more consistent across visual field locations. We conclude that the pattern pulse stimuli, which we term temporally sparse, maintain the visual system in a high contrast gain state. This more than compensates for the smaller number of presentations in the run, and provides signal-to-noise advantages that may be valuable in clinical application.

Cannabinoid CB1 receptor (via Gs) and dopamine D2 receptor (via Gi/o) antagonistically modulate goldfish cone membrane currents. As ON bipolar cells have CB1 and D1 receptors, but not D2 receptors, we focused on whether CB1 receptor agonist and dopamine interact to modulate voltage-dependent outward membrane K+ currents IK(V) of the ON mixed rod/cone (Mb) bipolar cells. Whole-cell currents were recorded from Mb bipolar cells in goldfish retinal slices. Mb bipolar cells were identified by intracellular filling with Lucifer yellow. The bath solution was calcium-free and contained 1 mM cobalt to block indirect calcium-dependent effects. Dopamine (10 μM) consistently increased IK(V) by a factor of 1.57 ± 0.12 (S.E.M., n = 15). A CB receptor agonist, WIN 55212-2 (0.25–1 μM), had no effect, but 4 μM WIN 55212-2 suppressed IK(V) by 60%. If IK(V) was first increased by 10 μM dopamine, application of WIN 55212-2 (0.25–1 μM) reversibly blocked the effect of dopamine even though these concentrations of WIN 55212-2 had no effect of their own. If WIN 55212-2 was applied first and dopamine (10 μM) was added to the WIN-containing solution, 0.1 μM WIN 55212-2 blocked the effect of dopamine. All effects of WIN 55212-2 were blocked by coapplication of SR 141716A (CB1 antagonist) and pretreatment with pertussis toxin (blocker of Gi/o) indicating action via CB1 receptor activation of G protein Gi/o. Coactivation of CB1 and D1 receptors on Mb bipolar cells produces reciprocal effects on IK(V). The CB1-evoked suppression of IK(V) is mediated by G protein Gi/o, whereas the D1-evoked enhancement is mediated by G protein Gs. As dopamine is a retinal “light” signal, these data support our notion that endocannabinoids function as a “dark” signal, interacting with dopamine to set retinal sensitivity.

The size of the receptive field of retinal horizontal cells changes with the state of dark/light adaptation. We have used a mathematical model to determine how changes in the membrane conductance affect the receptive-field properties of horizontal cells. We first modeled the nonlinear membrane properties of horizontal cells based on ionic current mechanisms. The dissociated horizontal cell model reproduced the voltage–current (V–I) relationships for various extracellular glutamate concentrations measured in electrophysiological studies. Second, a network horizontal cell model was also described, and it reproduced the V–I relationship observed in vivo. The network model showed a bell-shaped relationship between the receptive-field size and constant glutamate concentration. The simulated results suggest that the calcium current is a candidate for the bell-shaped length constant relationship.

Psychophysical measurements using achromatic grating resolution acuity in peripheral vision show a prominent retinal asymmetry in acuity which is consistent with predicted values based on available estimates of midget ganglion cell density. Recent studies have shown that peripheral grating resolution acuity values for short-wavelength-sensitive (SWS) isolating gratings in normal observers are closely related to predicted values based on the underlying small bistratified ganglion cell density. By measuring SWS resolution acuity at different locations across the visual field, we wished to see if any significant acuity asymmetry exists for the short-wavelength system. In addition to this, we wanted to compare SWS and achromatic resolution acuity at different retinal locations of equal eccentricity. SWS and achromatic grating resolution acuity was measured in two observers at a number of different retinal meridians of 10- and 25-deg eccentricity from the fovea, and out to 35-deg eccentricity along the horizontal meridian. Achromatic resolution acuity was higher than SWS resolution acuity at all locations. At 10-deg eccentricity there was slight radial asymmetry in SWS and achromatic acuity, both displaying highest acuity along the horizontal meridian. At 25-deg eccentricity, SWS and achromatic acuity showed significant asymmetry with acuity being higher in the nasal retina compared to the temporal retina and with higher acuity in the superior retina compared to the inferior retina. At 35-deg eccentricity, the acuity asymmetry along the horizontal meridian was maintained with acuity for both significantly higher in the nasal retina. The SWS acuity changes with eccentricity and meridian were qualitatively similar to that found for achromatic acuity at the majority of retinal locations. Like achromatic acuity, SWS acuity shows significant asymmetry at different retinal locations of equal eccentricity. This suggests that both the midget and small bistratified ganglion cell population density changes significantly with retinal location and eccentricity. SWS acuity appears to change in parallel with achromatic acuity for the majority of retinal locations measured, although the amount of nasotemporal asymmetry appears to be slightly less for the SWS system at 25- and 35-deg eccentricity.

