Prediction of spatiotemporal patterns of neural activity from pairwise correlations.

We designed a model-based analysis to predict the occurrence of population patterns in distributed spiking activity. Using a maximum entropy principle with a Markovian assumption, we obtain a model that accounts for both spatial and temporal pairwise correlations among neurons. This model is tested on data generated with a Glauber spin-glass system and is shown to correctly predict the occurrence probabilities of spatiotemporal patterns significantly better than Ising models only based on spatial correlations. This increase of predictability was also observed on experimental data recorded in parietal cortex during slow-wave sleep. This approach can also be used to generate surrogates that reproduce the spatial and temporal correlations of a given data set.

In vitro and in vivo measures of evoked excitatory and inhibitory conductance dynamics in sensory cortices.

In order to better understand the synaptic nature of the integration process operated by cortical neurons during sensory processing, it is necessary to devise quantitative methods which allow one to infer the level of conductance change evoked by the sensory stimulation and, consequently, the dynamics of the balance between excitation and inhibition. Such detailed measurements are required to characterize the static versus dynamic nature of the non-linear interactions triggered at the single cell level by sensory stimulus. This paper primarily reviews experimental data from our laboratory based on direct conductance measurements during whole-cell patch clamp recordings in two experimental preparations: (1) in vitro, during electrical stimulation in the visual cortex of the rat and (2) in vivo, during visual stimulation, in the primary visual cortex of the anaesthetized cat. Both studies demonstrate that shunting inhibition is expressed as well in vivo as in vitro. Our in vivo data reveals that a high level of diversity is observed in the degree of interaction (from linear to non-linear) and in the temporal interplay (from push-pull to synchronous) between stimulus-driven excitation (E) and inhibition (I). A detailed analysis of the E/I balance during evoked spike activity further shows that the firing strength results from a simultaneous decrease of evoked inhibition and increase of excitation. Secondary, the paper overviews the various computational methods used in the literature to assess conductance dynamics, measured in current clamp as well as in voltage clamp in different neocortical areas and species, and discuss the consistency of their estimations.

Paradoxical signal transduction in neurobiological systems.

Information processing in neurobiological systems is commonly thought to rely on the assessment of a signal-to-noise ratio as the key mechanism of signal detection; it assumes and requires that both signal and noise are concurrently available. An alternative theory holds that detection proceeds by the system appreciating any instantaneous input by the input's departure from the moving average of past activity. The evidence reviewed here suggests that this latter transduction mechanism provides a unique, formal account of the highly dynamic, neuroadaptative plasticity (i.e., tolerance, dependence, sensitization) that ensues upon mu-opioid receptor activation. The mechanism would appear already to operate with the receptor-G protein coupling that occurs upon agonist binding to mu-opioid receptors, and also with highly integrated responses such as whole-organism analgesia. The mechanism may perhaps operate ubiquitously with further neuronal and non-neuronal, cell surface, and intracellular-signaling systems, and may govern the experience-dependent regulation of synaptic strength. The transduction mechanism defines a continuously evolving process; the process's most peculiar feature is that it makes any input generate not one but two outcomes that are paradoxical, or opposite in sign.

The visual cortical association field: a Gestalt concept or a psychophysiological entity?

The receptive field of a visual neurone is classically defined as the region of space (or retina) where a visual stimulus evokes a change in its firing activity. Intracellular recordings in cat area 17 show that the visually evoked synaptic integration field extends over a much larger area than that established on the basis of spike activity. Synaptic depolarizing (dominant excitation) responses decrease in strength for stimuli that are flashed at increasing distances away from the centre of the discharge field, while their onset latency increases. A detailed spatio-temporal analysis of these electrophysiological data shows that subthreshold synaptic responses observed in the 'silent' surround of cortical receptive fields result from the intracortical spread of activation waves carried by slowly conducting horizontal axons within primary visual cortex. They also predict that a perceptual facilitation may occur when feedforward activation produced by the motion signal in the retina travels in phase in the primary visual cortex with the visually induced spread of horizontal activation. A psychophysical correlate has been obtained in humans, showing that apparent motion produced by a sequence of co-linear Gabor patches, known to preferentially activate V1 orientation selective cells, are perceived by human observers as much faster than non co-linear sequences of the same physical speed.

Activity-dependent regulation of receptive field properties of cat area 17 by supervised Hebbian learning.

