Abstract: The subiculum is in a pivotal position governing the output of the hippocampal formation. Despite this, it is a rather under-explored and sometimes ignored structure. Here, we discuss recent data indicating that the subiculum participates in a wide range of neurocognitive functions and processes. Some of the functions of subiculum are relatively well-known - these include providing a relatively coarse representation of space and participating in, and supporting certain aspects of, memory (particularly in the dynamic bridging of temporal intervals). The subiculum also participates in a wide variety of other neurocognitive functions too, however. Much less well-known are roles for the subiculum, and particularly the ventral subiculum, in the response to fear, stress and anxiety, and in the generation of motivated behaviour (particularly the behaviour that underlies drug addiction and the response to reward). There is an emerging suggestion that the subiculum participates in the temporal control of behaviour. It is notable that these latter findings have emerged from a consideration of instrumental behaviour using operant techniques; it may well be the case that the use of the watermaze or similar spatial tasks to assess subicular function (on the presumption that its functions are very similar to the hippocampus proper) has obscured rather than revealed neurocognitive functions of subiculum. The anatomy of subiculum suggests it participates in a rather subtle fashion in a very broad range of functions, rather than in a relatively more isolated fashion in a narrower range of functions, as might be the case for 'earlier' components of hippocampal circuitry, such as the CA1 and CA3 subfields. Overall, there appears to a strong dorso-ventral segregation of function within subiculum, with the dorsal subiculum relatively more concerned with space and memory, and the ventral hippocampus concerned with stress, anxiety and reward. Finally, it may be the case that the whole subiculum participates in the temporal control of reinforced behaviour, although further experimentation is required to clarify this hypothesis.

Abstract: The objective of this study was to explore a paradigm that would allow a temporary deprivation of whisker information lasting for a few hours. An additional requirement was to be non-invasive in order to be usable in awake chronically implanted rats without inducing stress. With that aim, electrophysiological recordings from the barrel cortex of anesthetized rats were obtained. The pressure of an air-puff (5-10 ms) delivered to the whiskers was adjusted to evoke a consistent response of around 100 microV (extracellular) or approximately 5 mV (intracellular) in the contralateral cortex. Lidocaine was then locally applied in different forms (cream, local injection, aerosol, drops) and concentrations (2-10%) to the base of the whiskers. The stimulus-induced response was monitored once every 5s for several hours (3-6h) in order to characterize its course of action. Local injection of lidocaine induced the fastest and most complete blockage, but was ruled out for being invasive. Out of the remaining forms of application, a lidocaine drop (0.4 ml, 10%) to the base of the whiskers was found to induce a reliable blockage (to an average 9% the original response). The maximum effect was reached after 150-200 min, and the response was totally recovered approximately 300 min after lidocaine application. This characterization should be useful to induce an efficient, short term and reversible blockage of whisker sensory transmission in both anesthetized and awake preparations, while not causing stress in an awake animal.

Abstract: High-frequency oscillations in cortical networks have been linked to a variety of cognitive and perceptual processes. They have also been recorded in small cortical slices in vitro, indicating that neuronal synchronization at these frequencies is generated in the local cortical circuit. However, in vitro experiments have hitherto necessitated exogenous pharmacological or electrical stimulation to generate robust synchronized activity in the beta/gamma range. Here, we demonstrate that the isolated cortical microcircuitry generates beta and gamma oscillations spontaneously in the absence of externally applied neuromodulators or synaptic agonists. We show this in a spontaneously active slice preparation that engages in slow oscillatory activity similar to activity during slow-wave sleep. beta and gamma synchronization appeared during the up states of the slow oscillation. Simultaneous intracellular and extracellular recordings revealed synchronization between the timing of incoming synaptic events and population activity. This rhythm was mechanistically similar to pharmacologically induced gamma rhythms, as it also included sparse, irregular firing of neurons within the population oscillation, predominant involvement of inhibitory neurons, and a decrease of oscillation frequency after barbiturate application. Finally, we show in a computer model how a synaptic loop between excitatory and inhibitory neurons can explain the emergence of both the slow (<1 Hz) and the beta-range oscillations in the neocortical network. We therefore conclude that oscillations in the beta/gamma range that share mechanisms with activity reported in vivo or in pharmacologically activated in vitro preparations can be generated during slow oscillatory activity in the local cortical circuit, even without exogenous pharmacological or electrical stimulation.

Abstract: Neurons in cat area 17 can be grouped in 4 different electrophysiological cell classes (regular spiking, intrinsically bursting, chattering, and fast spiking [FS]). However, little is known of the functional properties of these different cell classes. Here we compared orientation and direction selectivity between these cell classes in cat area 17 and found that a subset of FS inhibitory neurons, usually with complex receptive fields, exhibited little selectivity in comparison with other cell types. Differences in occurrence and amplitude of gamma-range membrane fluctuations, as well as in numbers of action potentials in response to optimal visual stimuli, did not parallel differences observed for orientation and direction selectivity. Instead, differences in selectivity resulted mostly from differences in tuning of the membrane potential responses, although variations in spike threshold also contributed: weakly selective FS neurons exhibited both a lower spike threshold and more broadly tuned membrane potential responses in comparison with the other cell classes. Our results are consistent with the hypothesis that a subgroup of FS neurons receives connections and possesses intrinsic properties allowing the generation of weakly selective responses. The existence of weakly selective inhibitory neurons is consistent with orientation selectivity models that rely on broadly tuned inhibition.

Abstract: Slow spontaneous rhythmic activity is generated and propagates in neocortical slices when bathed in an artificial cerebrospinal fluid with ionic concentrations similar to the ones in vivo. This activity is extraordinarily similar to the activation of the cortex in physiological conditions (e.g., slow-wave sleep), thus representing a unique in vitro model to understand how cortical networks maintain and control ongoing activity. Here we have characterized the activity generated in the olfactory or piriform cortex and endopiriform nucleus (piriform network). Because these structures are prone to generate epileptic discharges, it seems critical to understand how they generate and regulate their physiological rhythmic activity. The piriform network gave rise to rhythmic spontaneous activity consisting of a succession of up and down states at an average frequency of 1.8 Hz, qualitatively similar to the corresponding neocortical activity. This activity originated in the deep layers of the piriform network, which displayed higher excitability and denser connectivity. A remarkable difference with neocortical activity was the speed of horizontal propagation (114 mm/s), one order of magnitude faster in the piriform network. Properties of the piriform cortex subserving fast horizontal propagation may underlie the higher vulnerability of this area to epileptic seizures.

