Millisecond precision temporal encoding of stimulus features during cortically generated gamma oscillations in the rat somatosensory cortex.

KEY POINTS: Rodents explore their immediate environment using their whiskers. Such exploration leads to micromotions, which contain many high-frequency (50-200 Hz) components. High-frequency whisker motion is represented faithfully in the temporal structure of the spike trains of trigeminal neurons. However, the representation of high-frequency sensory inputs in cortex is not fully understood. By combining extracellular and intracellular recordings in the rat somatosensory cortex and thalamus, we show that high-frequency sensory inputs, either sinusoidal or white noise, elicit internally generated gamma (20-60 Hz) band oscillations in cortical networks. Gamma oscillations modulate cortical spike probability while preserving sub-millisecond phase relations with high-frequency sensory inputs. Consequently, our results indicate that millisecond precision stimulus-locked spiking activity and sensory-induced gamma oscillation can constitute independent multiplexed coding schemes at the single-cell level. ABSTRACT: In the natural environment, tactile exploration often leads to high-frequency vibrations at the level of the sensory organs. Single-unit recordings of cortical neurons have pointed towards either a rate or a temporal code for representing high-frequency tactile signals. In cortical networks, sensory processing results from the interaction between feedforward inputs relayed from the thalamus and internally generated activity. However, how the emergent activity represents high-frequency sensory input is not fully understood. Using multisite single-unit, local field potential and intracellular recordings in the somatosensory cortex and thalamus of lightly sedated male rats, we measured neuronal responses evoked by sinusoidal and band-pass white noise whisker stimulation at frequencies that encompass those observed during texture exploration (50-200 Hz). We found that high-frequency sensory inputs relayed from the thalamus elicit both sub-millisecond stimulus-locked responses and internally generated gamma (20-60 Hz) band oscillations in cortical networks. Gamma oscillations modulate spike probability while preserving sub-millisecond phase relations with sensory inputs. Therefore, precise stimulus-locked spiking activity and sensory-induced gamma oscillations can constitute independent multiplexed coding schemes at the single-cell level.

The many faces of T-type calcium channels.

Since the discovery of low-voltage-activated T-type calcium channels in sensory neurons and the initial characterization of their physiological function mainly in inferior olive and thalamic neurons, studies on neuronal T-type currents have predominantly focused on the generation of low-threshold spike (and associated action potential burst firing) which is strictly conditioned by a preceding hyperpolarization. This T-type current mediated activity has become an archetype of the function of these channels, constraining our view of the potential physiological and pathological roles that they may play in controlling the excitability of single cells and neural networks. However, greatly helped by the recent availability of the first potent and selective antagonists for this class of calcium channels, novel T-type current functions are rapidly being uncovered, including their surprising involvement in neuronal excitability at depolarized membrane potentials and their complex control of dendritic integration and neurotransmitter release. These and other data summarized in this short review clearly indicate a much wider physiological involvement of T-type channels in neuronal activity than previously expected.

Quantitative trait locus on distal chromosome 1 regulates the occurrence of spontaneous spike-wave discharges in DBA/2 mice.

PURPOSE: Most common forms of human epilepsy result from a complex combination of polygenetic and environmental factors. Quantitative trait locus (QTL) mapping is a first step toward the nonbiased discovery of epilepsy-related candidate genes. QTL studies of susceptibility to induced seizures in mouse strains have consistently converged on a distal region of chromosome 1 as a major phenotypic determinant; however, its influence on spontaneous epilepsy remains unclear. In the present study we characterized the influence of allelic variations within this QTL, termed Szs1, on the occurrence of spontaneous spike-wave discharges (SWDs) characteristic of absence seizures in DBA/2 (D2) mice. METHODS: We analyzed SWD occurrence and patterns in freely behaving D2, C57BL/6 (B6) and the congenic strains D2.B6-Szs1 and B6.D2-Szs1. KEY FINDINGS: We showed that congenic manipulation of the Szs1 locus drastically reduced the number and the duration of SWDs in D2.B6-Szs1 mice, which are homozygous for Szs1 from B6 strain on a D2 strain background. However, it failed to induce the full expression of SWDs in the reverse congenic animals B6.D2-Szs1. SIGNIFICANCE: Our results demonstrate that the occurrence of SWDs in D2 animals is under polygenic control and, therefore, the D2 and B6 strains might be a useful model to dissect the genetic determinants of polygenic SWDs characteristic of typical absence seizures. Furthermore, we point to the existence of epistatic interactions between at least one modifier gene within Szs1 and genes within unlinked QTLs in regulating the occurrence of spontaneous nonconvulsive forms of epilepsies.