Most algorithms currently used to model synaptic plasticity in self-organizing cortical networks suppose that the change in synaptic efficacy is governed by the same structuring factor, i.e., the temporal correlation of activity between pre- and postsynaptic neurons. Functional predictions generated by such algorithms have been tested electrophysiologically in the visual cortex of anesthetized and paralyzed cats. Supervised learning procedures were applied at the cellular level to change receptive field (RF) properties during the time of recording of an individual functionally identified cell. The protocols were devised as cellular analogs of the plasticity of RF properties, which is normally expressed during a critical period of postnatal development. We summarize here evidence demonstrating that changes in covariance between afferent input and postsynaptic response imposed during extracellular and intracellular conditioning can acutely induce selective long-lasting up- and down-regulations of visual responses. The functional properties that could be modified in 40% of cells submitted to differential pairing protocols include ocular dominance, orientation selectivity and orientation preference, interocular orientation disparity, and the relative dominance of ON and OFF responses. Since changes in RF properties can be induced in the adult as well, our findings also suggest that similar activity-dependent processes may occur during development and during active phases of learning under the supervision of behavioral attention or contextual signals. Such potential for plasticity in primary visual cortical neurons suggests the existence of a hidden connectivity expressing a wider functional competence than the one revealed at the spiking level. In particular, in the spatial domain the sensory synaptic integration field is larger than the classical discharge field. It can be shaped by supervised learning and its subthreshold extent can be unmasked by the pharmacological blockade of intracortical inhibition.

Horizontal propagation of visual activity in the synaptic integration field of area 17 neurons.

The receptive field of a visual neuron is classically defined as the region of space (or retina) where a visual stimulus evokes a change in its firing activity. At the cortical level, a challenging issue concerns the roles of feedforward, local recurrent, intracortical, and cortico-cortical feedback connectivity in receptive field properties. Intracellular recordings in cat area 17 showed that the visually evoked synaptic integration field extends over a much larger area than that established on the basis of spike activity. Synaptic depolarizing responses to stimuli flashed at increasing distances from the center of the receptive field decreased in strength, whereas their onset latency increased. These findings suggest that subthreshold responses in the unresponsive region surrounding the classical discharge field result from the integration of visual activation waves spread by slowly conducting horizontal axons within primary visual cortex.

A phenomenological model of visually evoked spike trains in cat geniculate nonlagged X-cells.

The visual information that first-order cortical cells receive is contained in the visually evoked spike trains of geniculate relay cells. To address functional issues such as the ON/OFF structure of visual cortical receptive fields with modelling studies, a geniculate cell model is needed where the spatial and temporal characteristics of the visual response are described quantitatively. We propose a model simulating the spike trains produced by cat geniculate nonlagged X-cells, based on a review of the electrophysiological literature. The level of description chosen is phenomenological, fitting the dynamics and amplitude of phasic and tonic responses, center/surround antagonism, surround excitatory responses, and the statistical properties of both spontaneous and visually evoked spike trains. The model, which has been constrained so as to reproduce the responses to centered light spots of expanding size and optimal light and dark annuli, predicts responses to thin and large bars flashed in various positions of the receptive field. The switching gamma renewal process method has been introduced for modelling spontaneous and visually evoked spike trains within the same mathematical framework. The statistical structure of the spike process is assumed to be more regular during phasic than tonic visual responses. On the whole, this model generates more realistic geniculate input to cortex than the currently used retinal models.

Visual input evokes transient and strong shunting inhibition in visual cortical neurons.

The function and nature of inhibition of neurons in the visual cortex have been the focus of both experimental and theoretical investigations. There are two ways in which inhibition can suppress synaptic excitation. In hyperpolarizing inhibition, negative and positive currents sum linearly to produce a net change in membrane potential. In contrast, shunting inhibition acts nonlinearly by causing an increase in membrane conductance; this divides the amplitude of the excitatory response. Visually evoked changes in membrane conductance have been reported to be nonsignificant or weak, supporting the hyperpolarization mode of inhibition. Here we present a new approach to studying inhibition that is based on in vivo whole-cell voltage clamping. This technique allows the continuous measurement of conductance dynamics during visual activation. We show, in neurons of cat primary visual cortex, that the response to optimally orientated flashed bars can increase the somatic input conductance to more than three times that of the resting state. The short latency of the visually evoked peak of conductance, and its apparent reversal potential suggest a dominant contribution from gamma-aminobutyric acid ((GABA)A) receptor-mediated synapses. We propose that nonlinear shunting inhibition may act during the initial stage of visual cortical processing, setting the balance between opponent 'On' and 'Off' responses in different locations of the visual receptive field.

Activity-dependent regulation of 'on' and 'off' responses in cat visual cortical receptive fields.