Abstract: We describe a phenomenon of hyperpolarization-activated graded persistent activity (HAGPA) in prefrontal cortex neurons. Successive hyperpolarizing pulses induced increasingly higher rates of tonic firing that remained stable for tens of seconds, allowing the neuron to retain a memory of the previous history of stimulation. This phenomenon occurred at the cellular level and in the absence of neuromodulators. Neurons with HAGPA had a sag during hyperpolarization, and blocking h-current eliminated the sag and prevented HAGPA, suggesting that the activation of this hyperpolarization-activated cationic current was necessary for the occurrence of the phenomenon. A single-neuron biophysical model including h-current modulation by intracellular calcium was able to display HAGPA. This form of neuronal memory not only allows the transformation of inhibition into an increase of firing rate, but also endows neurons with a mechanism to compute the properties of successive inputs into persistent activity, thus solving a difficult computational problem.

Abstract: The integration of the human brain with computers is an interesting new area of applied neuroscience, where one application is replacement of a person's real body by a virtual representation. Here we demonstrate that a virtual limb can be made to feel part of your body if appropriate multisensory correlations are provided. We report an illusion that is invoked through tactile stimulation on a person's hidden real right hand with synchronous virtual visual stimulation on an aligned 3D stereo virtual arm projecting horizontally out of their shoulder. An experiment with 21 male participants showed displacement of ownership towards the virtual hand, as illustrated by questionnaire responses and proprioceptive drift. A control experiment with asynchronous tapping was carried out with a different set of 20 male participants who did not experience the illusion. After 5 min of stimulation the virtual arm rotated. Evidence suggests that the extent of the illusion was also correlated with the degree of muscle activity onset in the right arm as measured by EMG during this period that the arm was rotating, for the synchronous but not the asynchronous condition. A completely virtual object can therefore be experienced as part of one's self, which opens up the possibility that an entire virtual body could be felt as one's own in future virtual reality applications or online games, and be an invaluable tool for the understanding of the brain mechanisms underlying body ownership.

Abstract: BACKGROUND: The cerebral cortex is permanently active during both awake and sleep states. This ongoing cortical activity has an impact on synaptic transmission and short-term plasticity. An activity pattern generated by the cortical network is a slow rhythmic activity that alternates up (active) and down (silent) states, a pattern occurring during slow wave sleep, anesthesia and even in vitro. Here we have studied 1) how network activity affects short term synaptic plasticity and, 2) how synaptic transmission varies in up versus down states. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular recordings obtained from cortex in vitro and in vivo were used to record synaptic potentials, while presynaptic activation was achieved either with electrical or natural stimulation. Repetitive activation of layer 4 to layer 2/3 synaptic connections from ferret visual cortex slices displayed synaptic augmentation that was larger and longer lasting in active than in silent slices. Paired-pulse facilitation was also significantly larger in an active network and it persisted for longer intervals (up to 200 ms) than in silent slices. Intracortical synaptic potentials occurring during up states in vitro increased their amplitude while paired-pulse facilitation disappeared. Both intracortical and thalamocortical synaptic potentials were also significantly larger in up than in down states in the cat visual cortex in vivo. These enhanced synaptic potentials did not further facilitate when pairs of stimuli were given, thus paired-pulse facilitation during up states in vivo was virtually absent. Visually induced synaptic responses displayed larger amplitudes when occurring during up versus down states. This was further tested in rat barrel cortex, where a sensory activated synaptic potential was also larger in up states. CONCLUSIONS/SIGNIFICANCE: These results imply that synaptic transmission in an active cortical network is more secure and efficient due to larger amplitude of synaptic potentials and lesser short term plasticity.

Abstract: Local neocortical circuits are characterized by stereotypical physiological and structural features that subserve generic computational operations. These basic computations of the cortical microcircuit emerge through the interplay of neuronal connectivity, cellular intrinsic properties, and synaptic plasticity dynamics. How these interacting mechanisms generate specific computational operations in the cortical circuit remains largely unknown. Here, we identify the neurophysiological basis of both the rate of change and anticipation computations on synaptic inputs in a cortical circuit. Through biophysically realistic computer simulations and neuronal recordings, we show that the rate-of-change computation is operated robustly in cortical networks through the combination of two ubiquitous brain mechanisms: short-term synaptic depression and spike-frequency adaptation. We then show how this rate-of-change circuit can be embedded in a convergently connected network to anticipate temporally incoming synaptic inputs, in quantitative agreement with experimental findings on anticipatory responses to moving stimuli in the primary visual cortex. Given the robustness of the mechanism and the widespread nature of the physiological machinery involved, we suggest that rate-of-change computation and temporal anticipation are principal, hard-wired functions of neural information processing in the cortical microcircuit.

Abstract:

Abstract: BACKGROUND: The neuronal cortical network generates slow (<1 Hz) spontaneous rhythmic activity that emerges from the recurrent connectivity. This activity occurs during slow wave sleep or anesthesia and also in cortical slices, consisting of alternating up (active, depolarized) and down (silent, hyperpolarized) states. The search for the underlying mechanisms and the possibility of analyzing network dynamics in vitro has been subject of numerous studies. This exposes the need for a detailed quantitative analysis of the membrane fluctuating behavior and computerized tools to automatically characterize the occurrence of up and down states. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular recordings from different areas of the cerebral cortex were obtained from both in vitro and in vivo preparations during slow oscillations. A method that separates up and down states recorded intracellularly is defined and analyzed here. The method exploits the crossover of moving averages, such that transitions between up and down membrane regimes can be anticipated based on recent and past voltage dynamics. We demonstrate experimentally the utility and performance of this method both offline and online, the online use allowing to trigger stimulation or other events in the desired period of the rhythm. This technique is compared with a histogram-based approach that separates the states by establishing one or two discriminating membrane potential levels. The robustness of the method presented here is tested on data that departs from highly regular alternating up and down states. CONCLUSIONS/SIGNIFICANCE: We define a simple method to detect cortical states that can be applied in real time for offline processing of large amounts of recorded data on conventional computers. Also, the online detection of up and down states will facilitate the study of cortical dynamics. An open-source MATLAB toolbox, and Spike 2-compatible version are made freely available.

