Effects of tACS-Like Electrical Stimulation on Off- and On-Off Center Retinal Ganglion Cells: Part II.

PURPOSE: Transcranial alternating current stimulation (tACS) is used as a brain stimulation mechanism to enhance learning, ameliorate some psychiatric disorders, and modify behavior. This study assessed the effects of near threshold tACS-like currents on Off-center and On-Off retinal ganglion cell responsiveness in the rabbit retina eyecup preparation as a model for central nervous system effects. MATERIALS AND METHODS: We made extracellular recordings in the isolated rabbit eyecup preparation using single electrodes and microelectrode arrays to measure light-evoked spike responses in different classes of Off-center and On-Off retinal ganglion cells before, during, and after brief applications of alternating currents of 1-2 microamperes, at frequencies of 10, 20, 30, and 40 Hz. RESULTS: tACS application sculpted the light-evoked response profiles without directly driving spiking activity of the 20 Off-center and On-Off ganglion cells we recorded from. During tACS application, Off responses were significantly enhanced for 6 cells and significantly suppressed for 14 cells, but after tACS application, Off responses were significantly enhanced for 7 cells and suppressed for 12 cells. The Off responses of the remaining two cells returned to baseline. On responses were less affected during and after tACS. CONCLUSION: tACS sculpts Off-center and On-Off retinal ganglion cell responsiveness. The dissimilarity of effects in different cells within the same class and the differential effects on the On and Off components of the light response within the same cell are consistent with the hypothesis that tACS acts at threshold on amacrine cells in the inner plexiform layer.

Effects of tACS-Like Electrical Stimulation on Correlated Firing of Retinal Ganglion Cells: Part III.

PURPOSE: Transcranial alternating current stimulation (tACS) is a stimulation protocol used for learning enhancement and mitigation of cognitive dysfunction. Correlated firing has been postulated to be a meta-code that links neuronal spike responses associated with a single entity and may be an important component of high-level cognitive functions. Thus, changes in the covariance firing structure of CNS neurons such as retinal ganglion cells are one potential mechanism by which tACS can exert its effects. MATERIALS AND METHODS: We used microelectrode arrays to record light-evoked spike responses of 24 retinal ganglion cells in 7 rabbit eyecup preparations and analyzed the covariance between 30 pairs of neighboring retinal ganglion cells before, during, and after 10-minute application of alternating currents of 1 microampere at 10 or 20 Hz. RESULTS: tACS stimulation significantly changed the covariance structure of correlated firing in 60% of simultaneously recorded retinal ganglion cells. Application of tACS in the retinal preparation increased cross-covariance in 26% of cell pairs, an effect usually associated with increased light-evoked ganglion cell firing. tACS associated decreases in cross-covariance occurred in 37% of cell pairs. Increased covariance was more common in response to the first, 10-minute application of tACS in isolated retina preparation. Changes in covariance were rare after repeated stimulation, and more likely to result in decreased covariance. CONCLUSION: Retinal ganglion cell correlated firing is modulated by 1 microampere tACS currents showing that electrical stimulation can significantly and persistently change the structure of the correlated firing of simultaneously recorded rabbit retinal ganglion cells.

Effects of tACS-Like Electrical Stimulation on On-Center Retinal Ganglion Cells: Part I.

PURPOSE: Electrical stimulation of the human central nervous system via surface electrodes has been used for both learning enhancement and the amelioration of neurodegenerative or psychiatric disorders. However, data are sparse on how such electrical stimulation affects neural circuits at the cellular level. This study assessed the effects of tACS-like currents at 10 Hz on On-center retinal ganglion cell responsiveness, using the rabbit retina eyecup preparation as a model for central nervous system effects. METHODS: We made extracellular recordings of light-evoked spike responses in different classes of On-center retinal ganglion cells before, during and after brief applications of 1 microampere alternating currents using single electrodes and microelectrode arrays. RESULTS: tACS-like currents (tACS) of 1 microampere produced effects on On-center ganglion cell response profiles immediately after initiation or cessation of tACS, without driving phase-locked firing in the absence of light stimuli. tACS affected the initial transient responses to light stimulation for all cells, sustained response components (if any) more strongly for sustained cells, and the center-surround balance more strongly for transient cells. CONCLUSION: tACS sculpted light-evoked responses that lasted for one or more hours after cessation of current without, itself, directly inducing significant firing changes. Functionally, tACS effects could result in effects on contrast thresholds for both broad classes of cells, but because tACs differentially affects the center-surround balance of transient On-center cells, there may be greater effects on the spatial resolution and gain. The isolated retina appears to be a useful model to understand tACS actions at the neuronal level.

