Cholinergic Switch between Two Types of Slow Waves in Cerebral Cortex.

Sleep slow waves are known to participate in memory consolidation, yet slow waves occurring under anesthesia present no positive effects on memory. Here, we shed light onto this paradox, based on a combination of extracellular recordings in vivo, in vitro, and computational models. We find two types of slow waves, based on analyzing the temporal patterns of successive slow-wave events. The first type is consistently observed in natural slow-wave sleep, while the second is shown to be ubiquitous under anesthesia. Network models of spiking neurons predict that the two slow wave types emerge due to a different gain on inhibitory versus excitatory cells and that different levels of spike-frequency adaptation in excitatory cells can account for dynamical distinctions between the two types. This prediction was tested in vitro by varying adaptation strength using an agonist of acetylcholine receptors, which demonstrated a neuromodulatory switch between the two types of slow waves. Finally, we show that the first type of slow-wave dynamics is more sensitive to external stimuli, which can explain how slow waves in sleep and anesthesia differentially affect memory consolidation, as well as provide a link between slow-wave dynamics and memory diseases.

A framework to reconcile frequency scaling measurements, from intracellular recordings, local-field potentials, up to EEG and MEG signals.

In this viewpoint article, we discuss the electric properties of the medium around neurons, which are important to correctly interpret extracellular potentials or electric field effects in neural tissue. We focus on how these electric properties shape the frequency scaling of brain signals at different scales, such as intracellular recordings, the local field potential (LFP), the electroencephalogram (EEG) or the magnetoencephalogram (MEG). These signals display frequency-scaling properties which are not consistent with resistive media. The medium appears to exert a frequency filtering scaling as 1/f, which is the typical frequency scaling of ionic diffusion. Such a scaling was also found recently by impedance measurements in physiological conditions. Ionic diffusion appears to be the only possible explanation to reconcile these measurements and the frequency-scaling properties found in different brain signals. However, other measurements suggest that the extracellular medium is essentially resistive. To resolve this discrepancy, we show new evidence that metal-electrode measurements can be perturbed by shunt currents going through the surface of the brain. Such a shunt may explain the contradictory measurements, and together with ionic diffusion, provides a framework where all observations can be reconciled. Finally, we propose a method to perform measurements avoiding shunting effects, thus enabling to test the predictions of this framework.

Intracellular Impedance Measurements Reveal Non-ohmic Properties of the Extracellular Medium around Neurons.

Determining the electrical properties of the extracellular space around neurons is important for understanding the genesis of extracellular potentials, as well as for localizing neuronal activity from extracellular recordings. However, the exact nature of these extracellular properties is still uncertain. Here, we introduce a method to measure the impedance of the tissue, one that preserves the intact cell-medium interface using whole-cell patch-clamp recordings in vivo and in vitro. We find that neural tissue has marked non-ohmic and frequency-filtering properties, which are not consistent with a resistive (ohmic) medium, as often assumed. The amplitude and phase profiles of the measured impedance are consistent with the contribution of ionic diffusion. We also show that the impact of such frequency-filtering properties is possibly important on the genesis of local field potentials, as well as on the cable properties of neurons. These results show non-ohmic properties of the extracellular medium around neurons, and suggest that source estimation methods, as well as the cable properties of neurons, which all assume ohmic extracellular medium, may need to be reevaluated.

Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties.

The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca(2+)-activated K(+) channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. SIGNIFICANCE STATEMENT: Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons contain three main compartments: dendritic, somatic, and axonal. How the neurons receive information, process it, and pass on new information depends upon how these three compartments operate. While it has long been assumed that axons are simply for conducting information from the cell body to the synapses, here we demonstrate that the axons of different types of interneurons, the inhibitory cells, possess differing electrophysiological properties. This result implies that differing types of interneurons perform different tasks in the cortex, not only through their anatomical connections, but also through how their axons operate.

Cortically-controlled population stochastic facilitation as a plausible substrate for guiding sensory transfer across the thalamic gateway.