Abstract: Repetitive stimulation of synaptic connections in the cerebral cortex often induces short-term synaptic depression (STD), a property directly related to the probability of transmitter release and critical for the computational properties of the network. In order to explore how spontaneous activity in the network affects this property, we first studied STD in cortical slices that were either silent or that displayed spontaneous rhythmic slow oscillations resembling those recorded during slow wave sleep in vivo. STD was considerably reduced by the occurrence of spontaneous rhythmic activity in the cortical network. Once the rhythmic activity started, depression decreased over time in parallel with the duration and intensity of the ongoing activity until a plateau was reached. Thalamocortical and intracortical synaptic potentials studied in vivo also showed stronger depression in a silent than in an active cortical network, and the depression values in the active cortical network in vivo were indistinguishable from those found in active slices in vitro. We suggest that this phenomenon is due to the different steady states of the synapses in active and in silent networks.

Abstract: Blind individuals often demonstrate enhanced non-visual perceptual abilities. Neuroimaging and transcranial magnetic stimulation experiments have suggested that computations carried out in the occipital cortex may underlie these enhanced somatosensory or auditory performances. Thus, cortical areas that are dedicated to the analysis of the visual scene may, in the blind, acquire the capacity to participate in other sensory processing. However, the neural substrate that underlies this transfer of function is not fully characterized. Here we studied the synaptic and anatomical basis of this phenomenon in cats that were visually deprived by dark rearing, either early visually deprived after birth (EVD), or late visually deprived after the end of the critical period (LVD); data were compared with those obtained in normally reared cats (controls). The presence of synaptic and spike responses to auditory stimulation was examined by means of intracellular recordings in area 17 and the border between areas 17 and 18. While none of the cells recorded in control and LVD cats showed responses to sound, 14% of the cells recorded in EVD cats showed both subthreshold synaptic responses and suprathreshold spike responses to auditory stimuli. Synaptic responses were of small amplitude, but well time-locked to the stimuli and had an average latency of 30+/-12ms. In an attempt to identify the origin of the inputs carrying auditory information to the visual cortex, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected in the visual cortex and retrograde labeling examined in the cortex and thalamus. No significant retrograde labeling was found in auditory cortical areas. However, the proportion of neurons projecting from supragranular layers of the posteromedial and posterolateral parts of the lateral suprasylvian region to V1 was higher than that in control cats. Retrograde labeling in the lateral geniculate nucleus showed no difference in the total number of neurons between control and visually deprived cats, but there was a higher proportion of labeling in C-laminae in deprived cats. Labeled cells were not found in the medial geniculate nucleus, a thalamic relay for auditory information, in either control or visually deprived cats. Finally, immunohistochemistry of the visual cortex of deprived cats revealed a striking decrease in pavalbumin- and calretinin-positive neurons, the functional implications of which we discuss.

Abstract: Short-term synaptic depression (STD) and spike-frequency adaptation (SFA) are two basic physiological cortical mechanisms for reducing the system's excitability under repetitive stimulation. The computational implications of each one of these mechanisms on information processing have been studied in detail, but not so the dynamics arising from their combination in a realistic biological scenario. We show here, both experimentally with intracellular recordings from cortical slices of the ferret and computationally using a biologically realistic model of a feedforward cortical network, that STD combined with presynaptic SFA results in the resensitization of cortical synaptic efficacies in the course of sustained stimulation. This fundamental effect is then shown in the computational model to have important implications for the network response to time-varying inputs. The main findings are: (1) the addition of SFA to the model endowed with STD improves the network sensitivity to the degree of synchrony in the incoming inputs; (2) presynaptic SFA, whether slow or fast, combined with STD results in postsynaptic neurons responding briskly to abrupt changes in the presynaptic input current and ignoring sustained stimulation, much more effectively than either SFA or STD alone; (3) for slow presynaptic SFA postsynaptic responses to strong inputs decrease inversely to the input, whereas for weak input current to presynaptic neurons transient postsynaptic responses are strongly facilitated, thus enhancing the system's sensitivity for subtle changes in weak presynaptic inputs. Taken together, these results suggest that in systems designed to respond to temporal aspects of the input, SFA and STD might constitute two necessary, linked elements whose simultaneous interplay is important for the performance of the system.

Abstract: BACKGROUND: Stanley Milgram's 1960s experimental findings that people would administer apparently lethal electric shocks to a stranger at the behest of an authority figure remain critical for understanding obedience. Yet, due to the ethical controversy that his experiments ignited, it is nowadays impossible to carry out direct experimental studies in this area. In the study reported in this paper, we have used a similar paradigm to the one used by Milgram within an immersive virtual environment. Our objective has not been the study of obedience in itself, but of the extent to which participants would respond to such an extreme social situation as if it were real in spite of their knowledge that no real events were taking place. METHODOLOGY: Following the style of the original experiments, the participants were invited to administer a series of word association memory tests to the (female) virtual human representing the stranger. When she gave an incorrect answer, the participants were instructed to administer an 'electric shock' to her, increasing the voltage each time. She responded with increasing discomfort and protests, eventually demanding termination of the experiment. Of the 34 participants, 23 saw and heard the virtual human, and 11 communicated with her only through a text interface. CONCLUSIONS: Our results show that in spite of the fact that all participants knew for sure that neither the stranger nor the shocks were real, the participants who saw and heard her tended to respond to the situation at the subjective, behavioural and physiological levels as if it were real. This result reopens the door to direct empirical studies of obedience and related extreme social situations, an area of research that is otherwise not open to experimental study for ethical reasons, through the employment of virtual environments.