1. A supervised learning procedure was applied to individual cat area 17 neurons to test the possible role of neuronal co-activity in controlling the plasticity of the spatial 'on-off' organization of visual cortical receptive fields (RFs). 2. Differential pairing between visual input evoked in a fixed position of the RF and preset levels of postsynaptic firing (imposed iontophoretically) were used alternately to boost the 'on' (or 'off') response to a 'high' level of firing (S+ pairing), and to reduce the opponent response (respectively 'off' or 'on') in the same position to a 'low' level (S- pairing). This associative procedure was repeated 50-100 times at a low temporal frequency (0.1-0.15 s-1). 3. Long-lasting modifications of the ratio of 'on-off' responses, measured in the paired position or integrated across the whole RF, were found in 44 % of the conditioned neurons (17/39), and in most cases this favoured the S+ paired characteristic. The amplitude change was on average half of that imposed during pairing. Comparable proportions of modified cells were obtained in 'simple' (13/27) and 'complex' (4/12) RFs, both in adult cats (4/11) and in kittens within the critical period (13/28). 4. The spatial selectivity of the pairing effects was studied by pseudorandomly stimulating both paired and spatially distinct unpaired positions within the RF. Most modifications were observed in the paired position (for 88 % of successful pairings). 5. In some cells (n = 13), a fixed delay pairing procedure was applied, in which the temporal phase of the onset of the current pulse was shifted by a few hundred milliseconds from the presentation or offset of the visual stimulus. Consecutive effects were observed in 4/13 cells, which retained the temporal pattern of activity imposed during pairing for 5-40 min. They were expressed in the paired region only. 6. The demonstration of long-lasting adaptive changes in the ratio of 'on' and 'off' responses, expressed in localized subregions of the RF, leads us to suggest that simple and complex RF organizations might be two stable functional states derived from a common connectivity scheme.

Synaptic origin and stimulus dependency of neuronal oscillatory activity in the primary visual cortex of the cat.

1. We have studied the oscillatory activity of single neurons (91 recorded extracellularly and 76 intracellularly) in the primary visual cortex of cats and kittens to characterize its origins and its stimulus dependency. A new method for the detection of oscillations was developed in order to maximize the range of detectable frequencies in both types of recordings. Three types of activity were examined: spontaneous background activity, responses to intracellular current steps and visual responses. 2. During spontaneous activity, persistent oscillatory activity was very rare in both types of recordings. However, when intracellular records were made using KCl-filled micropipettes, spontaneous activity appeared rhythmic and contained repeated depolarizing events at a variety of frequencies, suggestive of tonic periodic inhibitory input normally masked at resting potential. 3. Patterns of firing activity in response to intracellular current steps allowed us to classify neurons as regular spiking, intrinsically bursting, and fast-spiking types, as described in vitro. In the case of rhythmically firing cells, the spike frequency increased with the amount of injected current. Subthreshold current-induced oscillations were rarely observed (2 out of 76 cells). 4. Visual stimulation elicited oscillations in one-third of the neurons (55 out of 167), predominantly in the 7-20 Hz frequency range in 93% of the cases. Rhythmicity was observed in both simple and complex cells, and appeared to be more prominent at 5 and 6 weeks of age. 5. Intracellular recordings in bridge mode and voltage clamp revealed that visually evoked oscillations were driven by synaptic activity and did not depend primarily on the intrinsic properties of recorded neurons. Hyperpolarizing the membrane led to an increase in the size of the rhythmic depolarizing events without a change in frequency. In voltage-clamped cells, current responses showed large oscillations at the same frequency as in bridge mode, independently of the actual value of the holding potential. 6. In fourteen intracellularly recorded neurons, oscillations consisted of excitatory events that could be superimposed on a depolarizing or a hyperpolarizing slow wave. In two other neurons, visual responses consisted of excitatory and inhibitory events, alternating with a constant phase shift. 7. Drifting bars were much more efficient in evoking oscillatory responses than flashed bars. Except in three cells, the frequency of the oscillation did not depend on the physical characteristics of the stimulus that were tested (contrast, orientation, direction, ocularity and position in the receptive field). No significant correlation was found between the intensity of the visual response and the strength of the rhythmic component. 8. Although it cannot be excluded that the dominant frequency of oscillations might be related to the type of anaesthetics used, no correlation was found between local EEG and the oscillatory activity elicited by visual stimulation. 9. We conclude that the oscillations observed in the present work are generated by synaptic activity. It is likely that they represent an important mode of transmission in sensory processing, resulting from periodic packets of synchronized activity propagated across recurrent circuits. Their relevance to perceptual binding is further discussed.

Synaptic integration fields and associative plasticity of visual cortical cells in vivo.

