Visual responses in the lateral geniculate evoked by Cx36-independent rod pathways

Emerging evidence indicates rods can communicate with retinal ganglion cells (RGCs) via pathways that do not involve gap-junctions. Here we investigated the significance of such pathways for central visual responses, using mice lacking a key gap junction protein (Cx36^−/−) and carrying a mutation that disrupts cone phototransduction (Gnat2^cpfl3). Electrophysiological recordings spanning the lateral geniculate revealed rod-mediated ON and OFF visual responses in virtually every cell from all major anatomical sub-compartments of this nucleus. Hence, we demonstrate that one or more classes of RGC receive input from Cx36-independent rod pathways and drive extensive ON and OFF responses across the visual thalamus.     

视网膜电图和多焦视网膜电图ON/OFF反应的研究进展

ON/OFF反应是人们从视网膜电生理反应中记录到的视网膜给光、撤光反应。它是通过不同的光感受器细胞形成不同的ON/OFF通路来完成。视网膜电图（ERG）和多焦视网膜电图（mf-ERG）ON/OFF反应的异常可明确提示ON/OFF通路及通路相关细胞的异常,在临床多种疾病,如先天性静止性夜盲,X连锁青年性视网膜病变等的诊断与治疗中有着重要意义。就ON/OFF通路（视锥ON/OFF通路,视杆ON/OFF通路,视杆慢快ON/OFF通路）和ERG、mfERGON/OFF反应的最佳记录方法、条件及在临床中的应用进行综述。     

Spectral sensitivity of ON and OFF responses from the optic nerve of goldfish

The vertebrate retina processes visual information in parallel neural pathways known as the ON and OFF pathways. These pathways encode increments and decrements of light independently as excitatory responses. We examined the photopic spectral response of ON and OFF mechanisms in goldfish by measuring the sensitivity of optic nerve responses to the onset and termination of stimuli of various wavelengths. Using various adapting backgrounds, we found that the ON and OFF responses have different spectral sensitivities. The weighting of the cone inputs to the responses was estimated by an algebraic summation model. This model suggests that for the ON response, input from S-cones is stronger and more independent than for the OFF response, and M- and L-cones show stronger antagonism in the ON response than in the OFF response. The OFF response probably receives input from all cone types, but spectral antagonism is weak and its dominant input is from L-cones.     

Asymmetries in ON and OFF visual pathways of humans revealed using contrast-evoked cortical potentials

Positive- and negative-contrast stimuli yield the perceptions of brightness and darkness, respectively, and are processed separately by ON and OFF neural pathways. The properties of these morphologically and pharmacologically distinct subsystems were measured in humans by recording visual evoked potentials (VEPs). These electrical responses from the visual cortex were elicited by novel positive- and negative-contrast stimuli, designed to emphasize, selectively, contributions from ON and OFF pathways. Results revealed differential processing of the two types of contrast information, suggesting asymmetries in ON and OFF subsystems; OFF subsystems have finer spatial tuning and greater contrast gain than ON subsystems. These VEPs may be useful in diagnosing neurological disorders that involve primarily one subsystem.     

Scotopic sensitivity to ON and OFF stimulus transients

The luminance of a large diffuse field, viewed peripherally, was temporally modulated near absolute detection threshold. The field luminance either increased abruptly and decreased gradually (ON stimulus) or increased gradually and decreased abruptly (OFF stimulus). For all wavelengths shorter than 620 nm, sensitivity to the ON stimulus was greater than to the OFF. The spectral sensitivity curves obtained indicate that rods and/or their associated neural pathways are more sensitive to ON stimulus transients than to OFF.     

Integration and segregation of local motion signals: the role of contrast polarity.

In the initial stages of visual processing in primates, more or less separated ON and OFF pathways have been shown to exist. There is ample evidence, that this separation includes the initial stages of motion processing. In the present study, experiments were conducted to investigate whether this ON versus OFF distinction persists into the integration stage of local motion information. We constructed stimuli that consisted of clusters of checks with equal contrast polarity, which could be varied in size, and compared them to stimuli with a random polarity distribution. We found that the ON versus OFF distinction remains partly intact, while interactions between the two systems are also apparent. These interactions prove to be highly correlated with the spatial structure of the stimulus. We propose a mechanism of contrast-sign specific integration of local motion signals, after which these separate ON and OFF pools engage in mutually inhibitory interactions.     