Cortical neurons selective for the direction of motion often exhibit some limited response to motion in their nonpreferred directions. Here we examine the dependence of neuronal direction selectivity on stimulus contrast, both for first-order (luminance-modulated, sine-wave grating) and second-order (contrast-modulated envelope) stimuli. We measured responses from single neurons in area 18 of cat visual cortex to both kinds of moving stimuli over a wide range of contrasts (1.25–80%). Direction-selective contrast response functions (CRFs) were calculated as the preferred-minus-null difference in average firing frequency as a function of contrast. We also applied receiver operating characteristic analysis to our CRF data to obtain neurometric functions characterizing the potential ability of each neuron to discriminate motion direction at each contrast level tested. CRFs for sine-wave gratings were usually monotonic; however, a substantial minority of neurons (35%) exhibited nonmonotonic CRFs (such that the degree of direction selectivity decreased with increasing contrast). The underlying preferred and nonpreferred direction CRFs were diverse, often having different shapes in a given neuron. Neurometric functions for direction discrimination showed a similar degree of heterogeneity, including instances of nonmonotonicity. For contrast-modulated stimuli, however, CRFs for either carrier or envelope contrast were always monotonic. In a given neuron, neurometric thresholds were typically much higher for second- than for first-order stimuli. These results demonstrate that the degree of a cell's direction selectivity depends on the contrast at which it is measured, and therefore is not a characteristic parameter of a neuron. In general, contrast response functions for first-order stimuli were very heterogeneous in shape and sensitivity, while those for second-order stimuli showed less sensitivity and were quite stereotyped in shape.

The superficial layers of the frog optic tectum receive a projection from the contralateral eye that forms a point-to-point map of the visual field. The monocular part of the visual field of the contralateral eye is represented in the caudolateral region of the tectum while the binocular part of the visual field is represented in the rostromedial tectum. Within the representation of the binocular field (rostromedial tectum), the maps of visual space from each eye are aligned. The tectal representation of the binocular visual field of the ipsilateral eye is mediated through a crossed projection from the midbrain nucleus isthmi. This isthmotectal projection also terminates in the caudolateral region of the optic tectum, yet there has been no indication that it forms a functional connection. By extracellular recording in intermediate layer 7 of the caudolateral tectum, we have discovered electrical activity driven by visual stimulation in the monocular visual field of the ipsilateral eye. The units driven from the ipsilateral eye burst upon initial presentation of the stimulus. At individual layer 7 recording sites in the caudolateral tectum, the multiunit receptive field evoked from the ipsilateral eye is located at the mirror image spatial location to the multiunit receptive field driven by the contralateral eye. Thus, as revealed electrophysiologically, there are superimposed topographic maps of the monocular visual fields in the caudolateral tectum. The ipsilateral eye monocular visual field representation can be abolished by electrolytic ablation of contralateral nucleus isthmi.

A rare type of rodent retinal ganglion cell expresses melanopsin (Opn4), the majority of which project to the suprachiasmatic nuclei. Many of these cells are directly light sensitive and appear to regulate the circadian system in the absence of rod and cone photoreceptors. However, the rodent retina contains no overt regions of specialization, and the different ganglion cell types are hard to distinguish. Consequently, attempts to distinguish the distribution of melanopsin ganglion cells in relation to regions of retinal specialization or subtype have proved problematic. Retinal cells with a common function tend to be regularly distributed. In this study, we isolate cat melanopsin and label melanopsin expressing cells using in situ hybridization. The labelled cells were all confined to the ganglion cell layer, their density was low, and their distribution was random. Melanopsin containing cells showed no clear center-to-periphery gradient in their distribution and were comprised of a relatively uniform cellular population.

(article appeared in Visual Neuroscience (2004), 21, 283–289

Due to a production error, the second author affiliation is incorrectly cited. It should have read as follows:

INSERM U371, Cerveau et Vision, IFR 19, Institut Fédératif des Neurosciences, Université Claude Bernard Lyon I, Bron France