Two major constraints in connectivity decide the spatial extent of visual cortical receptive fields, both during development and adult functioning: 1) feedforward input, extrinsic to visual cortex, is organized in an orderly projection to form a point-to-point mapping of the retina onto the cortical mantle and constitutes the core of the minimal discharge field (MDF) after amplification by local intracortical circuits; and 2) a second type of connectivity consists of long distance horizontal intracortical connections which are thought to favor the binding of local visual operations occurring simultaneously in different parts of the visual field. We review here possible factors, intrinsic to the considered cortical cell, that may control the effectiveness of post-synaptic integration. Their expression during sensory recognition could depend on the spatio-temporal distribution of active inputs onto the target cell dendrite and on their interplay with non-linearities of the membrane properties. On the basis of intracellular recordings in cat area, 17, we have observed that peripheral responses (excitatory and inhibitory) could be boosted by coincident postsynaptic depolarization. This effect is lost if the response and the postsynaptic depolarization are mismatched by 1,000 ms, suggesting that temporal correlation of central and peripheral responses could regulate in a non-linear manner the gain of center-surround interactions. This temporal selectivity is compatible with up-regulation of composite potentials by the transient voltage-dependent activation of slowly inactivating conductances in visual cortical neurons. A direct consequence of these different considerations is that the receptive field (RF) of neurons in visual pathways should not be considered as a static hardwired window probing the outer environment, but as an active filter which may continuously adapt and be updated as a function of global context and past experience.

Dynamics of functional connectivity in visual cortical networks: an overview.

The aim of the Royaumont Symposium was to review various dynamic aspects of adaptive changes in functional connectivity, expressed in cortical networks during development, learning, and possibly during recognition and cognitive processing. The link between the various experimental and theoretical models was the comparison of cellular and molecular mechanisms that could be involved in the up- and down-regulation of functional connectivity, over different time scales. These processes have been investigated using several approaches in parallel: 1) at the molecular/subcellular level, to identify postsynaptic receptors (NMDA, mGluR) and second messengers (calcium protein kinases and phosphatases) involved in the induction of synaptic potentiation and depression, and to characterize diffusible factors (NO), released pre- or postsynaptically, involved in the spatial generalization of local changes to neighboring synapses; 2) at the level of integrating networks, to develop electrophysiological (single and multiple recording), pharmacological and optical imaging techniques in order to compare the dynamics of adaptive processes put into play during the natural development of cortical specificity and connectivity, versus those triggered during forced regimes of temporal correlations between pre- and post synaptic activities. Both in vitro and in vivo approaches have been combined in the primary visual cortex of the developing and adult vertebrate (rat, guinea-pig, ferret, cat and monkey). The various forms of 'slow' synaptic plasticity, demonstrated during epigenesis and selective phases of learning in the adult, can be compared with 'fast' forms of functional coupling (or synchronous firing) shown to develop during the time span required for perception and cognitive processing Phenomenology of the dynamics in functional connectivity and their relative dependence on temporal correlation in neuronal activity have been analyzed in each of these situations. Experimental results have been compared at different levels of neuronal integration (synapse, column map and cell assembly) in order to gain a better understanding of functional grouping within cortical networks.

Voltage-clamp measurement of visually-evoked conductances with whole-cell patch recordings in primary visual cortex.

Whole cell patch recordings have been realized in the primary visual cortex of the anesthetized and paralyzed cat, in order to better characterize input resistance and time constant of visual cortical cells in vivo. Measurements of conductance changes evoked by visual stimulation were derived from voltage clamp recordings achieved in continuous mode at two or more different subthreshold holding potentials. They show that the magnitude of the conductance increase can reach up to 300% of the mean conductance at rest. The observation of similar changes for the preferred and antagonist responses, when flashing ON and OFF, a test stimulus in pure ON and OFF subfields supports the hypothesis of a role for shunting inhibition in the spatial organization of simple receptive fields.

An intracellular study of space and time representation in primary visual cortical receptive fields.