Unilateral electronegative ERG of non-vascular aetiology

BACKGROUND: Full field and pattern electroretinograms (ERG, PERG) are performed to assess generalised retinal function and macular function, respectively. An (electro) negative full field ERG usually describes an ISCEV standard maximal response in which the b-wave is smaller than a normal or minimally reduced a-wave and indicates dysfunction that is post-phototransduction. The most common cause of a unilateral negative ERG is central retinal artery occlusion (CRAO) or birdshot chorioretinopathy (BCR). This study examines the clinical and electrophysiological features of patients with unilateral negative ERG who do not have CRAO or BCR. METHODS: 12 patients were ascertained with a unilateral negative ERG in whom a vascular aetiology and BCR were excluded. Most presented with symptoms of central retinal dysfunction. In 11 of the 12 patients additional long duration photopic stimuli were used to test cone system ON and OFF responses. RESULTS: All 12 patients had unilateral electronegative bright flash full field ERGs indicating total or relative preservation of rod photoreceptor function, but dysfunction post-phototransduction. Seven of these patients had non-specific inflammatory changes in the eye with the negative ERG. Six patients, including five with inflammatory signs, had involvement of the cone ON response with complete preservation of cone OFF responses. A further three patients showed evidence of cone ON response abnormality with less severe OFF response involvement. CONCLUSION: The ERGs in this heterogeneous group of patients predominantly showed post-phototransduction involvement of the ON pathways. Sparing of the cone OFF response was often observed. The majority of patients had signs of previous inflammation and it is speculated that these highly unusual unilateral changes may be mediated via an autoimmune mechanism.     

Spatial summation of S-cone ON and OFF signals: effects of retinal eccentricity

We studied spatial summation for S-cone ON and OFF signals as a function of retinal eccentricity in human subjects. S-cone isolation was obtained by the two-colour threshold method of Stiles, modified by adding blue light to the yellow background. Test stimuli were blue light increments or decrements within a circular area of variable size. These were presented for 100 ms at 0 to 20 deg along the horizontal temporal retinal meridian. Ricco's area of complete spatial summation was measured from the threshold vs. area curves. This was nearly constant and approximately the same for both types of stimuli within the 0-5 deg range and increased beyond this range. The decremental area increased faster, suggesting that separate mechanisms, presumably ON and OFF, integrate S-cone increments and decrements. The results appear to provide new evidence for the existence of separate S-cone ON and OFF pathways. We compare the data with known morphology of primate retina and assume that, if S-cone decrements are detected via separate OFF cells, these should differ in density and dendritic field size from the S-cone ON cells, but only in the retinal periphery.     

Stratification of α ganglion cells and ON/OFF directionally selective ganglion cells in the rabbit retina

The correlation between cholinergic sensitivity and the level of stratification for ganglion cells was examined in the rabbit retina. As examples, we have used ON or OFF alpha ganglion cells and ON/OFF directionally selective (DS) ganglion cells. Nicotine, a cholinergic agonist, depolarized ON/OFF DS ganglion cells and greatly enhanced their firing rates but it had modest excitatory effects on ON or OFF alpha ganglion cells. As previously reported, we conclude that DS ganglion cells are the most sensitive to cholinergic drugs. Confocal imaging showed that ON/OFF DS ganglion cells ramify precisely at the level of the cholinergic amacrine cell dendrites, and co-fasciculate with the cholinergic matrix of starburst amacrine cells. However, neither ON or OFF alpha ganglion cells have more than a chance association with the cholinergic matrix. Z -axis reconstruction showed that OFF alpha ganglion cells stratify just below the cholinergic band in sublamina a while ON alpha ganglion cells stratify just below cholinergic b . The latter is at the same level as the terminals of calbindin bipolar cells. Thus, the calbindin bipolar cell appears to be a prime candidate to provide the bipolar cell input to ON alpha ganglion cells in the rabbit retina. We conclude that the precise level of stratification is correlated with the strength of cholinergic input. Alpha ganglion cells receive a weak cholinergic input and they are narrowly stratified just below the cholinergic bands.     