Abstract: Fast-spiking (FS) neurons are a class of inhibitory interneurons classically characterized as having short-duration action potentials (<0.5 ms at half height) and displaying little to no spike-frequency adaptation during short (<500 ms) depolarizing current pulses. As a consequence, the resulting injected current intensity versus firing frequency relationship is typically steep, and they can achieve firing frequencies of < or =1 kHz. Here we have investigated the properties of FS neurons discharges on a longer time scale. Twenty second discharges were induced in electrophysiologically identified FS neurons by means of current injection either with sinusoidal current or with square pulses. We found that virtually all FS neurons recorded in cortical slices do show spike-frequency adaptation but with a slow time course (tau = 2-19 s). This slow time course has precluded the observation of this property in previous studies that used shorter pulses. Contrary to the classical view of FS neurons functional properties, long-duration discharges were followed by a slow afterhyperpolarization lasting < or =23 s. During this postadaptation period, the excitability of the neurons was decreased on average for 16.7 +/- 6.8 s, therefore rendering the cell less responsive to subsequent afferent inputs. Slow adaptation is also reported here for FS neurons recorded in vivo. This longer time scale of adaptation in FS neurons may be critical for balancing excitation and inhibition as well as for the understanding of cortical network computations.

Abstract: Immersive virtual environments can break the deep, everyday connection between where our senses tell us we are and where we are actually located and whom we are with. The concept of 'presence' refers to the phenomenon of behaving and feeling as if we are in the virtual world created by computer displays. In this article, we argue that presence is worthy of study by neuroscientists, and that it might aid the study of perception and consciousness.

Abstract: We examined the mechanisms through which the prolonged presentation of either a high-contrast stimulus or an artificial scotoma [equivalent to the stimulation of the receptive field (RF) surround] induces changes in the RF properties of neurons intracellularly recorded in cat primary visual cortex. Discharge and synaptic RFs were quantitatively characterized using bright and dark bars randomly flashed in various positions. Compared with the lack of stimulation (0% contrast for 15-30 s), stimulation with high-contrast sine-wave gratings (15-30 s) was followed by a strong reduction in gain and a weak but significant reduction in width of spike discharge RFs. These reductions were accompanied by a membrane potential hyperpolarization, a decrease of synaptic RF width, and varying changes of synaptic RF gain. Passive hyperpolarization by DC injection also produced significant reduction in the width and gain of discharge RF. Mimicking, in single neurons, high-contrast stimulation with high-intensity current injection also induced a membrane potential hyperpolarization, whose amplitude was correlated with discharge RF gain and width changes. Recovery from adaptation to high-contrast stimulation during the period of gray screen or scotoma presentation was associated with an increase in gain and discharge RF size. Stimulation of the RF surround with an artificial scotoma did not have any additional aftereffects over those of adaptation to a gray screen, indicating that the contraction and expansion of RF gain and size are attributable to intrinsic and synaptic mechanisms underlying adaptation and de-adaptation to strong visual stimuli.

Abstract: Normalized Lempel-Ziv complexity, which measures the generation rate of new patterns along a digital sequence, is closely related to such important source properties as entropy and compression ratio, but, in contrast to these, it is a property of individual sequences. In this article, we propose to exploit this concept to estimate (or, at least, to bound from below) the entropy of neural discharges (spike trains). The main advantages of this method include fast convergence of the estimator (as supported by numerical simulation) and the fact that there is no need to know the probability law of the process generating the signal. Furthermore, we present numerical and experimental comparisons of the new method against the standard method based on word frequencies, providing evidence that this new approach is an alternative entropy estimator for binned spike trains.

Abstract: Slow oscillatory activity (<1 Hz) is observed in vivo in the cortex during slow-wave sleep or under anesthesia and in vitro when the bath solution is chosen to more closely mimic cerebrospinal fluid. Here we present a biophysical network model for the slow oscillations observed in vitro that reproduces the single neuron behaviors and collective network firing patterns in control as well as under pharmacological manipulations. The membrane potential of a neuron oscillates slowly (at <1 Hz) between a down state and an up state; the up state is maintained by strong recurrent excitation balanced by inhibition, and the transition to the down state is due to a slow adaptation current (Na(+)-dependent K(+) current). Consistent with in vivo data, the input resistance of a model neuron, on average, is the largest at the end of the down state and the smallest during the initial phase of the up state. An activity wave is initiated by spontaneous spike discharges in a minority of neurons, and propagates across the network at a speed of 3-8 mm/s in control and 20-50 mm/s with inhibition block. Our work suggests that long-range excitatory patchy connections contribute significantly to this wave propagation. Finally, we show with this model that various known physiological effects of neuromodulation can switch the network to tonic firing, thus simulating a transition to the waking state.

Abstract: To facilitate the characterization of cortical neuronal function, the responses of cells in cat area 17 to intracellular injection of current pulses were quantitatively analyzed. A variety of response variables were used to separate the cells into subtypes using cluster analysis. Four main classes of neurons could be clearly distinguished: regular spiking (RS), fast spiking (FS), intrinsic bursting (IB), and chattering (CH). Each of these contained significant subclasses. RS neurons were characterized by trains of action potentials that exhibited spike frequency adaptation. Morphologically, these cells were spiny stellate cells in layer 4 and pyramidal cells in layers 2, 3, 5, and 6. FS neurons had short-duration action potentials (<0.5 ms at half height), little or no spike frequency adaptation, and a steep relationship between injected current intensity and spike discharge frequency. Morphologically, these cells were sparsely spiny or aspiny nonpyramidal cells. IB neurons typically generated a low frequency (<425 Hz) burst of spikes at the beginning of a depolarizing current pulse followed by a tonic train of action potentials for the remainder of the pulse. These cells were observed in all cortical layers, but were most abundant in layer 5. Finally, CH neurons generated repetitive, high-frequency (350-700 Hz) bursts of short-duration (<0.55 ms) action potentials. Morphologically, these cells were layer 2-4 (mainly layer 3) pyramidal or spiny stellate neurons. These results indicate that firing properties do not form a continuum and that cortical neurons are members of distinct electrophysiological classes and subclasses.