In contrast with previous knowledge based on extracellular recordings, the recent development of intracellular techniques in vivo (sharp electrode or 'blind patch') ideally allows experimenters to analyze and dissect the contribution of feedforward and lateral connectivity in the functional expression of a synaptic 'integration field'. We will present recent data which demonstrate that the visual receptive field of cortical neurons described at the level of subthreshold synaptic events extends over much larger regions of the visual field than previously thought, and that the capacity of cells to amplify subthreshold responses depends on the immediate past history of their membrane potential. Our data suggest that visual cortical receptive fields should not be considered as a fixed entity but more as a dynamic field of integration and association. Two types of dynamics can be argued for: 1) the spatial structure of the minimal discharge field (defined by suprathreshold activation of the cell) can be profoundly reorganized at least during development and most probably during selective phases of learning under the control of activity-dependent mechanisms. Adaptive changes in visual responses are thought to reflect long-lasting potentiation and/or depression of synaptic efficacies conveying ON- and OFF-center information; and 2) during sensory processing, reconfiguration of synaptic weights may be achieved on a much faster time-scale and linked to nor-linear properties of the postsynaptic membrane as well as that of recruited networks. Association of information available in the central part of the receptive field (RF) and of input coming from the reputedly 'unresponsive' regions surrounding it, or arising simultaneously from different parts of the visual field, might be suppressive in certain cases and capable of boosting hidden responses in other cases, depending on the global stimulus configuration.

Temporal constraints in associative synaptic plasticity in hippocampus and neocortex.

We present comparative experimental evidence for the induction of synaptic potentiation and depression in organotypic cultures of hippocampus and in visual cortex in vitro and in vivo. The effects of associative pairings on the efficacy of synaptic transmission are analyzed as a function of the temporal delay between presynaptic activity and post-synaptic changes imposed in membrane potential. Synchronous association at a low temporal frequency (< 0.5 Hz) between presynaptic input and postsynaptic depolarization resulted in homosynaptic potentiation of functionally identified postsynaptic potentials in the three types of preparation. Synchronous pairing of afferent activity with hyperpolarization of the postsynaptic cell resulted in homosynaptic depression in visual cortex in vivo and in vitro. An associative form of depression was induced in hippocampus when the test input was followed repeatedly with a fixed-delay postsynaptic depolarization imposed either by intracellular current injection or synaptically. The latter process might play a significant role in heterosynaptic plasticity in visual cortex in vivo and in vitro, if it is assumed that associative depression still operates in visual cortex a few seconds after the initial surge of calcium in the postsynaptic cell. We conclude that the precise timing between presynaptic activity and polarization changes in postsynaptic membrane potential up- and down-regulates the efficacy of active pathways.

Temporal covariance of pre- and postsynaptic activity regulates functional connectivity in the visual cortex.

1. It has been suggested from mathematical models and in vivo experiments in the visual cortex that periods of temporal covariance of pre- and postsynaptic activity can lead to a potentiation or depression of synaptic efficacy. We directly tested this hypothesis in vitro in the guinea pig and cat visual cortex. 2. Intracellular recordings were made in brain slices from 63 neurons in layers 2-4 in bicuculline-free artificial cerebrospinal fluid. Twenty-nine cells (n = 25 from pigmented guinea pigs and 4 from cats) were taken through a complete series of control and test protocols to evaluate the covariance hypothesis. Some (n = 7) cells that were taken through the complete experimental protocols were also filled intracellularly with biocytin. Compound postsynaptic potentials (PSPs) were evoked by low-frequency (0.2-1.0 Hz), weak (20% of threshold intensity) stimulation of the cortical white matter and/or intracortical sites in layers 2-3. 3. In one series of experiments we paired PSPs with imposed coincident depolarizing (S+) or hyperpolarizing (S-) pulses (mean +/- 2.8 nA for 50-80 ms) of the postsynaptic neuron (n = 54 PSPs; > 1 pairing protocol was often run on an individual cell). Controls consisted of analyzing the same number of S+ or S- pairings but with long temporal delays [called fixed delay pairings (FDPs)] between the test pathway stimulation and the onset of the intracellular current pulse (120 ms) and pseudopairings (PP) consisting of evoked PSPs and delivery of intracellular current injection pulses in a phase-independent manner. Twenty-one of 54 PSPs subjected to pairing were significantly modified by the protocol. The S+ protocol significantly (P < 0.05, Kolmogorov-Smirnov test) increased the peak amplitudes of 8 of 22 PSPs (+20 to +55%); the S- protocol significantly decreased the peak amplitudes of 13 of 32 PSPs (-15 to -88%), whereas the FDP and PP protocols generally did not cause significant changes in the PSPs (0% and 4%, respectively). Significant changes in PSPs persisted in most cases for 10-20 min. 4. Another series of experiments consisted of evaluating for the same cell the effects of evoking a PSP from one stimulation site without concomitant postsynaptic activation and alternately evoking a PSP from the other stimulation site with S+ or S- pairing (n = 25 PSPs). Only the paired pathway showed the predicted effects on the PSP (S+ pairing causing an increase in peak PSP amplitude and S- pairing causing a decrease in peak PSP amplitude).(ABSTRACT TRUNCATED AT 400 WORDS)