The thalamus is the primary gateway that relays sensory information to the cerebral cortex. While a single recipient cortical cell receives the convergence of many principal relay cells of the thalamus, each thalamic cell in turn integrates a dense and distributed synaptic feedback from the cortex. During sensory processing, the influence of this functional loop remains largely ignored. Using dynamic-clamp techniques in thalamic slices in vitro, we combined theoretical and experimental approaches to implement a realistic hybrid retino-thalamo-cortical pathway mixing biological cells and simulated circuits. The synaptic bombardment of cortical origin was mimicked through the injection of a stochastic mixture of excitatory and inhibitory conductances, resulting in a gradable correlation level of afferent activity shared by thalamic cells. The study of the impact of the simulated cortical input on the global retinocortical signal transfer efficiency revealed a novel control mechanism resulting from the collective resonance of all thalamic relay neurons. We show here that the transfer efficiency of sensory input transmission depends on three key features: i) the number of thalamocortical cells involved in the many-to-one convergence from thalamus to cortex, ii) the statistics of the corticothalamic synaptic bombardment and iii) the level of correlation imposed between converging thalamic relay cells. In particular, our results demonstrate counterintuitively that the retinocortical signal transfer efficiency increases when the level of correlation across thalamic cells decreases. This suggests that the transfer efficiency of relay cells could be selectively amplified when they become simultaneously desynchronized by the cortical feedback. When applied to the intact brain, this network regulation mechanism could direct an attentional focus to specific thalamic subassemblies and select the appropriate input lines to the cortex according to the descending influence of cortically-defined "priors".

T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex.

The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.

Comparison of different neuron models to conductance-based post-stimulus time histograms obtained in cortical pyramidal cells using dynamic-clamp in vitro.

A wide diversity of models have been proposed to account for the spiking response of central neurons, from the integrate-and-fire (IF) model and its quadratic and exponential variants, to multiple-variable models such as the Izhikevich (IZ) model and the well-known Hodgkin-Huxley (HH) type models. Such models can capture different aspects of the spiking response of neurons, but there is few objective comparison of their performance. In this article, we provide such a comparison in the context of well-defined stimulation protocols, including, for each cell, DC stimulation, and a series of excitatory conductance injections, arising in the presence of synaptic background activity. We use the dynamic-clamp technique to characterize the response of regular-spiking neurons from guinea-pig visual cortex by computing families of post-stimulus time histograms (PSTH), for different stimulus intensities, and for two different background activities (low- and high-conductance states). The data obtained are then used to fit different classes of models such as the IF, IZ, or HH types, which are constrained by the whole data set. This analysis shows that HH models are generally more accurate to fit the series of experimental PSTH, but their performance is almost equaled by much simpler models, such as the exponential or pulse-based IF models. Similar conclusions were also reached by performing partial fitting of the data, and examining the ability of different models to predict responses that were not used for the fitting. Although such results must be qualified by using more sophisticated stimulation protocols, they suggest that nonlinear IF models can capture surprisingly well the response of cortical regular-spiking neurons and appear as useful candidates for network simulations with conductance-based synaptic interactions.

Network-state modulation of power-law frequency-scaling in visual cortical neurons.

Various types of neural-based signals, such as EEG, local field potentials and intracellular synaptic potentials, integrate multiple sources of activity distributed across large assemblies. They have in common a power-law frequency-scaling structure at high frequencies, but it is still unclear whether this scaling property is dominated by intrinsic neuronal properties or by network activity. The latter case is particularly interesting because if frequency-scaling reflects the network state it could be used to characterize the functional impact of the connectivity. In intracellularly recorded neurons of cat primary visual cortex in vivo, the power spectral density of V(m) activity displays a power-law structure at high frequencies with a fractional scaling exponent. We show that this exponent is not constant, but depends on the visual statistics used to drive the network. To investigate the determinants of this frequency-scaling, we considered a generic recurrent model of cortex receiving a retinotopically organized external input. Similarly to the in vivo case, our in computo simulations show that the scaling exponent reflects the correlation level imposed in the input. This systematic dependence was also replicated at the single cell level, by controlling independently, in a parametric way, the strength and the temporal decay of the pairwise correlation between presynaptic inputs. This last model was implemented in vitro by imposing the correlation control in artificial presynaptic spike trains through dynamic-clamp techniques. These in vitro manipulations induced a modulation of the scaling exponent, similar to that observed in vivo and predicted in computo. We conclude that the frequency-scaling exponent of the V(m) reflects stimulus-driven correlations in the cortical network activity. Therefore, we propose that the scaling exponent could be used to read-out the "effective" connectivity responsible for the dynamical signature of the population signals measured at different integration levels, from Vm to LFP, EEG and fMRI.