Abstract: In a previous paper (Proceedings of the World Congress on Neuroinformatics (2001)) the authors applied the so-called Lempel-Ziv complexity to study neural discharges (spike trains) from an information-theoretical point of view. Along with other results, it is shown there that this concept of complexity allows to characterize the responses of primary visual cortical neurons to both random and periodic stimuli. To this aim we modeled the neurons as information sources and the spike trains as messages generated by them. In this paper, we study further consequences of this mathematical approach, this time concerning the number of states of such neuronal information sources. In this context, the state of an information source means an internal degree of freedom (or parameter) which allows outputs with more general stochastic properties, since symbol generation probabilities at every time step may additionally depend on the value of the current state of the neuron. Furthermore, if the source is ergodic and Markovian, the number of states is directly related to the stochastic dependence lag of the source and provides a measure of the autocorrelation of its messages. Here, we find that the number of states of the neurons depends on the kind of stimulus and the type of preparation ( in vivo versus in vitro recordings), thus providing another way of differentiating neuronal responses. In particular, we observed that (for the encoding methods considered) in vitro sources have a higher lag than in vivo sources for periodic stimuli. This supports the conclusion put forward in the paper mentioned above that, for the same kind of stimulus, in vivo responses are more random (hence, more difficult to compress) than in vitro responses and, consequently, the former transmit more information than the latter.

Abstract: Local cortical networks in the prefrontal cortex and visual cortex are capable of spontaneously generating sustained activity for periods of seconds or longer. This sustained activity is generated through recurrent excitation between pyramidal cells that is controlled by feedback inhibition and can have both a rapid onset and a rapid offset. The period of activity is associated with a marked increase in neuronal responsiveness to the intracellular injection of current pulses, especially those of smaller amplitude. Independently mimicking the depolarization, increase in membrane conductance and increase in noise associated with sustained activity revealed that the depolarization is largely responsible for the increase in neuronal responsiveness, although an increase in membrane noise also facilitates responses to small inputs. These results indicate that the persistent activity associated with the performance of working memory tasks may be generated largely through recurrent networks. They also suggest that feedback pathways, such as those involved in selective attention, may exert a powerful influence on neuronal responsiveness through synaptic bombardment.

Abstract: Limiting redundancy in the real-world sensory inputs is of obvious benefit for efficient neural coding, but little is known about how this may be accomplished by biophysical neural mechanisms. One possible cellular mechanism is through adaptation to relatively constant inputs. Recent investigations in primary visual (V1) cortical neurons have demonstrated that adaptation to prolonged changes in stimulus contrast is mediated in part through intrinsic ionic currents, a Ca2+-activated K+ current (IKCa) and especially a Na+-activated K+ current (IKNa). The present study was designed to test the hypothesis that the activation of adaptation ionic currents may provide a cellular mechanism for temporal decorrelation in V1. A conductance-based neuron model was simulated, which included an IKCa and an IKNa. We show that the model neuron reproduces the adaptive behavior of V1 neurons in response to high contrast inputs. When the stimulus is stochastic with 1/f 2 or 1/f-type temporal correlations, these autocorrelations are greatly reduced in the output spike train of the model neuron. The IKCa is effective at reducing positive temporal correlations at approximately 100-ms time scale, while a slower adaptation mediated by IKNa is effective in reducing temporal correlations over the range of 1-20 s. Intracellular injection of stochastic currents into layer 2/3 and 4 (pyramidal and stellate) neurons in ferret primary visual cortical slices revealed neuronal responses that exhibited temporal decorrelation in similarity with the model. Enhancing the slow afterhyperpolarization resulted in a strengthening of the decorrelation effect. These results demonstrate the intrinsic membrane properties of neocortical neurons provide a mechanism for decorrelation of sensory inputs.

Abstract: Pattern matching is a simple method for studying the properties of information sources based on individual sequences (Wyner et al 1998 IEEE Trans. Inf. Theory 44 2045-56). In particular, the normalized Lempel-Ziv complexity (Lempel and Ziv 1976 IEEE Trans. Inf. Theory 22 75-88), which measures the rate of generation of new patterns along a sequence, is closely related to such important source properties as entropy and information compression ratio. We make use of this concept to characterize the responses of neurons of the primary visual cortex to different kinds of stimulus, including visual stimulation (sinusoidal drifting gratings) and intracellular current injections (sinusoidal and random currents), under two conditions (in vivo and in vitro preparations). Specifically, we digitize the neuronal discharges with several encoding techniques and employ the complexity curves of the resulting discrete signals as fingerprints of the stimuli ensembles. Our results show, for example, that if the neural discharges are encoded with a particular one-parameter method ('interspike time coding'), the normalized complexity remains constant within some classes of stimuli for a wide range of the parameter. Such constant values of the normalized complexity allow then the differentiation of the stimuli classes. With other encodings (e.g. 'bin coding'), the whole complexity curve is needed to achieve this goal. In any case, it turns out that the normalized complexity of the neural discharges in vivo are higher (and hence carry more information in the sense of Shannon) than in vitro for the same kind of stimulus.

Abstract: Contrast adaptation is a psychophysical phenomenon, the neuronal bases of which reside largely in the primary visual cortex. The cellular mechanisms of contrast adaptation were investigated in the cat primary visual cortex in vivo through intracellular recording and current injections. Visual cortex cells, and to a much less extent, dorsal lateral geniculate nucleus (dLGN) neurons, exhibited a reduction in firing rate during prolonged presentations of a high-contrast visual stimulus, a process we termed high-contrast adaptation. In a majority of cortical and dLGN cells, the period of adaptation to high contrast was followed by a prolonged (5-80 sec) period of reduced responsiveness to a low-contrast stimulus (postadaptation suppression), an effect that was associated, and positively correlated, with a hyperpolarization of the membrane potential and an increase in apparent membrane conductance. In simple cells, the period of postadaptation suppression was not consistently associated with a decrease in the grating modulated component of the evoked synaptic barrages (the F1 component). The generation of the hyperpolarization appears to be at least partially intrinsic to the recorded cells, because the induction of neuronal activity with the intracellular injection of current resulted in both a hyperpolarization of the membrane potential and a decrease in the spike response to either current injections or visual stimuli. Conversely, high-contrast visual stimulation could suppress the response to low-intensity sinusoidal current injection. We conclude that control of the membrane potential by intrinsic neuronal mechanisms contributes importantly to the adaptation of neuronal responsiveness to varying levels of contrast. This feedback mechanism, internal to cortical neurons, provides them with the ability to continually adjust their responsiveness as a function of their history of synaptic and action potential activity.