Centrally expressed Cav3.2 T-type calcium channel is critical for the initiation and maintenance of neuropathic pain.

Cav3.2 T-type calcium channel is a major molecular actor of neuropathic pain in peripheral sensory neurons, but its involvement at the supraspinal level is almost unknown. In the anterior pretectum (APT), a hub of connectivity of the somatosensory system involved in pain perception, we show that Cav3.2 channels are expressed in a subpopulation of GABAergic neurons coexpressing parvalbumin (PV). In these PV-expressing neurons, Cav3.2 channels contribute to a high-frequency-bursting activity, which is increased in the spared nerve injury model of neuropathy. Specific deletion of Cav3.2 channels in APT neurons reduced both the initiation and maintenance of mechanical and cold allodynia. These data are a direct demonstration that centrally expressed Cav3.2 channels also play a fundamental role in pain pathophysiology.

Comprehensive mapping of whisker-evoked responses reveals broad, sharply tuned thalamocortical input to layer 4 of barrel cortex.

Cortical neurons are organized in columns, distinguishable by their physiological properties and input-output organization. Columns are thought to be the fundamental information-processing modules of the cortex. The barrel cortex of rats and mice is an attractive model system for the study of cortical columns, because each column is defined by a layer 4 (L4) structure called a barrel, which can be clearly visualized. A great deal of information has been collected regarding the connectivity of neurons in barrel cortex, but the nature of the input to a given L4 barrel remains unclear. We measured this input by making comprehensive maps of whisker-evoked activity in L4 of rat barrel cortex using recordings of multiunit activity and current source density analysis of local field potential recordings of animals under light isoflurane anesthesia. We found that a large number of whiskers evoked a detectable response in each barrel (mean of 13 suprathreshold, 18 subthreshold) even after cortical activity was abolished by application of muscimol, a GABA(A) agonist. We confirmed these findings with intracellular recordings and single-unit extracellular recordings in vivo. This constitutes the first direct confirmation of the hypothesis that subcortical mechanisms mediate a substantial multiwhisker input to a given cortical barrel.

T current potentiation increases the occurrence and temporal fidelity of synaptically evoked burst firing in sensory thalamic neurons.

A growing number of in vivo experiments shows that high frequency bursts of action potentials can be recorded in thalamocortical neurons of awake animals. The mechanism underlying these bursts, however, remains controversial, because they have been proposed to depend on T-type Ca(2+) channels that are inactivated at the depolarized membrane potentials usually associated with the awake state. Here, we show that the transient potentiation of the T current amplitude, which is induced by neuronal depolarization, drastically increases the probability of occurrence and the temporal precision of T-channel-dependent high frequency bursts. The data, therefore, provides the first biophysical mechanism that might account for the generation of these high frequency bursts of action potentials in the awake state. Remarkably, this regulation finely tunes the response of thalamocortical neurons to the corticofugal excitatory and intrathalamic inhibitory afferents but not to sensory inputs.

Layer 2/3 Pyramidal Neurons Control the Gain of Cortical Output.