Cross-talk between ON and OFF channels in the salamander retina: indirect bipolar cell inputs to ON-OFF ganglion cells

It has been widely accepted that ON and OFF channels in the visual system are segregated with little cross-communication, except for the mammalian rod bipolar cell-AII amacrine cell-ganglion cell pathway. Here, we show that in the tiger salamander retina the light responses of a subpopulation of ON-OFF ganglion cells are mediated by crossing the ON and OFF bipolar cell pathways. Although the majority of ON-OFF ganglion cells (type I cells) receive direct excitatory inputs from depolarizing and hyperpolarizing bipolar cells (DBCs and HBCs), about 5% (type II cells) receive indirect excitatory inputs from DBCs and 20% (type III cells) receive indirect excitatory inputs from HBCs. These indirect bipolar cell inputs are likely to be mediated by a subpopulation of amacrine cells that exhibit transient hyperpolarizing light responses (AC(H)s) and make GABAergic/glycinergic synapses on DBC or HBC axon terminals. GABA and glycine receptor antagonists enhanced the ON and OFF excitatory cation current (DeltaI(C)) in type I ganglion cells, but completely suppressed the ON DeltaI(C) mediated by DBCs in type II cells and the OFF DeltaI(C) mediated by HBCs in types III cells. Dendrites of type I cells ramify in both sublamina A and B, type II cells exclusively in sublamina A, and type III cells exclusively in sublamina B of the inner plexiform layer. These results demonstrate that indirect, amacrine cell-mediated bipolar cell-ganglion cell synaptic pathways exist in a non-mammalian retina, and that bidirectional cross-talk between ON and OFF channels is present in the vertebrate retina.     

Visual experience and maturation of retinal synaptic pathways

The retinal synaptic network continues its maturational refinement after eye opening in mammals. This synaptic refinement is reflected in changes of retinal neuron synaptic activity and connectivity. In mature retina, the dendrites of retinal ganglion cells (RGCs) in the inner plexiform layer (IPL) of retina are separated into ON or OFF sublamina. At early developmental stage, however, the dendrites of most RGCs are ramified throughout the IPL. Recently we found that the postnatal maturational processes converting bistratified ON-OFF responsive RGCs to monostratified ON and OFF responsive RGCs depend upon visual stimulation after eye opening.     

Balanced interactions in ganglion-cell receptive fields.

Receptive fields of retinal ganglion cells in turtle have excitatory and inhibitory components that are balanced along the dimensions of wavelength, functional ON and OFF responses, and spatial assignments of center and surround. These components were analyzed by spectral light adaptations and by the glutamate agonist, 2-amino-4-phosphonobutyric acid (APB). Extracellular recordings to stationary and moving spots of light were used to map changes in receptive fields. ON spike counts minus OFF spike counts, derived from flashed stationary light spots, quantified functional shifts by calculating normalized mean response modulations. The data show that receptive fields are not static, but rather are dynamic arrangements which depend on linked, antagonistic balances among the three dimensions of wavelength, ON and OFF response functions, and center/surround areas.     

Novel electrophysiological instrument for rapid and objective assessment of magnocellular deficits associated with glaucoma

Purpose To introduce a rapid and objective electrophysiological technique that can assess visual function in the magnocellular pathway, which is thought to be affected in early-stage glaucoma. Methods Low-contrast bright or dark isolated-checks were luminance-modulated against a static background at 10 Hz in order to drive preferentially the magnocellular ON or OFF pathway. Visual evoked potentials were recorded during 1-s epochs of stimulation and responses at the stimulus frequency were measured. Artifact rejection features ensured that eight valid runs were obtained per eye. Signal-to-noise ratios (SNR) were derived based on a multivariate statistic. In order to demonstrate its functionality, a small group of patients with glaucoma (N = 18, Snellen acuity of 20/30 or better) and control observers (N = 16) were tested. A participant failed the test if either eye yielded an SNR ≤ 1. Receiver-operating-characteristic curve analysis was used to estimate the accuracy of group classification. Results The instrument was found to elicit reliable responses from control observers. For the 15% bright condition, all control observers yielded significant isolated-check VEPs (icVEPs), whereas the majority of patients failed to do so, indicating significant losses in central visual function. This condition produced the highest classification accuracy (94%), followed by the 10% dark condition (91%). Conclusions Both ON and OFF divisions of the magnocellular pathway can be assessed rapidly through the application of the icVEP technique. This measure of central visual function may be of value in the detection of glaucomatous deficits and may complement tests of peripheral function. Financial Relationships George Hu is President of Synabridge Corporation and the following remaining authors were consultants to Synabridge Corp.—Zemon, Tsai, Forbes, Chen, Gordon, Greenstein, Strugstad, Jindra.     