Abstract: The neocortex generates periods of recurrent activity, such as the slow (0.1-0.5 Hz) oscillation during slow-wave sleep. Here we demonstrate that slices of ferret neocortex maintained in vitro generate this slow (< 1 Hz) rhythm when placed in a bathing medium that mimics the extracellular ionic composition in situ. This slow oscillation seems to be initiated in layer 5 as an excitatory interaction between pyramidal neurons and propagates through the neocortex. Our results demonstrate that the cerebral cortex generates an 'up' or depolarized state through recurrent excitation that is regulated by inhibitory networks, thereby allowing local cortical circuits to enter into temporarily activated and self-maintained excitatory states. The spontaneous generation and failure of this self-excited state may account for the generation of a subset of cortical rhythms during sleep.

Abstract: The cellular mechanisms of spike-frequency adaptation during prolonged discharges and of the slow afterhyperpolarization (AHP) that follows, as occur in vivo with contrast adaptation, were investigated with intracellular recordings of cortical neurons in slices of ferret primary visual cortex. Intracellular injection of 2 Hz sinusoidal or constant currents for 20 sec resulted in a slow (tau = 1-10 sec) spike-frequency adaptation, the degree of which varied widely among neurons. Reducing either [Ca(2+)](o) or [Na(+)](o) reduced the rate of spike-frequency adaptation. After the prolonged discharge was a slow (12-75 sec) AHP that was associated with an increase in membrane conductance and a rightward shift in the discharge frequency versus injected current relationship. The reversal potential of the slow AHP was sensitive to changes in [K(+)](o), indicating that it was mediated by a K(+) current. Blockade of transmembrane Ca(2+) conductances did not reduce the slow AHP. In contrast, reductions of [Na(+)](o) reduced the slow AHP, even in the presence of pronounced Ca(2+) spikes. We suggest that the activation of Na(+)-activated and Ca(2+)-activated K(+) currents plays an important role in prolonged spike-frequency adaptation and therefore may contribute to contrast adaptation and other forms of adaptation in the visual system in vivo.

Abstract: The inhibitory gamma-aminobutyric acid-containing (GABAergic) neurons of the thalamic reticular and perigeniculate nuclei are involved in the generation of normal and abnormal synchronized activity in thalamocortical networks. An important factor controlling the generation of activity in this system is the amplitude and duration of inhibitory postsynaptic potentials (IPSPs) in thalamocortical cells, which depend on the pattern of activity generated in thalamic reticular and perigeniculate cells. Activation of single ferret perigeniculate neurons generated three distinct patterns of GABAergic IPSPs in thalamocortical neurons of the dorsal lateral geniculate nucleus: Low-frequency tonic discharge resulted in small-amplitude IPSPs mediated by GABAA receptors, burst firing resulted in large-amplitude GABAA IPSPs, and prolonged burst firing activated IPSPs mediated by GABAA and GABAB receptors. These functional properties of GABAergic inhibition can reconfigure the operations of thalamocortical networks into patterns of activity associated with waking, slow-wave sleep, and generalized seizures.

Abstract: Cortical neurons in vivo respond to sensory stimuli with the generation of action potentials that can show a high degree of variability in both their number and timing with repeated presentations as wells as, on occasion, a high degree of synchronization with other cortical neurons, including in the gamma frequency range of 30-70 Hz. Here we examined whether or not this variability may arise from the intrinsic mechanisms of action potential generation in cortical regular spiking, fast spiking and intrinsic burst-generating neurons maintained in vitro. For this purpose, we performed intracellular recordings in slices of ferret visual cortex and activated these cells with the intracellular injection of various current waveforms. Some of these waveforms were derived from barrages of postsynaptic potentials evoked by visual stimulation recorded in vivo; others were artificially created and contained various amounts of gamma range fluctuations; finally, others consisted of swept-sinewave current (ZAP current) functions. Using such stimuli, we found that, as expected given the resistive and capacitive properties of cortical neurons, low frequencies have a larger effect on the membrane potential of cortical neurons than do higher frequencies. However, increasing the amount of gamma range fluctuations in a stimulus leads to more precise timing of action potentials. This suggests that different frequencies play different roles, low frequencies being efficient for depolarizing cells with high frequencies increasing the precision of action potential timing. In parallel to increases in temporal precision, the addition of higher frequency components increases the range of interspike intervals present in the action potential discharge. These results suggest that higher frequency components such as gamma range fluctuations may facilitate the generation of action potentials with a high temporal precision while at the same time exhibiting a high degree of variability in interspike intervals on single trials. This temporal precision may facilitate the use of temporal codes or the generation of precise synchronization for the transmission and analysis of information within cortical networks.

Abstract: The properties of the inhibitory influence of neurons in the perigeniculate (PGN) nucleus on thalamocortical cells were examined with intracellular recordings in the ferret geniculate slice maintained in vitro. Activation of PGN neurons with the local application of glutamate caused IPSPs in thalamocortical neurons that were mediated by both GABAA and GABAB receptors, as well as the activation of spindle waves. With low intensity stimulation of the PGN, local application of bicuculline to the dorsal lateral geniculate nucleus (LGNd) strongly inhibited evoked and spindle-associated IPSPs, indicating that these are largely mediated by GABAA receptors. The generation of GABAB receptor-mediated IPSPs in thalamocortical cells that were large enough to generate rebound low threshold Ca2+ spikes required substantially increased activation of the PGN with glutamate. The activation of synchronous bicuculline-induced slowed oscillations in thalamocortical neurons required the block of GABAA receptors in the LGNd as well as in the PGN. These results indicate that bursts of action potentials in PGN neurons can result in the activation of both GABAA and GABAB receptors in thalamocortical neurons, with the strong activation of GABAB receptors requiring an intense, simultaneous discharge of a number of PGN neurons. Functionally, these results suggest that PGN neurons inhibit thalamocortical cells preferentially through the activation of GABAA receptors, although the strong activation of GABAB receptors may occur under pathological conditions and contribute to the generation of abnormal, synchronous slow oscillations.