Effect of transcranial direct current stimulation (tDCS) on food craving and eating when using a control method that minimizes guessing of the real vs. control condition.

PURPOSE: Validation of transcranial direct current stimulation (tDCS) to treat obesity is hampered by evidence that participants can distinguish real from the traditional-control condition. Correctly guessing the real condition precludes knowing if it is neuromodulation or expectation that suppresses food craving and eating. Therefore, this study tested the putative efficacy of tDCS to the dorsolateral prefrontal cortex (DLPFC) to reduce food craving and eating when an alternative control condition was used that would be difficult to distinguish from the real condition. METHODS: N = 28 adults with a 26-50 BMI range received a typical 20-min 2 mA current session of tDCS targeting the DLPFC as the real condition and a same duration/current tDCS session targeting the sensorimotor cortex (SMC), a region not expected to affect appetite, as the control. Food image craving ratings, in-lab food consumption, and momentary ratings of physical sensations were measured. RESULTS: DLPFC failed to reduce food craving and consumption compared to SMC stimulation. When interviewed, 71% of participants were unable to guess real from control conditions. Those who guessed DLPFC tDCS as real attributed their guess to increased number and frequency of sensations. However, their sensation ratings during tDCS did not differ between conditions. CONCLUSIONS: The results question if tDCS suppresses craving and eating at all, or if the DLPFC is the best target to do so. The results also indicate that alternate-site constant stimulation as the control method may strengthen the scientific evaluation of tDCS to treat obesity. LEVEL OF EVIDENCE: Level I, experimental study.

The effect of expectation on transcranial direct current stimulation (tDCS) to suppress food craving and eating in individuals with overweight and obesity.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique with potential to treat eating disorders and obesity. As for any potential treatment, it is important to assess the degree to which expectation effects contribute to its reported efficacy. This study assessed the effect of tDCS on amount of food craving and eating while tightly controlling treatment expectation. N = 74 adults with overweight or obesity were informed of the known effects of tDCS to suppress craving and eating. Once electrodes were on the head, half of the participants were told they were receiving real, and the other half sham tDCS. Within these groups, approximately half actually received real and the other half sham tDCS. Stimulation parameters used were those previously found to reduce craving and eating, including in our lab: 2 mA, anode right/cathode left targeting the dorsolateral prefrontal cortex for 20 min (real), or only for the first and last minute (sham). Analyses controlled for demographics, hunger, trait impulsiveness, eating motives, dieting, binge eating, suggestibility, and baseline craving and eating. Participants told they were receiving real tDCS craved and ate less than participants told they were receiving sham tDCS (both p < 0.01), regardless of tDCS condition administered. There was no main effect of real vs. sham tDCS on craving or eating or an interaction between tDCS condition and expectation. The scientific validation of tDCS as a treatment for eating-related conditions hinges on controlling for the powerful effects of expectation. This can include the type of information provided on consent forms and participants' ability to guess real from sham conditions.

Effects of tDCS-like electrical stimulation on retinal ganglion cells.