Recording Rod ON and OFF Responses in ERG and Multifocal ERG

The 5 Hz rectangle stimulus was generally used to record cone ON and OFF response. In this study, the feasibility and recording conditions of recording rod ON and OFF responses in electroretinograms (ERG) and multifocal electroretinograms (mf-ERG) were described, and the character and influence factors of these responses were observed. The result demonstrated that the rod ON and OFF responses of ERG can be recorded with sawtooth rapid-on and rapid-off stimulus. There is a small positive wave in downhill of negative wave in rod OFF response. Rod ON response of mf-ERG can be recorded with simulated rapid-on stimulus. We speculated that the simulated rapid-ON, sawtooth rapid-on and rapid-off stimulus can be an useful tool to investigate retinal disease and have certain clinical values.     

Variability in ganglion cell firing patterns; implications for separate “on” and “off” processes

Correlation matrices and autocorrelation functions were calculated from responses of goldfish retinal ganglion cells to repeated photic stimuli effective only for the long-wavelength cones. Both of these analyses indicated that the ON response is generated by a process independent of the one that generates the OFF response, while the maintained discharge is a mixture of the two. In most cases, the maintained discharge seems to be primarily a product of the process responsible for the OFF response. The properties of the variability of the center and surround mechanisms were compared and found to be distinct: thus the center and surround of the receptive field each possesses a separate ON and OFF process. The transient characteristics of the responses are generated primarily within these processes. A model is presented to account for these findings.     

Physiological and morphological properties of off- and on-center bipolar cells in the Xenopus retina: effects of glycine and GABA.

We studied the morphology and center-surround organization of Lucifer Yellow injected OFF- and ON-center bipolar cells in the light-adapted Xenopus retina and the effects of glycine and GABA on their cone-mediated light responses. In both classes of cell, prominent antagonistic surround responses up to 20 mV in amplitude could be evoked without first suppressing the center responses with steady illumination. An additional feature of the light-evoked bipolar cell response was a pronounced (up to -24 mV) delayed hyperpolarizing after potential (DHAP) which followed the depolarizing responses of both classes of bipolar cell. The morphological features of dye-injected bipolar cells conformed to the general idea of segregation of ON and OFF pathways in the inner and outer interplexiform layer, however, the morphology of axonal arborizations was different for both classes. OFF-center cells ramified symmetrically around the primary branchpoint, whereas ON-center cells had a strongly asymmetrical arrangement of their axonal tree. The center and surround responses were differentially sensitive to glycine and GABA. Glycine eliminated the antagonistic surround responses in both OFF and ON cells; the center responses were reduced to some extent but were not eliminated. In contrast, GABA affected the hyperpolarizing responses much more strongly than the depolarizing response components. That is, the amplitude of the center response in the OFF cell and the surround response in the ON cell was reduced 80-90% during exposure to GABA, whereas the surround and center depolarizations of OFF and ON cells, respectively, were reduced only 0-10%. Our findings implicate a role for GABAergic and glycinergic pathways in the center-surround organization of bipolar cells in Xenopus retina. In addition, the results suggest that the pathways mediating center-surround antagonism may be different in OFF-bipolar cells vs. ON-bipolar cells.     

Spatial structure, contrast polarity and motion integration

It has been shown that in the initial stages of motion processing, the ON and OFF pathways stay more or less separated. There is evidence that this distinction between motion signals from opposite contrast polarities remains at least partly intact in the integration stage of local motion information. At the same time, interactions between the two systems are also apparent. Here we constructed stimuli that contained a constant number of moving checks. The checks were either assigned only one contrast polarity, or contrast polarity was distributed across the checks either randomly or evenly. We investigated how the spatial configuration of the moving stimulus affected direction discrimination thresholds for the different polarity distributions. Our results provide new evidence for contrast-sign-specific integration of local motion signals within areas of limited size, and inhibitory interactions between these separate ON and OFF motion sensor pools.     