Synaptic background activity controls spike transfer from thalamus to cortex.

Characterizing the responsiveness of thalamic neurons is crucial to understanding the flow of sensory information. Typically, thalamocortical neurons possess two distinct firing modes. At depolarized membrane potentials, thalamic cells fire single action potentials and faithfully relay synaptic inputs to the cortex. At hyperpolarized potentials, the activation of T-type calcium channels promotes burst firing, and the transfer is less accurate. Our results suggest that this duality no longer holds if synaptic background activity is taken into account. By injecting stochastic conductances into guinea-pig thalamocortical neurons in slices, we show that the transfer function of these neurons is strongly influenced by conductance noise. The combination of synaptic noise with intrinsic properties gives a global responsiveness that is more linear, mixing single-spike and burst responses at all membrane potentials. Because in thalamic neurons, background synaptic input originates mainly from cortex, these results support a determinant role of corticothalamic feedback during sensory information processing.

Characterizing synaptic conductance fluctuations in cortical neurons and their influence on spike generation.

Cortical neurons are subject to sustained and irregular synaptic activity which causes important fluctuations of the membrane potential (V(m)). We review here different methods to characterize this activity and its impact on spike generation. The simplified, fluctuating point-conductance model of synaptic activity provides the starting point of a variety of methods for the analysis of intracellular V(m) recordings. In this model, the synaptic excitatory and inhibitory conductances are described by Gaussian-distributed stochastic variables, or "colored conductance noise". The matching of experimentally recorded V(m) distributions to an invertible theoretical expression derived from the model allows the extraction of parameters characterizing the synaptic conductance distributions. This analysis can be complemented by the matching of experimental V(m) power spectral densities (PSDs) to a theoretical template, even though the unexpected scaling properties of experimental PSDs limit the precision of this latter approach. Building on this stochastic characterization of synaptic activity, we also propose methods to qualitatively and quantitatively evaluate spike-triggered averages of synaptic time-courses preceding spikes. This analysis points to an essential role for synaptic conductance variance in determining spike times. The presented methods are evaluated using controlled conductance injection in cortical neurons in vitro with the dynamic-clamp technique. We review their applications to the analysis of in vivo intracellular recordings in cat association cortex, which suggest a predominant role for inhibition in determining both sub- and supra-threshold dynamics of cortical neurons embedded in active networks.

Minimal Hodgkin-Huxley type models for different classes of cortical and thalamic neurons.

We review here the development of Hodgkin-Huxley (HH) type models of cerebral cortex and thalamic neurons for network simulations. The intrinsic electrophysiological properties of cortical neurons were analyzed from several preparations, and we selected the four most prominent electrophysiological classes of neurons. These four classes are "fast spiking", "regular spiking", "intrinsically bursting" and "low-threshold spike" cells. For each class, we fit "minimal" HH type models to experimental data. The models contain the minimal set of voltage-dependent currents to account for the data. To obtain models as generic as possible, we used data from different preparations in vivo and in vitro, such as rat somatosensory cortex and thalamus, guinea-pig visual and frontal cortex, ferret visual cortex, cat visual cortex and cat association cortex. For two cell classes, we used automatic fitting procedures applied to several cells, which revealed substantial cell-to-cell variability within each class. The selection of such cellular models constitutes a necessary step towards building network simulations of the thalamocortical system with realistic cellular dynamical properties.

Biophysical and phenomenological models of multiple spike interactions in spike-timing dependent plasticity.

Spike-timing dependent plasticity (STDP) is a form of associative synaptic modification which depends on the respective timing of pre- and post-synaptic spikes. The biophysical mechanisms underlying this form of plasticity are currently not known. We present here a biophysical model which captures the characteristics of STDP, such as its frequency dependency, and the effects of spike pair or spike triplet interactions. We also make links with other well-known plasticity rules. A simplified phenomenological model is also derived, which should be useful for fast numerical simulation and analytical investigation of the impact of STDP at the network level.

