Synchronization Of Neuronal Discharges Research Articles

Neural synchrony in cortical networks: mechanisms and implications for neural information processing and coding.

Synchronization of neuronal discharges on the millisecond scale has long been recognized as a prevalent and functionally important attribute of neural activity. In this article, I review classical concepts and corresponding evidence of the mechanisms that govern the synchronization of distributed discharges in cortical networks and relate those mechanisms to their possible roles in coding and cognitive functions. To accommodate the need for a selective, directed synchronization of cells, I propose that synchronous firing of distributed neurons is a natural consequence of spike-timing-dependent plasticity (STDP) that associates cells repetitively receiving temporally coherent input: the “synchrony through synaptic plasticity” hypothesis. Neurons that are excited by a repeated sequence of synaptic inputs may learn to selectively respond to the onset of this sequence through synaptic plasticity. Multiple neurons receiving coherent input could thus actively synchronize their firing by learning to selectively respond at corresponding temporal positions. The hypothesis makes several predictions: first, the position of the cells in the network, as well as the source of their input signals, would be irrelevant as long as their input signals arrive simultaneously; second, repeating discharge patterns should get compressed until all or some part of the signals are synchronized; and third, this compression should be accompanied by a sparsening of signals. In this way, selective groups of cells could emerge that would respond to some recurring event with synchronous firing. Such a learned response pattern could further be modulated by synchronous network oscillations that provide a dynamic, flexible context for the synaptic integration of distributed signals. I conclude by suggesting experimental approaches to further test this new hypothesis.

Research on the Direction of Ion Channel Related to Epileptic Seizures

Epilepsy is a group of chronic brain diseases characterized by transient central nervous system dysfunction caused by repeated abnormal synchronization of neuronal discharges in the brain, with sudden onset and repeated seizures. Epilepsy has been listed as one of the five major neuropsychiatric diseases of the World Health Organization (WHO). Hereditary epilepsy refers to epilepsy syndromes previously classified as idiopathic generalized epilepsies (IGEs), which encompasses several different epilepsy syndromes ranging in clinical severity from relatively benign febrile convulsions (FS) and childhood absence epilepsy (CAE) to the more severe juvenile myoclonic epilepsy (JME) and generalized epileptic seizures with febrile convulsions (GEFS+). This article analyzes the direction of ion channel related to epileptic seizures. It will look forward to the future research direction of some of the ion channels related to epileptogenesis.

Organization of prefrontal network activity by respiration-related oscillations

The medial prefrontal cortex (mPFC) integrates information from cortical and sub-cortical areas and contributes to the planning and initiation of behaviour. A potential mechanism for signal integration in the mPFC lies in the synchronization of neuronal discharges by theta (6–12 Hz) activity patterns. Here we show, using in vivo local field potential (LFP) and single-unit recordings from awake mice, that prominent oscillations in the sub-theta frequency band (1–5 Hz) emerge during awake immobility in the mPFC. These oscillation patterns are distinct from but phase-locked to hippocampal theta activity and occur synchronized with nasal respiration (hence termed prefrontal respiration rhythm [PRR]). PRR activity modulates the amplitude of prefrontal gamma rhythms with greater efficacy than theta oscillations. Furthermore, single-unit discharges of putative pyramidal cells and GABAergic interneurons are entrained by prefrontal PRR and nasal respiration. Our data thus suggest that PRR activity contributes to information processing in the prefrontal neuronal network.

Modulation of 4-aminopyridine-induced neuronal activity and local pO(2)in rat hippocampal slices by changing the flow rate of the superfusion medium.

The brain slice preparation is the most frequently used tool for testing of pharmacological agents on the neuronal excitability. However in the absence of blood circulation in vitro, the tissue oxygenation strongly depends on the experimental conditions. It is well established that both hypoxia as well as hyperoxia can modulate the neuronal network activity. Thereby changes in tissue oxygen level during experiment may affect the final result. In the present study we investigated the effect of oxygenation on seizure susceptibility in the hippocampal slice preparation using 4-aminopyridine (4-AP) model of ictogenesis in inmature rats. We found that changing the medium perfusion rate in the range of 1-5 ml/min greatly affects the tissue oxygenation, amplitude and frequency of 4-AP-induced synchronous neuronal activity. The decrease in the flow rate as well as substitution of the oxygen in the extracellular medium with nitrogen causes a strong reduction of 4-AP-induced synchronous neuronal discharges. Our results demonstrate a significant linear correlation between the power of 4-AP-induced neuronal activity and the oxygen level in slice tissue. Also we demonstrated that the presence of medium flow is a necessary condition to support the constant level of the slice oxygenation. These data suggest that the oxygen supply of the brain slice strongly depends on experimental protocol and could modulate in vitro neuronal network excitability which should be taken into consideration when planning epilepsy-related studies.