Initial anatomical and physiological studies suggested that sensory information relayed from the periphery by the thalamus is serially processed in primary sensory cortical areas. It is thought to propagate from layer 4 (L4) up to L2/3 and down to L5, which constitutes the main output of the cortex. However, more recent experiments point toward the existence of a direct processing of thalamic input by L5 neurons. Therefore, the role of L2/3 neurons in the sensory processing operated by L5 neurons is now highly debated. Using cell type-specific and reversible optogenetic manipulations in the somatosensory cortex of both anesthetized and awake mice, we demonstrate that L2/3 pyramidal neurons play a major role in amplifying sensory-evoked responses in L5 neurons. The amplification effect scales with the velocity of the sensory stimulus, indicating that L2/3 pyramidal neurons implement gain control in deep-layer neurons.

Reconstructing the functional connectivity of multiple spike trains using Hawkes models.

BACKGROUND: Statistical models that predict neuron spike occurrence from the earlier spiking activity of the whole recorded network are promising tools to reconstruct functional connectivity graphs. Some of the previously used methods are in the general statistical framework of the multivariate Hawkes processes. However, they usually require a huge amount of data, some prior knowledge about the recorded network, and/or may produce an increasing number of spikes along time during simulation. NEW METHOD: Here, we present a method, based on least-square estimators and LASSO penalty criteria, for a particular class of Hawkes processes that can be used for simulation. RESULTS: Testing our method on small networks modeled with Leaky Integrate and Fire demonstrated that it efficiently detects both excitatory and inhibitory connections. The few errors that occasionally occur with complex networks including common inputs, weak and chained connections, can be discarded based on objective criteria. COMPARISON WITH EXISTING METHODS: With respect to other existing methods, the present one allows to reconstruct functional connectivity of small networks without prior knowledge of their properties or architecture, using an experimentally realistic amount of data. CONCLUSIONS: The present method is robust, stable, and can be used on a personal computer as a routine procedure to infer connectivity graphs and generate simulation models from simultaneous spike train recordings.

Altered resonance properties of somatosensory responses in mice deficient for the schizophrenia risk gene Neuregulin 1.

To reveal the neuronal underpinnings of sensory processing deficits in patients with schizophrenia, previous studies have investigated brain activity in response to sustained sensory stimulation at various frequencies. This paradigm evoked neural activity at the stimulation frequency and harmonics thereof. During visual and auditory stimulation that elicited enhanced or 'resonant' responses in healthy controls, patients with schizophrenia displayed reduced activity. The present study sought to elucidate the cellular basis of disease-related deficits in sensory resonance properties using mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1 (NRG1). We applied repetitive whisker stimulation at 1-15 Hz, a range relevant to whisking behavior in mice, and measured cellular activity in the primary somatosensory cortex. At frequencies where control mice displayed enhancements in measures of response magnitude and precision, NRG1 (+/-) mutants showed reductions. Our results demonstrate for the first time a link between a mutation of a schizophrenia risk gene and altered neuronal resonance properties in sensory cortex.

Sensory encoding in Neuregulin 1 mutants.

Schizophrenic patients show altered sensory perception as well as changes in electrical and magnetic brain responses to sustained, frequency-modulated sensory stimulation. Both the amplitude and temporal precision of the neural responses differ in patients as compared to control subjects, and these changes are most pronounced for stimulation at gamma frequencies (20-40 Hz). In addition, patients display enhanced spontaneous gamma oscillations, which has been interpreted as 'neural noise' that may interfere with normal stimulus processing. To investigate electrophysiological markers of aberrant sensory processing in a model of schizophrenia, we recorded neuronal activity in primary somatosensory cortex of mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1. Sensory responses to sustained 20-70 Hz whisker stimulation were analyzed with respect to firing rates, spike precision (phase locking) and gamma oscillations, and compared to baseline conditions. The mutants displayed elevated spontaneous firing rates, a reduced gain in sensory-evoked spiking and gamma activity, and reduced spike precision of 20-40 Hz responses. These findings present the first in vivo evidence of the linkage between a genetic marker and altered stimulus encoding, thus suggesting a novel electrophysiological endophenotype of schizophrenia.

Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures.

Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.