Stimulating human accommodation without changes in focus

PURPOSE: Inspired by the finding in chickens that preferential stimulation of the ON retinal system suppresses myopia induced by negative spectacle lens wear and that stimulation of the OFF system suppresses the hyperopia induced by positive lens wear, we sought to determine whether stimulation of the ON-OFF retinal systems could drive directional accommodation responses in humans. If emmetropisation and accommodation use similar image processing algorithms, more accommodation would be expected with OFF stimulation. METHODS: Accommodation responses were measured while viewing a computer-generated pattern designed to stimulate the ON-OFF systems. The stimulus comprised a rectangular field (12 x 9.5 cm) on a black background filled with 196 discs (diameters: 0.4-1.0 cm). These were presented on an LCD monitor in a dark room at a viewing distance of 55 cm (1.8 D). Thirteen subjects aged 21-37 years took part. The individual discs had saw-tooth shaped temporal luminance profiles with the same time period but with random phases with respect to each other, so that the mean brightness of the stimulus was constant. To eliminate accommodation responses based on other cues (i.e. proximity) a 0.5 mm artificial pupil was used to open the accommodation loop. Refraction in the vertical pupil meridian was continuously recorded with an infrared photorefractor (the PowerRefractor). To verify that computer-based stimuli presented within our experimental design were effective in driving accommodation, previously studied stimuli were also tested: changes in size (looming) and incremental low pass filtering. RESULTS: Preferential stimulation of the ON or OFF subsystems produced a convincing depth illusion in all subjects (which was psychophysically confirmed in four subjects). Although the stimulus appeared to move in depth it did not produce accommodation responses that were consistent with that, i.e. the accommodation system did not appear to fluctuate in rhythm with the temporal oscillations of the stimulus. As the target appeared to loom it induced a greater accommodation response then when it appeared to recede. The looming target produced changes in the accommodation response in nine of 13 subjects that were consistent with its perceived change in proximity (although the target did not actually move in depth). Incremental low pass filtering produced non-directional drifts of accommodation in all subjects. Combinations of the stimuli (i.e. looming and low pass filtering, ON/OFF and looming) were not more effective stimuli to accommodation. After removal of the artificial pupil (closed loop conditions), accommodation was no longer induced with any of these stimuli. CONCLUSIONS: Although the preferential ON or OFF stimulation produced a pronounced illusion of motion in depth despite constant average brightness, proximal accommodation was induced in only one subject. Therefore, the ON/OFF stimulation appeared to have only minor input into proximal accommodation. Potential inputs into reflex accommodation need to be defined in further studies.     

On-response deficit in the electroretinogram of the cone system in X-linked retinoschisis

PURPOSE: The purpose of this study was to evaluate the hypothesis that the reduced b-wave to a-wave ratio of the brief-flash electroretinogram (ERG) of the cone system typically observed in X-linked retinoschisis (XLRS) represents a relatively greater deficit in the ON response (response to light onset) than the OFF response (response to light offset). A second purpose was to investigate the use of sawtooth flicker as a stimulus for eliciting ERG ON and OFF responses. METHODS: Light-adapted, full-field ERGs were recorded in six patients with XLRS and six age-similar control subjects in response to 8-Hz rapid-on and rapid-off sawtooth flicker to emphasize ON and OFF responses, respectively. ERG responses were analyzed in terms of the amplitudes and implicit times of the a-wave, b-wave, and d-wave components. RESULTS: There was no significant difference between the patients with XLRS and the control subjects for either the amplitude of the a-wave of the ON response or the amplitude of the d-wave of the OFF response. However, the amplitude of the b-wave of the ON response was reduced significantly in the patients with XLRS, resulting in a significantly reduced b-wave to d-wave ratio. The patients' implicit times were increased significantly for all waveform components. CONCLUSIONS: The reduced b-wave to d-wave ratio of the ERG of the cone system in these patients with XLRS is consistent with a relative dysfunction of the cone ON bipolar cell pathway in this disorder. The results show further that sawtooth flicker is a promising stimulus for eliciting well-defined ERG waveforms that can provide a quantitative assessment of the properties of ON and OFF responses in retinal disease.     

Involvement of ON and OFF retinal channels in the eye and head horizontal optokinetic nystagmus of the frog

The specific role of ON and OFF retinal information channels in the generation of the horizontal optokinetic nystagmus (OKN) of the frog was studied. Coil recordings of monocular eye and head OKN were obtained before and after intravitreal injection of two drugs that block either ON or OFF channels. The intravitreal injection of 2-amino-4-phosphonobutyrate (APB), a glutamate analog that selectively blocks the ON retinal channel, strongly reduced or even cancelled the monocular OKN of the head and of the eye. The intravitreal injection of another glutamate analog, the cis-2,3-piperidine dicarboxylic acid (PDA) that especially blocks the OFF retinal channel, did not affect the gain velocity of the slow phase of both the horizontal monocular head and eye OKN, for low stimulus velocities. Our results suggest that the retinal ON information channel, but not the OFF channel, is involved in the generation of the slow phase of the OKN of the frog, at least at low drum velocities.