Abstract: Perigeniculate neurons form an interactive sheet of cells that inhibit one another as well as thalamocortical neurons in the dorsal lateral geniculate nucleus (LGNd). The inhibitory influence of the GABAergic neurons of the perigeniculate nucleus (PGN) onto other PGN neurons was examined with intracellular recordings in vitro. Intracellular recordings from PGN neurons during the generation of spindle waves revealed barrages of EPSPs and IPSPs. The excitation of local regions of the PGN with the local application of glutamate resulted in activation of IPSPs in neighboring PGN neurons. These IPSPs displayed an average reversal potential of -77 mV and were blocked by application of bicuculline methiodide or picrotoxin, indicating that they are mediated by GABAA receptors. In the presence of GABAA receptor blockade, the activation of PGN neurons with glutamate could result in slow IPSPs that were mediated by GABAB receptors in a subset (40%) of cells. Similarly, application of specific agonists muscimol and baclofen demonstrated that PGN neurons possess both functional GABAA and GABAB receptors. Examination of the axon arbors of biocytin-filled PGN neurons often revealed the presence of beaded axon collaterals within the PGN, suggesting that this may be an anatomical substrate for PGN to PGN inhibition. Functionally, activation of inhibition between PGN neurons could result in a shortening or a complete abolition of the low threshold Ca2+ spike or an inhibition of tonic discharge. We suggest that the mutual inhibition between PGN neurons forms a mechanism by which the excitability of these cells is tightly controlled. The activation of a point within the PGN may result in the inhibition of neighboring PGN neurons. This may be reflected in the LGNd as a center of inhibition surrounded by an annulus of disinhibition, thus forming a "center-surround" mechanism for thalamic function.

Abstract: The ferret dorsal lateral geniculate nucleus (LGNd) contains interneurons within the interlaminar zones situated between the laminae corresponding to the ipsi- and contralateral eyes. We found that a subset of these neurons exhibits electrophysiological properties similar to those previously reported for perigeniculate (PGN) neurons, including the generation of rhythmic sequences of rebound low-threshold Ca2+ spikes at a frequency of 1-4 Hz after the intracellular injection of a hyperpolarizing current pulse. These "PGN-like" interlaminar interneurons innervated restricted regions of the A-laminae, inhibited thalamocortical cells through GABAA, and perhaps GABAB, receptors, and were excited by axon collaterals from thalamocortical cells. This reciprocal relationship is identical to that formed by PGN cells and allowed the PGN-like interlaminar neurons to participate in the generation of spindle waves and other network oscillations. Pharmacologically, PGN-like interlaminar interneurons were also similar to PGN neurons: both generated a prolonged depolarization in response to the local application of serotonin, 1S,3R-ACPD, and CCK8S, and a rapid depolarization followed by a more prolonged hyperpolarization in response to acetylcholine. Examination of parvalbumin and calbindin staining in the ferret LGNd revealed that both PGN and a subset of interlaminar neurons were parvalbumin-positive. In contrast, calbindin-positive cells were relatively absent in the PGN and sparsely present in the interlaminar zones, but were numerous in the A and C laminae. Our results indicate that the interlaminar zone in between laminae A and A1 and A1 and C in the ferret LGNd possesses a cell type that is electrophysiologically, pharmacologically, anatomically, immunocytochemically, and functionally similar to neurons in the PGN.

Abstract: PURPOSE. To identify electrophysiologically the functional types of sensory fibers innervating the iris and the ciliary body of the cat's eye. METHODS. The uveal tract tract of cat's eye was excised and placed in a superfusion chamber. Recordings were made from single afferent units of ciliary nerve branches responding to mechanical stimulation of the iridal surface, the ciliary body, and the choroid with a nylon filament or a glass rod. Chemical sensitivity was explored by applying acetic acid, hypertonic NaCl, and bradykinin. Warm (60 degrees C) and cold (4 degrees C) saline and a servocontrolled thermode were used for thermal stimulation. RESULTS. Thirty per cent of the studied population of sensory units (n = 95) were spontaneously active when the recording was started. Approximately 30% of the fibers conducted in the lowest range of the A-delta group; the remaining 70% were C fibers. Sustained mechanical stimulation of the receptive area elicited a tonic response in approximately 60% of the units, and a phasic response in the remaining 40%. Exposure of the receptive field of mechanosensitive fibers to 600 mM NaCl evoked a long-lasting discharge in 50% of the units; application of 1 to 10 mM acetic acid elicited a short discharge in 30% of the fibers, often followed by inactivation. Bradykinin (1 to 100 microMs) produced a long-lasting response in almost 50% of the units. Warming the receptive field recruited 20% of the explored units, whereas 17% were activated by low temperature. CONCLUSIONS. Two main functional types of sensory fibers innervating the iris and the ciliary body were distinguished: (1) mechanoreceptors, corresponding to afferent units sensitive only to mechanical stimuli were generally silent at rest, had relatively higher force thresholds, and discharged phasically in response to long-lasting mechanical stimulation; (2) polymodal nociceptors, which were activated by mechanical as well as by chemical and/or thermal stimuli, usually displayed spontaneous activity, had lower force thresholds, and fired tonically upon sustained mechanical stimulation.