An evaluation of the links between microRNA, autophagy, and epilepsy.

Epilepsy is a serious chronic neurologic disorder characterized by recurrent unprovoked seizures resulting from abnormal and highly synchronous neuronal discharges within the brain. Small noncoding RNAs, called microRNAs, play vital roles in epileptogenesis, with potential contributions as valuable biomarkers and targets for the treatment of epilepsy. To maintain cellular homeostasis, cellular components, such as organelles, proteins, protein complexes/oligomers, and pathogens, are delivered to the lysosome for degradation through a process called autophagy, which plays either a protective or a harmful role under epileptic stress. Several autophagic mechanisms have been implicated in epileptogenesis, including the mammalian target of rapamycin pathway, aberrant substrate accumulation, and the formation of epileptic networks. In addition, the regulation of autophagy through microRNAs (miRNAs) represents a novel posttranscriptional regulatory mechanism through 'autophagamiRNAs'. The correlation between autophagy and miRNA has increased our understanding of the underlying pathogenesis of human diseases. Here, we review the current findings regarding the correlations between miRNA, autophagy, and epilepsy to provide a solid foundation for further examination of the miRNA-autophagy pathway involved in epilepsy pathophysiology.

Three‐dimensional surface maps link local atrophy and fast ripples in human epileptic hippocampus

There is compelling evidence that pathological high-frequency oscillations (HFOs), called fast ripples (FR, 150-500Hz), reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy. Interictal HFOs were recorded from hippocampal microelectrodes in 10 patients with MTLE. Rates of FR and ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3-dimensional magnetic resonance imaging (MRI) hippocampal modeling. Rates of FR discharge were 3 times higher in areas of significant local HA compared with rates in nonatrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of ripple discharge between local atrophic and nonatrophic areas. The proximity between local HA and microelectrode-recorded FR suggests that morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a noninvasive means to localize epileptogenic regions in hippocampus.

Prevalence of chronic kidney disease in South Asian and Black minorities: findings from a population based screening study in London, UK

Sensorimotor transformations in the mammalian superior colliculus (SC) are mediated by large sets of distributed neurons. For such distributed coding systems, stimulus superposition poses problems attributable to the merging of...

Soman induces ictogenesis in the amygdala and interictal activity in the hippocampus that are blocked by a GluR5 kainate receptor antagonist in vitro

Exposure to organophosphorus nerve agents induces brain seizures, which can cause profound brain damage resulting in death or long-term cognitive deficits. The amygdala and the hippocampus are two of the most seizure-prone brain structures, but their relative contribution to the generation of seizures after nerve agent exposure is unclear. Here, we report that application of 1 μM soman for 30 min, in rat coronal brain slices containing both the hippocampus and the amygdala, produces prolonged synchronous neuronal discharges (10–40 s duration, 1.5–5 min interval of occurrence) resembling ictal activity in the basolateral nucleus of the amygdala (BLA), but only interictal-like activity (“spikes” of 100–250 ms duration; 2–5 s interval) in the pyramidal cell layer of the CA1 hippocampal area. BLA ictal- and CA1 interictal-like activity were synaptically driven, as they were blocked by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. As the expression of the GluR5 subunit of kainate receptors is high in the amygdala, and kainate receptors containing this subunit (GluR5KRs) play an important role in the regulation of neuronal excitability in both the amygdala and the hippocampus, we tested the efficacy of a GluR5KR antagonist against the epileptiform activity induced by soman. The GluR5KR antagonist UBP302 reduced the amplitude of the hippocampal interictal-like spikes, and eliminated the seizure-like discharges in the BLA, or reduced their duration and frequency, with no significant effect on the evoked field potentials. This is the first study reporting in vitro ictal-like activity in response to a nerve agent. Our findings, along with previous literature, suggest that the amygdala may play a more important role than the hippocampus in the generation of seizures following soman exposure, and provide the first evidence that GluR5KR antagonists may be an effective treatment against nerve agent–induced seizures.