A novel synaptic plasticity rule explains homeostasis of neuromuscular transmission.

Excitability differs among muscle fibers and undergoes continuous changes during development and growth, yet the neuromuscular synapse maintains a remarkable fidelity of execution. Here we show in two evolutionarily distant vertebrates (Xenopus laevis cell culture and mouse nerve-muscle ex-vivo) that the skeletal muscle cell constantly senses, through two identified calcium signals, synaptic events and their efficacy in eliciting spikes. These sensors trigger retrograde signal(s) that control presynaptic neurotransmitter release, resulting in synaptic potentiation or depression. In the absence of spikes, synaptic events trigger potentiation. Once the synapse is sufficiently strong to initiate spiking, the occurrence of these spikes activates a negative retrograde feedback. These opposing signals dynamically balance the synapse in order to continuously adjust neurotransmitter release to a level matching current muscle cell excitability.

Local recording of biological magnetic fields using Giant Magneto Resistance-based micro-probes.

The electrical activity of brain, heart and skeletal muscles generates magnetic fields but these are recordable only macroscopically, such as in magnetoencephalography, which is used to map neuronal activity at the brain scale. At the local scale, magnetic fields recordings are still pending because of the lack of tools that can come in contact with living tissues. Here we present bio-compatible sensors based on Giant Magneto-Resistance (GMR) spin electronics. We show on a mouse muscle in vitro, using electrophysiology and computational modeling, that this technology permits simultaneous local recordings of the magnetic fields from action potentials. The sensitivity of this type of sensor is almost size independent, allowing the miniaturization and shaping required for in vivo/vitro magnetophysiology. GMR-based technology can constitute the magnetic counterpart of microelectrodes in electrophysiology, and might represent a new fundamental tool to investigate the local sources of neuronal magnetic activity.

Barrages of synaptic activity control the gain and sensitivity of cortical neurons.

Ongoing synaptic activity, ever present in cortical neurons, may vary widely in its amplitude and characteristics, potentially having a strong influence on neuronal processing. Intracellular recordings in layer 5 pyramidal cells in prefrontal and visual cortical slices maintained in vitro revealed spontaneous periods of synaptic bombardment. Testing the responsiveness of these cortical cells to synaptic inputs or the injection of artificial excitatory postsynaptic conductances of various amplitudes revealed that background synaptic activity dramatically increased the probability of response to small inputs, decreased the slope of the input-output curve, and decreased both the latency and jitter of action potential activation. Examining the effects of different components of synaptic barrages (namely, depolarization, increase in membrane conductance, and increase in membrane potential variance) revealed that the effects observed were dominated by the membrane depolarization and increase in variance. Depolarization increased the peak cross-correlation between injected complex in vivo-like waveforms through enhancement of responsiveness to small inputs, whereas increases in variance did so through a shift in firing mode from one of threshold detection to probabilistic discharge. These results indicate that rapid increases in neuronal responsiveness, as well as increases in spike timing precision, can be achieved through balanced barrages of excitatory and inhibitory synaptic activity.

Corticothalamic Synaptic Noise as a Mechanism for Selective Attention in Thalamic Neurons.

A reason why the thalamus is more than a passive gateway for sensory signals is that two-third of the synapses of thalamocortical neurons are directly or indirectly related to the activity of corticothalamic axons. While the responses of thalamocortical neurons evoked by sensory stimuli are well characterized, with ON- and OFF-center receptive field structures, the prevalence of synaptic noise resulting from neocortical feedback in intracellularly recorded thalamocortical neurons in vivo has attracted little attention. However, in vitro and modeling experiments point to its critical role for the integration of sensory signals. Here we combine our recent findings in a unified framework suggesting the hypothesis that corticothalamic synaptic activity is adapted to modulate the transfer efficiency of thalamocortical neurons during selective attention at three different levels: First, on ionic channels by interacting with intrinsic membrane properties, second at the neuron level by impacting on the input-output gain, and third even more effectively at the cell assembly level by boosting the information transfer of sensory features encoded in thalamic subnetworks. This top-down population control is achieved by tuning the correlations in subthreshold membrane potential fluctuations and is adapted to modulate the transfer of sensory features encoded by assemblies of thalamocortical relay neurons. We thus propose that cortically-controlled (de-)correlation of subthreshold noise is an efficient and swift dynamic mechanism for selective attention in the thalamus.