PURPOSE: Transcranial direct current stimulation (tDCS) has been studied in humans for its effects on enhancement of learning, amelioration of psychiatric disorders, and modification of other behaviors for over 50 years. Typical treatments involve injecting 2 mA current through scalp electrodes for 20 minutes, sometimes repeated weekly for two to five sessions. Little is known about the direct effects of tDCS at the neural circuit or the cellular level. This study assessed the effects of tDCS-like currents on the central nervous system by recording effects on retinal ganglion cell responsiveness using the rabbit retina eyecup preparation. MATERIALS AND METHODS: We examined changes in firing to On and Off light stimuli during and after brief applications of a range of currents and polarity and in different classes of ganglion cells. RESULTS: The responses of Sustained cells were consistently suppressed during the first round of current application, but responses could be enhanced after subsequent rounds of stimulation. The observed first round suppression was independent of current polarity, amplitude, or number of trials. However, the light responses of Transient cells were more likely to be enhanced by negative currents and unaffected or suppressed by first round positive currents. Short-duration currents, that is, minutes, as low as 2.5 µA produced a remarkable persistency of firing changes, for up to 1.5 hours, after cessation of current. CONCLUSION: The results are consistent with postulated tDCS alteration of central nervous system function, which outlast the tDCS session and provide evidence for the isolated retina as a useful model to understand tDCS actions at the neuronal level.

Nicotinic and muscarinic acetylcholine receptors shape ganglion cell response properties.

The purpose of this study was to evaluate the expression patterns of nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively) in relation to one another and to understand their effects on rabbit retinal ganglion cell response properties. Double-label immunohistochemistry revealed labeled inner-retinal cell bodies and complex patterns of nAChR and mAChR expression in the inner plexiform layer. Specifically, the expression patterns of m1, m4, and m5 muscarinic receptors overlapped with those of non-α7 and α7 nicotinic receptors in presumptive amacrine and ganglion cells. There was no apparent overlap in the expression patterns of m2 muscarinic receptors with α7 nicotinic receptors or of m3 with non-α7 nicotinic receptors. Patch-clamp recordings demonstrated cell type-specific effects of nicotinic and muscarinic receptor blockade. Muscarinic receptor blockade enhanced the center responses of brisk-sustained/G4 On and G4 Off ganglion cells, whereas nicotinic receptor blockade suppressed the center responses of G4 On-cells near the visual streak but enhanced the center responses of nonstreak G4 On-cells. Blockade of muscarinic or nicotinic receptors suppressed the center responses of brisk-sustained Off-cells and the center light responses of subsets of brisk-transient/G11 On- and Off-cells. Only nicotinic blockade affected the center responses of G10 On-cells and G5 Off-cells. These data indicate that physiologically and morphologically identified ganglion cell types have specific patterns of AChR expression. The cholinergic receptor signatures of these cells may have implications for understanding visual defects in disease states that result from decreased ACh availability.

Processing speed training increases the efficiency of attentional resource allocation in young adults.

Cognitive training has been shown to improve performance on a range of tasks. However, the mechanisms underlying these improvements are still unclear. Given the wide range of transfer effects, it is likely that these effects are due to a factor common to a wide range of tasks. One such factor is a participant's efficiency in allocating limited cognitive resources. The impact of a cognitive training program, Processing Speed Training (PST), on the allocation of resources to a set of visual tasks was measured using pupillometry in 10 young adults as compared to a control group of a 10 young adults (n = 20). PST is a well-studied computerized training program that involves identifying simultaneously presented central and peripheral stimuli. As training progresses, the task becomes increasingly more difficult, by including peripheral distracting stimuli and decreasing the duration of stimulus presentation. Analysis of baseline data confirmed that pupil diameter reflected cognitive effort. After training, participants randomized to PST used fewer attentional resources to perform complex visual tasks as compared to the control group. These pupil diameter data indicated that PST appears to increase the efficiency of attentional resource allocation. Increases in cognitive efficiency have been hypothesized to underlie improvements following experience with action video games, and improved cognitive efficiency has been hypothesized to underlie the benefits of PST in older adults. These data reveal that these training schemes may share a common underlying mechanism of increasing cognitive efficiency in younger adults.

Separability of stimulus parameter encoding by on-off directionally selective rabbit retinal ganglion cells.