Comparison of AR and Welch Methods in Epileptic Seizure Detection

Brain is one of the most critical organs of the body. Synchronous neuronal discharges generate rhythmic potential fluctuations, which can be recorded from the scalp through electroencephalography. The electroencephalogram (EEG) can be roughly defined as the mean electrical activity measured at different sites of the head. EEG patterns correlated with normal functions and diseases of the central nervous system. In this study, EEG signals were analyzed by using autoregressive (parametric) and Welch (non-parametric) spectral estimation methods. The parameters of autoregressive (AR) method were estimated by using Yule-Walker, covariance and modified covariance methods. EEG spectra were then used to compare the applied estimation methods in terms of their frequency resolution and the effects in determination of spectral components. The variations in the shape of the EEG power spectra were examined in order to epileptic seizures detection. Performance of the proposed methods was evaluated by means of power spectral densities (PSDs). Graphical results comparing the performance of the proposed methods with that of Welch technique were given. The results demonstrate consistently superior performance of the covariance methods over Yule-Walker AR and Welch methods.

Spike detection in human muscle sympathetic nerve activity using the kurtosis of stationary wavelet transform coefficients

The accurate assessment of autonomic sympathetic function is important in the diagnosis and study of various autonomic and cardiovascular disorders. Sympathetic function in humans can be assessed by recording the muscle sympathetic nerve activity, which is characterized by synchronous neuronal discharges separated by periods of neural silence dominated by colored Gaussian noise. The raw nerve activity is generally rectified, integrated, and quantified using the integrated burst rate or area. We propose an alternative quantification involving spike detection using a two-stage stationary wavelet transform (SWT) de-noising method. The SWT coefficients are first separated into noise-related and burst-related coefficients on the basis of their local kurtosis. The noise-related coefficients are then used to establish a threshold to identify spikes within the bursts. This method demonstrated better detection performance than an unsupervised amplitude discriminator and similar wavelet-based methods when confronted with simulated data of varying burst rate and signal to noise ratio. Additional validation on data acquired during a graded head-up tilt protocol revealed a strong correlation between the mean spike rate and the mean integrate burst rate (r=0.85) and burst area rate (r=0.91). In conclusion, the kurtosis-based wavelet de-noising technique is a potentially useful method of studying sympathetic nerve activity in humans.

Features of neuronal synchrony in mouse visual cortex.

Synchronization of neuronal discharges has been hypothesized to play a role in defining cell assemblies representing particular constellations of stimulus features. In many systems and species, synchronization is accompanied by an oscillatory response modulation at frequencies in the gamma-band. The cellular mechanisms underlying these phenomena of synchronization and oscillatory patterning have been studied mainly in vitro due to the difficulty in designing a direct in vivo assay. With the prospect of using conditional genetic manipulations of cortical network components, our objective was to test whether the mouse would meet the criteria to provide a model system for the study of gamma-band synchrony. Multi-unit and local field potential recordings were made from the primary visual cortex of anesthetized C57BL/6J mice. Neuronal responses evoked by moving gratings, bars, and random dot patterns were analyzed with respect to neuronal synchrony and temporal patterning. Oscillations at gamma-frequencies were readily evoked with all types of stimuli used. Oscillation and synchronization strength were largest for gratings and decreased when the noise level was increased in random-dot patterns. The center peak width of cross-correlograms was smallest for bars and increased with noise, yielding a significant difference between coherent random dot patterns versus patterns with 70% noise. Field potential analysis typically revealed increases of power in the gamma-band during response periods. Our findings are compatible with a role for neuronal synchrony in mediating perceptual binding and suggest the usefulness of the mouse model for testing hypotheses concerning both the mechanisms and the functional role of temporal patterning.