Abstract: In sympathetic neurons, axotomy induces a marked depression in synaptic transmission. We asked whether the decrease in synaptic efficacy observed in a given axotomized cell is more severe if most of the postsynaptic neurons are also injured. Accordingly, we studied if the synaptic depression induced by axotomy in neurons with axons running in a postganglionic nerve is influenced by section of other postganglionic nerves. The excitatory postsynaptic potentials evoked by preganglionic stimulation were recorded intracellularly in an in vitro preparation of the superior cervical ganglion. Eight days after cutting the inferior postganglionic nerve, postsynaptic potentials recorded from neurons projecting through this nerve were smaller (median = 6 mV, n = 62) than the controls (median = 34 mV, n = 89), but were similar to those found after sectioning the inferior nerve plus most postganglionic nerves (median = 5 mV, n = 70). If the inferior nerve was left intact, but most postganglionic branches were cut, the synaptic potentials recorded from inferior nerve neurons were normal (median = 33 mV, n = 77). It is concluded that the synaptic depression induced by axotomy in a sympathetic neuron is not affected by axotomy of nearby ganglion cells, even if they share part of their presynaptic axons. This suggests that the effect of axotomy is restricted to the synaptic terminals on the injured neuron.

Abstract: Some of the marked biochemical and electrophysiological changes provoked by section of the axon in mature neurons suggest that the intracellular calcium concentration ([Ca2+]i) may be increased. We have measured the [Ca2+]i using the fluorescent indicator Indo-1 microinjected into rat superior cervical ganglion neurons. No differences in resting [Ca2+]i levels were found between control neurons and cells which had been axotomized 7-10 days before. However, the rise in [Ca2+]i evoked by orthodromic or antidromic stimulation and the recovery after the stimulating train were considerably slower in axotomized neurons than in control cells. We also found that the number of calbindin-D28k-immunopositive cells in the ganglion increases after axotomy, which could be related to the observed differences in calcium homeostasis.

Abstract: 1. Seven to ten days after sectioning their axons, rat sympathetic neurons were studied using intracellular recording techniques in an in vitro preparation of the superior cervical ganglion. 2. In 75% of axotomized cells, an after-depolarization (ADP) was observed following spike firing or depolarization with intracellular current pulses. Discontinuous single-electrode voltage-clamp techniques were employed to study the ADP. When the membrane potential was clamped at the resting level just after an action potential, a slow inward current was recorded in cells that showed an ADP. 3. In the presence of TTX and TEA, inward peaks and outward currents were recorded during depolarizing voltage jumps, followed by slowly decaying inward tail currents accompanied by large increases in membrane conductance. The inward peak and tail currents activated between -10 and -20 mV and reached maximum amplitudes around 0 mV. With depolarizing jumps to between +40 and +50 mV, net outward currents were recorded during the depolarizing jumps but inward tail currents were still activated. 4. In the presence of the Ca2+ channel blocker cadmium, or when Ca2+ was substituted by Mg2+, the ADP disappeared. In voltage-clamped cells, cadmium blocked the inward tail currents. The reversal potential for the inward tail current was approximately -15 mV. Substitution of the extracellular NaCl by sucrose or sodium isethionate increased the amplitude of the inward tail current, and displaced its equilibrium potential to more positive values. Changes in extracellular [K+] did not appreciably affect the inward tail current amplitude or equilibrium potential. Niflumic acid, a blocker of chloride channels activated by Ca2+, almost completely blocked the tail current. 5. No ADPs were observed in non-axotomized neurons, and when depolarizing pulses were applied while in voltage clamp no inward tail currents were evoked in these normal cells. 6. It is concluded that axotomy of sympathetic ganglion cells produces the appearance of a Ca(2+)-dependent chloride current responsible for the ADP observed following spike firing.

Abstract: 1. The electrical properties of rat superior cervical ganglion cells were examined in vitro with intracellular microelectrodes after axotomy or atrophy of the submandibular salivary gland. 2. Membrane time constant, input resistance and excitatory synaptic potentials (EPSPs) were decreased to about 50% of their control values 7-10 days after axotomy. 3. Axotomized ganglion cells also showed reduced action potentials and after-hyperpolarizations (AHPs). The AHP duration was reduced to 40% of the control value. 4. In 25% of the axotomized cells, the action potential was followed by an after-depolarization (ADP) instead of the AHP that was always present in control cells. In eleven out of seventeen axotomized cells with ADP, preganglionic stimulation failed to evoke an EPSP, whereas the failure of the synaptic response was never observed in control cells and occurred only in two of fifty-three axotomized cells with AHP. 5. In some axotomized cells with AHP, a depolarizing potential developed after a train of action potentials. This was never observed in control cells. 6. Sympathetic neurones innervating the submandibular gland in control animals had membrane properties similar to those observed in other ganglion cells. 7. The properties of neurones innervating the submandibular gland remained unaltered after the experimentally induced atrophy of the gland. 8. It is concluded that the marked effects of short-term axotomy on membrane properties of sympathetic ganglion cells are not reproduced by long-term atrophy of the target tissue.

Abstract: IAHP is a calcium dependent potassium current that underlies slow afterhyperpolarizations following action potentials in bullfrog sympathetic ganglion neurons. The decay rate of IAHP increases with increasing calcium loads. This effect was found not to be due to mobilization on intracellular calcium from ryanodine and caffeine sensitive stores. The relation is not affected by ryanodine at concentrations that block mobilization in the presence of caffeine, a drug that enhances mobilization of those stores. Nor does the relation seem to be due to a reduction of the driving force of the Na/Ca exchange process. The relation between decay rate and calcium load persists when Na+ is replaced by Li+. Our results suggest that Na/Ca exchange and mobilization of intracellular calcium normally have little influence in determining the time course of IAHP in these neurons.

Abstract: Intercellular communication is considered to have a role during pattern specification processes in early embryonic development. This report analyzes the changing gap junctional communication properties of chick neuroepithelial cells depending on their position relative to the segmental partitions of the rhombencephalon. Intercellular electrical coupling and dye transfer were studied with microelectrode techniques. Neuroepithelial cells were electrically coupled irrespective of their location relative to interneuromeric boundaries. Iontophoretic injection of biocytin or Lucifer Yellow into single cells inside the rhombomeres was followed by transjunctional diffusion to the surrounding cells. In contrast, dye transfer was strictly limited when the diffusion zone contacted the cells forming the interneuromeric limits. Label injected into the boundary cells did not spread to other cells at all. Avian interrhombomeric boundaries are thus sites of reduced junctional permeability during early morphogenesis.