The ganglion cell output of the retina constitutes a bottleneck in sensory processing in that ganglion cells must encode multiple stimulus parameters in their responses. Here we investigate encoding strategies of On-Off directionally selective retinal ganglion cells (On-Off DS RGCs) in rabbits, a class of cells dedicated to representing motion. The exquisite axial discrimination of these cells to preferred vs. null direction motion is well documented: it is invariant with respect to speed, contrast, spatial configuration, spatial frequency, and motion extent. However, these cells have broad direction tuning curves and their responses also vary as a function of other parameters such as speed and contrast. In this study, we examined whether the variation in responses across multiple stimulus parameters is systematic, that is the same for all cells, and separable, such that the response to a stimulus is a product of the effects of each stimulus parameter alone. We extracellularly recorded single On-Off DS RGCs in a superfused eyecup preparation while stimulating them with moving bars. We found that spike count responses of these cells scaled as independent functions of direction, speed, and luminance. Moreover, the speed and luminance functions were common across the whole sample of cells. Based on these findings, we developed a model that accurately predicted responses of On-Off DS RGCs as products of separable functions of direction, speed, and luminance (r = 0.98; P < 0.0001). Such a multiplicatively separable encoding strategy may simplify the decoding of these cells' outputs by the higher visual centers.

Avatar assistant: improving social skills in students with an ASD through a computer-based intervention.

This study assessed the efficacy of FaceSay, a computer-based social skills training program for children with Autism Spectrum Disorders (ASD). This randomized controlled study (N = 49) indicates that providing children with low-functioning autism (LFA) and high functioning autism (HFA) opportunities to practice attending to eye gaze, discriminating facial expressions and recognizing faces and emotions in FaceSay's structured environment with interactive, realistic avatar assistants improved their social skills abilities. The children with LFA demonstrated improvements in two areas of the intervention: emotion recognition and social interactions. The children with HFA demonstrated improvements in all three areas: facial recognition, emotion recognition, and social interactions. These findings, particularly the measured improvements to social interactions in a natural environment, are encouraging.

Parallel optical monitoring of visual signal propagation from the photoreceptors to the inner retina layers.

Understanding of visual signal processing can benefit from simultaneous measurement of different types of retinal neurons working together. In this Letter, we demonstrate that intrinsic optical signal (IOS) imaging of frog retina slices allows simultaneous observation of stimulus-evoked responses propagating from the photoreceptors to the inner neurons. High-resolution imaging revealed robust IOSs at the photoreceptor, the inner plexiform, and the ganglion cell layers. While IOSs of the photoreceptor layer were mainly confined to the area directly stimulated by the visible light, IOSs of the inner retinal layers spread from the stimulus site into relatively large areas with a characteristic near-to-far time course.

The response dynamics of rabbit retinal ganglion cells to simulated blur.

Retinal ganglion cells (RGCs) are highly sensitive to changes in contrast, which is crucial for the detection of edges in a visual scene. However, in the natural environment, edges do not just vary in contrast, but edges also vary in the degree of blur, which can be caused by distance from the plane of fixation, motion, and shadows. Hence, blur is as much a characteristic of an edge as luminance contrast, yet its effects on the responses of RGCs are largely unexplored.We examined the responses of rabbit RGCs to sharp edges varying by contrast and also to high-contrast edges varying by blur. The width of the blur profile ranged from 0.73 to 13.05 deg of visual angle. For most RGCs, blurring a high-contrast edge produced the same pattern of reduction of response strength and increase in latency as decreasing the contrast of a sharp edge. In support of this, we found a significant correlation between the amount of blur required to reduce the response by 50% and the size of the receptive fields, suggesting that blur may operate by reducing the range of luminance values within the receptive field. These RGCs cannot individually encode for blur, and blur could only be estimated by comparing the responses of populations of neurons with different receptive field sizes. However, some RGCs showed a different pattern of changes in latency and magnitude with changes in contrast and blur; these neurons could encode blur directly.We also tested whether the response of a RGC to a blurred edge was linear, that is, whether the response of a neuron to a sharp edge was equal to the response to a blurred edge plus the response to the missing spatial components that were the difference between a sharp and blurred edge. Brisk-sustained cells were more linear; however, brisk-transient cells exhibited both linear and nonlinear behavior.