Positive Modulation of AMPA Receptors Increases Neurotrophin Expression by Hippocampal and Cortical Neurons

This study investigated whether positive modulators of AMPA-type glutamate receptors influence neurotrophin expression by forebrain neurons. Treatments with the ampakine CX614 markedly and reversibly increased brain-derived neurotrophic factor (BDNF) mRNA and protein levels in cultured rat entorhinal/hippocampal slices. Acute effects of CX614 were dose dependent over the range in which the drug increased synchronous neuronal discharges; threshold concentrations for acute responses had large effects on mRNA content when applied for 3 d. Comparable results were obtained with a second, structurally distinct ampakine CX546. Ampakine-induced upregulation was broadly suppressed by AMPA, but not NMDA, receptor antagonists and by reducing transmitter release. Antagonism of L-type voltage-sensitive calcium channels blocked induction in entorhinal cortex but not hippocampus. Prolonged infusions of suprathreshold ampakine concentrations produced peak BDNF mRNA levels at 12 hr and a return to baseline levels by 48 hr. In contrast, BDNF protein remained elevated throughout a 48 hr incubation with the drug. Nerve growth factor mRNA levels also were increased by ampakines but with a much more rapid return to control levels during chronic administration. Finally, intraperitoneal injections of CX546 increased hippocampal BDNF mRNA levels in aged rats and middle-aged mice. The present results provide evidence of regional differences in mechanisms via which activity regulates neurotrophin expression. Moreover, these data establish that changes in synaptic potency produce sufficient network level physiological effects for inducing neurotrophin genes, indicate that the response becomes refractory during prolonged ampakine exposure, and raise the possibility of using positive AMPA modulators to regulate neurotrophin levels in aged brain.

Temporal Binding, Binocular Rivalry, and Consciousness

Cognitive functions like perception, memory, language, or consciousness are based on highly parallel and distributed information processing by the brain. One of the major unresolved questions is how information can be integrated and how coherent representational states can be established in the distributed neuronal systems subserving these functions. It has been suggested that this so-called “binding problem” may be solved in the temporal domain. The hypothesis is that synchronization of neuronal discharges can serve for the integration of distributed neurons into cell assemblies and that this process may underlie the selection of perceptually and behaviorally relevant information. As we intend to show here, this temporal binding hypothesis has implications for the search of the neural correlate of consciousness. We review experimental results, mainly obtained in the visual system, which support the notion of temporal binding. In particular, we discuss recent experiments on the neural mechanisms of binocular rivalry which suggest that appropriate synchronization among cortical neurons may be one of the necessary conditions for the buildup of perceptual states and awareness of sensory stimuli.

Patterns of Synchronization in the Superior Colliculus of Anesthetized Cats

Sensorimotor transformations in the mammalian superior colliculus (SC) are mediated by large sets of distributed neurons. For such distributed coding systems, stimulus superposition poses problems attributable to the merging of neural populations coding for different stimuli. Such superposition problems could be overcome by synchronization of neuronal discharges, because it allows the selection of a subset of distributed responses for further joint processing. To assess the putative role of such a temporal binding mechanism in the SC, we have applied correlation analysis to visually evoked collicular activity. We performed recordings of single-unit and multiunit activity in the SC of anesthetized and paralyzed cats with multiple electrodes. Autocorrelation analysis revealed that collicular neurons often discharged in broad (20-100 msec) bursts or with an oscillatory patterning in the alpha- and beta-frequency range. Significantly modulated cross-correlograms were observed in 50% (128 of 258) of the collicular multiunit recording pairs, and for these pairs significant correlations occurred in 44% of the stimulation epochs. For the single-unit pairs, significant interactions were observed in 14 of 48 cases studied (29%). Collicular cross-correlograms were often oscillatory, and these oscillations covered a broad frequency range of up to 100 Hz, with a predominance of oscillation frequencies in the alpha- and beta-range. In the majority of the significant correlograms (64%) the phase lag of the center peak was <5 msec. The probability of collicular synchronization increased with the overlap of the receptive fields and the proximity of the recording sites. Correlations were also observed between cells in the superficial and deep SC layers. Collicular synchronization required activation of the respective cells with a single coherent stimulus and broke down when the neurons were activated with two different stimuli. These data are consistent with the notion that collicular synchrony could define assemblies of functionally related cells.

Role of the temporal domain for response selection and perceptual binding.

Most cognitive functions are based on highly parallel and distributed information processing by the brain. A paradigmatic example is provided by the vertebrate visual system where numerous cortical areas have been described which analyse different types of visual information. At present, it is unclear how information can be integrated and how coherent representational states can be established in such distributed systems. We suggest that this so-called 'binding problem' may be solved in the temporal domain. The hypothesis is that synchronization of neuronal discharges can serve for the integration of distributed neurons into cell assemblies and that this process may underlie the selection of perceptually and behaviourally relevant information. We review experimental results, mainly obtained in the visual system, which support this temporal binding hypothesis.