Exploring spike transfer through the thalamus using hybrid artificial-biological neuronal networks.

We use dynamic clamp to construct "hybrid" thalamic circuits by connecting a biological neuron in situ to silicon- or software-generated "neurons" through artificial synapses. The purpose is to explore cellular sensory gating mechanisms that regulate the transfer efficiency of signals during different sleep-wake states. Hybrid technology is applied in vitro to different paradigms such as: (1) simulating interactions between biological thalamocortical neurons, artificial reticular thalamic inhibitory interneurons and a simulated sensory input, (2) grafting an artificial sensory input to a wholly biological thalamic network that generates spontaneous sleep-like oscillations, (3) injecting in thalamocortical neurons a background synaptic bombardment mimicking the activity of corticothalamic inputs. We show that the graded control of the strength of intrathalamic inhibition, combined with the membrane polarization and the fluctuating synaptic noise in thalamocortical neurons, is able to govern functional shifts between different input/output transmission states of the thalamic gate.

Oversampling method to extract excitatory and inhibitory conductances from single-trial membrane potential recordings.

Variations of excitatory and inhibitory conductances determine the membrane potential (V(m)) activity of neurons, as well as their spike responses, and are thus of primary importance. Methods to estimate these conductances require clamping the cell at several different levels of V(m), thus making it impossible to estimate conductances from "single trial" V(m) recordings. We present here a new method that allows extracting estimates of the full time course of excitatory and inhibitory conductances from single-trial V(m) recordings. This method is based on oversampling of the V(m). We test the method numerically using models of increasing complexity. Finally, the method is evaluated using controlled conductance injection in cortical neurons in vitro using the dynamic-clamp technique. This conductance extraction method should be very useful for future in vivo applications.

Characterizing neuronal activity by describing the membrane potential as a stochastic process.

Cortical neurons behave similarly to stochastic processes, as a consequence of their irregularity and dense connectivity. Their firing pattern is close to a Poisson process, and their membrane potential (V(m)) is analogous to colored noise. One way to characterize this activity is to identify V(m) to a multidimensional stochastic process. We review here this approach and how it can be used to extract important statistical signatures of neuronal activity. The "VmD method" consists of fitting the V(m) distribution obtained intracellularly to analytic expressions derived from stochastic processes, and thereby deduce synaptic conductance parameters. However, this method requires at least two levels of V(m), which prevents applications to single-trial measurements. We also discuss methods that can be applied to single V(m) traces, such as power spectral analysis and the "STA method" to calculate spike-triggered average conductances based on a maximum likelihood procedure. A recently proposed method, the "VmT method", is based on the fusion of these two concepts. This method is analogous to the VmD method and estimates the mean excitatory and inhibitory conductances and their variances. However, it does so by using a maximum-likelihood estimation, and can thus be applied to single V(m) traces. All methods were tested using controlled conductance injection in dynamic-clamp experiments.

High-resolution intracellular recordings using a real-time computational model of the electrode.

Intracellular recordings of neuronal membrane potential are a central tool in neurophysiology. In many situations, especially in vivo, the traditional limitation of such recordings is the high electrode resistance and capacitance, which may cause significant measurement errors during current injection. We introduce a computer-aided technique, Active Electrode Compensation (AEC), based on a digital model of the electrode interfaced in real time with the electrophysiological setup. The characteristics of this model are first estimated using white noise current injection. The electrode and membrane contribution are digitally separated, and the recording is then made by online subtraction of the electrode contribution. Tests performed in vitro and in vivo demonstrate that AEC enables high-frequency recordings in demanding conditions, such as injection of conductance noise in dynamic-clamp mode, not feasible with a single high-resistance electrode until now. AEC should be particularly useful to characterize fast neuronal phenomena intracellularly in vivo.