High spatiotemporal resolution imaging of fast intrinsic optical signals activated by retinal flicker stimulation.

High resolution monitoring of stimulus-evoked retinal neural activities is important for understanding retinal neural mechanisms, and can be a powerful tool for retinal disease diagnosis and treatment outcome evaluation. Fast intrinsic optical signals (IOSs), which have the time courses comparable to that of electrophysiological activities in the retina, hold the promise for high resolution imaging of retinal neural activities. However, application of fast IOS imaging has been hindered by the contamination of slow, high magnitude optical responses associated with transient hemodynamic and metabolic changes. In this paper we demonstrate the feasibility of separating fast retinal IOSs from slow optical responses by combining flicker stimulation and dynamic (temporal) differential image processing. A near infrared flood-illumination microscope equipped with a high-speed (1000 Hz) digital camera was used to conduct concurrent optical imaging and ERG measurement of isolated frog retinas. High spatiotemporal resolution imaging revealed that fast IOSs could follow flicker frequency up to at least 6 Hz. Comparable time courses of fast IOSs and ERG kinetics provide evidence that fast IOSs are originated from stimulus activated retinal neurons.

Muscarinic acetylcholine receptor localization and activation effects on ganglion response properties.

PURPOSE: The activation and blockade of muscarinic acetylcholine receptors (mAChRs) affects retinal ganglion cell light responses and firing rates. This study was undertaken to identify the full complement of mAChRs expressed in the rabbit retina and to assess mAChR distribution and the functional effects of mAChR activation and blockade on retinal response properties. METHODS: RT-PCR, Western blot analysis, and immunohistochemistry were used to identify the complement and distribution of mAChRs in the rabbit retina. Extracellular electrophysiology was used to determine the effects of the activation or blockade of mAChRs on ganglion cell response properties. RESULTS: RT-PCR of whole neural retina resulted in the amplification of mRNA transcripts for the m1 to m5 mAChR subtypes. Western blot and immunohistochemical analyses confirmed that all five mAChR subtypes were expressed by subpopulations of bipolar, amacrine, and ganglion cells in the rabbit retina, including subsets of cells in cholinergic and glycinergic circuits. Nonspecific muscarinic activation and blockade resulted in the class-specific modulation of maintained ganglion cell firing rates and light responses. CONCLUSIONS: The expression of mAChR subtypes on subsets of bipolar, amacrine, and ganglion cells provides a substrate for both enhancement and suppression of retinal responses via activation by cholinergic agents. Thus, the muscarinic cholinergic system in the retina may contribute to the modulation of complex stimuli. Understanding the distribution and function of mAChRs in the retina has the potential to provide important insights into the visual changes that are caused by decreased ACh in the retinas of Alzheimer's patients and the potential visual effects of anticholinergic treatments for ocular diseases.

Properties of stimulus-dependent synchrony in retinal ganglion cells.

Neighboring retinal ganglion cells often spike synchronously, but the possible function and mechanism of this synchrony is unclear. Recently, the strength of the fast correlation between ON-OFF directionally selective cells of the rabbit retina was shown to be stimulus dependent. Here, we extend that study, investigating stimulus-dependent correlation among multiple ganglion-cell classes, using multi-electrode recordings. Our results generalized those for directionally selective cells. All cell pairs exhibiting significant spike synchrony did it for an extended edge but rarely for full-field stimuli. The strength of this synchrony did not depend on the amplitude of the response and correlations could be present even when the cells' receptive fields did not overlap. In addition, correlations tended to be orientation selective in a manner predictable by the relative positions of the receptive fields. Finally, extended edges and full-field stimuli produced significantly greater and smaller correlations than predicted by chance respectively. We propose an amacrine-network model for the enhancement and depression of correlation. Such an apparently purposeful control of correlation adds evidence for retinal synchrony playing a functional role in vision.