Genetic and phenotypic heterogeneity of inherited spike-wave epilepsy: two mutant gene loci with independent cerebral excitability defects

Two recessive gene loci controlling cerebral excitability in the mouse ( tg, chr 8 and stg, chr 15) share generalized neocortical spike-wave seizures as a common mutant phenotype. Although the primary molecular defects are unknown, homozygous tg mutants display a gene-linked hyperplasia of central noradrenergic axons originating in the locus ceruleus, and early selective lesions of these fibers correct the epileptic phenotype in the adult. In contrast, we find that stg homozygotes, despite a more severe seizure disorder, show no alterations in regional noradrenergic fiber innervation, and seizure frequency is unaffected by neonatal noradrenergic depletion. These mutations demonstrate that excessive synchronous neuronal discharges alone are insufficient to trigger abnormal growth of locus ceruleus fibers, and reveal the existence of two distinct intervening brain neuromodulatory mechanisms, norepinephrine (NE)-dependent and NE-independent, underlying the inheritance of this common pattern of epilepsy.

Altered hippocampal network excitability in the hypernoradrenergic mutant mouse tottering

A latent, gene-linked alteration of hippocampal network excitability in tg/tg mutant mice was unmasked in vitro by convulsant-activated synchronous neuronal discharges. Exposure to elevated extracellular potassium ions or 4-aminopyridine, but not picrotoxin, revealed an abnormally prolonged network discharge duration in the mutant CA3 pyramidal cell region. In both phenotypes, noradrenaline, and a selective β-noradrenergic receptor agonist, isoproterenol, reversibly accelerated the frequency of the discharges. These findings identify an intrinsic alteration in the excitability of an isolated neuronal network in a model of inherited generalized spike-wave epilepsy, and further implicate noradrenergic mechanisms in the temporal modulation of hippocampal synchronization and epileptogenesis.

Inhibitory control of local excitatory circuits in the guinea-pig hippocampus.

1. Exposure to the gamma-aminobutyric acid antagonist, picrotoxin, causes the discharge of hippocampal pyramidal cells to become synchronized. Synaptic mechanisms underlying the development of synchrony were investigated by recording from pairs of cells in the CA3 region of guinea-pig hippocampal slices. 2. Picrotoxin suppressed unitary inhibitory synaptic events. It appeared not to affect monosynaptic excitatory connections. Picrotoxin revealed latent excitatory connections in seven out of twenty-one dual recordings from burst-firing cells. 3. Post-synaptic events revealed by picrotoxin were elicited rarely by single action potentials. They were evoked with mean latencies of at least 8 ms and with more than 30% failures of transmission by bursts of three or more action potentials. They were suppressed by increasing extracellular Ca2+. They were considered to be mediated by polysynaptic excitatory pathways. 4. Polysynaptic excitatory post-synaptic potentials (e.p.s.p.s) had a smooth rising phase with time-to-peak of 15-40 ms and a falling phase of similar duration. Their amplitude was 2-3 mV at membrane potentials close to -70 mV. This shape was similar to that of summed e.p.s.p.s evoked by a burst of three to six action potentials at monosynaptic connections between CA3 cells. 5. One cell could evoke excitatory synaptic events in more than one follower cell, suggesting that axon collaterals mediating recurrent excitation were divergent. More than one polysynaptic excitatory pathway could exist between two cells. 6. We examined the role of recurrent excitatory synapses in the development of synchrony. As inhibition was suppressed by picrotoxin, simultaneous excitatory synaptic events appeared in recordings from pairs of cells. They occurred rhythmically at intervals of 0.5-3 s and grew in amplitude with time. Synchronous neuronal discharges were observed when the threshold for action potential generation was exceeded. 7. Firing induced in one cell could sometimes evoke a sequence of post-synaptic events in another cell as inhibition was suppressed. Initially, no connection was detected. On adding picrotoxin, a polysynaptic e.p.s.p. was revealed and with time longer-latency components were recruited to the synaptic event. The amplitude of later components grew until firing threshold was reached. 8. We suggest that synchronous firing develops due to the loss of inhibitory control over the spread of firing between CA3 pyramidal cells via divergent, polysynaptic, recurrent excitatory pathways.