Robust directional computation in on-off directionally selective ganglion cells of rabbit retina.

The spatial and temporal interactions in the receptive fields of On-Off directionally selective (DS) ganglion cells endow them with directional selectivity. Using a variety of stimuli, such as sinusoidal gratings, we show that these interactions make directional selectivity of the DS ganglion cell robust with respect to stimulus parameters such as contrast, speed, spatial frequency, and extent of motion. Moreover, unlike the directional selectivity of striate-cortex cells, On-Off DS ganglion cells display directional selectivity to motions not oriented perpendicularly to the contour of the objects. We argue that these cells may achieve such high robustness by combining multiple mechanisms of directional selectivity.

Nicotinic acetylcholine receptor expression by directionally selective ganglion cells.

Acetylcholine (ACh) enhances the preferred direction responses of directionally selective ganglion cells (DS GCs; Ariel & Daw, 1982; Ariel & Adolph, 1985) through the activation of nicotinic acetylcholine receptors (nAChRs; Ariel & Daw, 1982; Massey et al., 1997; Kittila & Massey, 1997). DS GCs appear to express at least two types of nAChRs, those that are sensitive to the partially subtype-specific antagonist methyllycaconitine (MLA), and those that are MLA-insensitive (Reed et al., 2002). Our purpose was to confirm the expression of alpha7 nAChRs by DS GCs and to assess the contributions of other nAChR subtypes to DS GC responses. Using choline as a nAChR partially subtype-specific agonist, we found that the majority of DS GCs demonstrated responses to choline while under synaptic blockade. The blockade or reduction of choline-induced responses by bath application of nanomolar (nM) concentrations of MLA provided direct evidence that the choline responses were mediated by alpha7 nAChRs. Because choline is a partial agonist for alpha3beta4 nAChRs (Alkondon et al., 1997), the residual choline responses are consistent with mediation by alpha3beta4 nAChRs. Additionally, a subset of DS GCs responded to nicotine but not to choline, indicating the expression of a third nAChR subtype. The pharmacological results were supported by single cell reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry experiments. The expression of alpha7 and specific non-alpha7 nAChR subtypes was correlated with the preferred direction. This indicates the possibility of differential responses to ACh depending on the direction of movement. This is the first description of differential expression of multiple nAChR subtypes by DS GCs.

Rabbit retinal ganglion cells express functional alpha7 nicotinic acetylcholine receptors.

It is well known that cholinergic agents affect ganglion cell (GC) firing rates and light responses in the retinas of many species, but the specific receptor subtypes involved in mediating these effects have been only partially characterized. We sought to determine whether functional alpha(7) nicotinic acetylcholine receptors (nAChRs) contribute to the responses of specific retinal GC classes in rabbit retina. We used electrophysiology, pharmacology, immunohistochemistry, and reverse transcriptase-polymerase chain reaction to determine the pharmacological properties and expression of nAChR subtypes by specific rabbit retinal GC classes. Choline was used as an alpha(7) nAChR agonist. Methyllycaconitine (MLA) was used as a competitive alpha(7) nAChR antagonist. The application of choline before synaptic blockade resulted in changes in retinal GC activity, including increases or decreases in maintained firing and/or enhancement or suppression of light responses. Many physiologically identified GC types, including sustained off, sustained on, transient off, and transient on cells, demonstrated responses to choline application while under synaptic blockade. The choline-induced responses could be blocked with MLA, confirming alpha(7) nAChR activation. Individual choline-responsive GCs displayed mRNA transcripts consistent with the expression of functional alpha(7) nAChRs. Other GCs demonstrated physiological responses and mRNA expression consistent with the expression of both alpha(7) and non-alpha(7) nAChRs. Thus mRNA is present for multiple nAChR subunits in whole retina extracts, and functional alpha(7) nAChRs are capable of modulating the responses of GCs in adult rabbit retina. We also demonstrate through physiological responses that subsets of GCs express more than one nAChR subtype.

Retinal ganglion cell coding in simulated active vision.

The image on the retina is almost never static. Eye, head, and body movements, and externally generated motion create rapid and continual changes in the retinal image ("active vision"). Virtually all vision in animals such as primates, which make saccades as often as 3-4 times/s, is based on information that must be derived from the first few hundred milliseconds after sudden, global changes in the retinal image. These changes may be accompanied by large changes in area mean luminance, as well as higher order image contrast statistics. This study investigated how retinal ganglion cell responses, whose response properties have been typically studied and defined in a stable stimulus regime, are affected by sudden changes in mean luminance that are characteristic of active vision. Specifically, the steady-state responses of retinal ganglion cells to static or moving square-wave grating stimuli were recorded in an isolated, superfused rabbit eyecup preparation and compared to responses after saccade-like changes in luminance. The manner of coding after luminance changes was different for different ganglion cell classes; both suppression and enhancement of responses to patterns following luminance changes were found. Brisk-transient Off cells unambiguously signaled the darkening of the overall image, but were also modulated by the subsequently appearing grating stimulus. Several types of On-center cell behavior were observed, ranging from strong suppression of the subsequent response by luminance changes, to strong enhancement. Overall, most ganglion cells distinguished static patterns after a luminance change via differences in their spike discharges nearly as well as before, although there were clear asymmetries between the On and Off pathways. Changes in mean luminance in some ganglion cells, such as On-Off directionally selective ganglion cells, could create large phase shifts in the response to patterned, moving stimuli, although these stimuli were still detected immediately after luminance changes. The results of this study show that the image dynamics of active vision may be a fundamental challenge for the visual system because of strong effects on retinal ganglion cell function. However, rapid extraction of unambiguous information after luminance changes appears to be encoded in differences in the spike discharges in different retinal ganglion cell classes. Asymmetries among ganglion cell classes in sensitivity to luminance changes may provide a basis by which some provide the "context" for interpreting the firing of others.

Stimulus-dependent correlated firing in directionally selective retinal ganglion cells.

Synchronous spiking has been postulated to be a meta-signal in visual cortex and other CNS loci that tags neuronal spike responses to a single entity. In retina, however, synchronized spikes have been postulated to arise via mechanisms that would largely preclude their carrying such a code. One such mechanism is gap junction coupling, in which synchronous spikes would be a by-product of lateral signal sharing. Synchronous spikes have also been postulated to arise from common-source inputs to retinal ganglion cells having overlapping receptive fields, and thus code for stimulus location in the overlap area. On-Off directionally selective ganglion cells of the rabbit retina exhibit a highly precise tiling pattern in which gap junction coupling occurs between some neighboring, same-preferred-direction cells. Depending on how correlated spikes arise, and for what purpose, one could postulate that synchronized spikes in this system (1) always arise in some subset of same-direction cells because of gap junctions, but never in non-same-preferred-directional cells; (2) never arise in same-directional cells because their receptive fields do not overlap, but arise only in different-directional cells whose receptive fields overlap, as a code for location in the overlap region; or (3) arise in a stimulus-dependent manner for both same- and different-preferred-direction cells for a function similar to that postulated for neurons in visual cortex. Simultaneous, extracellular recordings were obtained from neighboring On-Off directionally selective (DS) ganglion cells having the same and different preferred directions in an isolated rabbit retinal preparation. Stimulation by large flashing spots elicited responses from DS ganglion-cell pairs that typically showed little synchronous firing. Movement of extended bars, however, often produced synchronous spikes in cells having similar or orthogonal preferred directions. Surprisingly, correlated firing could occur for the opposite contrast polarity edges of moving stimuli when the leading edge of a sweeping bar excited the receptive field of one cell as its trailing edge stimulated another. Pharmacological manipulations showed that the spike synchronization is enhanced by excitatory cholinergic amacrine-cell inputs, and reduced by inhibitory GABAergic inputs, in a motion-specific manner. One possible interpretation is that this synchronous firing could be a signal to higher centers that the outputs of the two DS ganglion cells should be "bound" together as responding to a contour of a common object.