Burst Firing Mode Research Articles

Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.

A low-power artificial spiking neuron based on ionic memristor for modulated frequency coding

Neurons encode information through firing spikes with rich spatiotemporal dynamics. Using artificial neuron hardware based on memristors to emulate neuronal firing is of great significance for advancing the development of brain-like computing and artificial intelligence. However, it is still challenging to achieve low power frequency coding in memristive artificial neurons. Here, a low-power ionic memristor based on Pt/HfO2/Ag is reported for artificial spiking neurons. The device is driven by a low bias current and the filament dynamically ruptures and forms, producing oscillated voltage spikes that resemble neuronal spikes. The oscillation frequency increases from 0.5 Hz to ∼2.18 Hz with the stimulation current increasing from 1 nA to 5 nA, enabling the emulation of neuronal frequency-coding function. The low power consumption of ∼70 pJ per pulse indicates that the device is promising for energy-efficient neuromorphic computing applications. In addition, the device is found to be capable of simulating the phasic,adaptive, and burst firing modes of neurons.

Large-scale biophysically detailed model of somatosensory thalamocortical circuits in NetPyNE.

The primary somatosensory cortex (S1) of mammals is critically important in the perception of touch and related sensorimotor behaviors. In 2015, the Blue Brain Project (BBP) developed a groundbreaking rat S1 microcircuit simulation with over 31,000 neurons with 207 morpho-electrical neuron types, and 37 million synapses, incorporating anatomical and physiological information from a wide range of experimental studies. We have implemented this highly detailed and complex S1 model in NetPyNE, using the data available in the Neocortical Microcircuit Collaboration Portal. NetPyNE provides a Python high-level interface to NEURON and allows defining complicated multiscale models using an intuitive declarative standardized language. It also facilitates running parallel simulations, automates the optimization and exploration of parameters using supercomputers, and provides a wide range of built-in analysis functions. This will make the S1 model more accessible and simpler to scale, modify and extend in order to explore research questions or interconnect to other existing models. Despite some implementation differences, the NetPyNE model preserved the original cell morphologies, electrophysiological responses and spatial distribution for all 207 cell types; and the connectivity properties of all 1941 pathways, including synaptic dynamics and short-term plasticity (STP). The NetPyNE S1 simulations produced reasonable physiological firing rates and activity patterns across all populations. When STP was included, the network generated a 1 Hz oscillation comparable to the original model in vitro-like state. By then reducing the extracellular calcium concentration, the model reproduced the original S1 in vivo-like states with asynchronous activity. These results validate the original study using a new modeling tool. Simulated local field potentials (LFPs) exhibited realistic oscillatory patterns and features, including distance- and frequency-dependent attenuation. The model was extended by adding thalamic circuits, including 6 distinct thalamic populations with intrathalamic, thalamocortical (TC) and corticothalamic connectivity derived from experimental data. The thalamic model reproduced single known cell and circuit-level dynamics, including burst and tonic firing modes and oscillatory patterns, providing a more realistic input to cortex and enabling study of TC interactions. Overall, our work provides a widely accessible, data-driven and biophysically-detailed model of the somatosensory TC circuits that can be employed as a community tool for researchers to study neural dynamics, function and disease.

Deletion of Phospholipase C β1 in the Thalamic Reticular Nucleus Induces Absence Seizures.

Absence seizures are caused by abnormal synchronized oscillations in the thalamocortical (TC) circuit, which result in widespread spike-and-wave discharges (SWDs) on electroencephalography (EEG) as well as impairment of consciousness. Thalamic reticular nucleus (TRN) and TC neurons are known to interact dynamically to generate TC circuitry oscillations during SWDs. Clinical studies have suggested the association of Plcβ1 with early-onset epilepsy, including absence seizures. However, the brain regions and circuit mechanisms related to the generation of absence seizures with Plcβ1 deficiency are unknown. In this study, we found that loss of Plcβ1 in mice caused spontaneous complex-type seizures, including convulsive and absence seizures. Importantly, TRN-specific deletion of Plcβ1 led to the development of only spontaneous SWDs, and no other types of seizures were observed. Ex vivo slice patch recording demonstrated that the number of spikes, an intrinsic TRN neuronal property, was significantly reduced in both tonic and burst firing modes in the absence of Plcβ1. We conclude that the loss of Plcβ1 in the TRN leads to decreased excitability and impairs normal inhibitory neuronal function, thereby disrupting feedforward inhibition of the TC circuitry, which is sufficient to cause hypersynchrony of the TC system and eventually leads to spontaneous absence seizures. Our study not only provides a novel mechanism for the induction of SWDs in Plcβ1-deficient patients but also offers guidance for the development of diagnostic and therapeutic tools for absence epilepsy.

Tonic serotonergic input increases the burst firing mode and diminishes the firing rate of reticular thalamic nucleus neurons through 5-HT1A receptors activation in anesthetized rats.

The reticular thalamic nucleus (RTn) is a thin shell of GABAergic neurons that covers the dorsal thalamus that regulate the global activity of all thalamic nuclei. RTn controls the flow of information between thalamus and cerebral cortex since it receives glutamatergic information from collaterals of thalamo-cortical (TCs) and cortico-thalamic neurons. It also receives aminergic information from several brain stem nuclei, including serotonergic fibers originated in the dorsal raphe nucleus. RTn neurons express serotonergic receptors including the 5-HT1A subtype, however, the role of this receptor in the RTn electrical activity has been scarcely analyzed. In this work, we recorded in vivo the unitary spontaneous electrical activity of RTn neurons in anesthetized rats; our study aimed to obtain information about the effects of 5-HT1A receptors in RTn neurons. Local application of fluoxetine (a serotonin reuptake inhibitor) increases burst firing index accompanied by a decrease in the basal spiking rate. Local application of different doses of serotonin and 8-OH-DPAT (a specific 5-HT1A receptor agonist) causes a similar response to fluoxetine effects. Local 5-HT1A receptors blockade produces opposite effects and suppresses the effect by 8-OH-DPAT. Our findings indicate the presence of a serotonergic tonic discharge in the RTn that increases the burst firing index and simultaneously decreases the basal spiking frequency through 5-HT1A receptors activation.

Somatosensory Thalamic Activity Modulation by Posterior Insular Stimulation: Cues to Clinical Application Based on Comparison of Frequencies in a Cat Model

BackgroundThe posterior insula (PI) has been proposed as a potential neurostimulation target for neuropathic pain relief as it represents a key-structure in pain processing. However, currently available data remain inconclusive as to efficient stimulation parameters. ObjectivesAs frequency was shown to be the most correlated parameter to pain relief, this study aims to evaluate the potential modulatory effects of low frequency (LF-IS, 50 Hz) and high-frequency (HF-IS, 150 Hz) posterior insular stimulation on the activity of somatosensory thalamic nuclei. Materials and MethodsEpidural bipolar electrodes were placed over the PI of healthy adult cats, and extracellular single-unit activities of nociceptive (NS), nonnociceptive (NN), and wide dynamic range (WDR) thalamic cells were recorded within the ventral posterolateral nucleus and the medial division of the thalamic posterior complex. Mean discharge frequency and burst firing mode were analyzed before and after either LF-IS or HF-IS. ResultsLF-IS showed a significant thalamic modulatory effects increasing the firing rate of NN cells (p ≤ 0.03) and decreasing the burst firing of NS cells (p ≤ 0.03), independently of the thalamic nucleus. Conversely, HF-IS did not induce any change in firing properties of the three recorded cell types. ConclusionThese data indicate that 50 Hz IS could be a better candidate to control neuropathic pain.

Mathematical Modeling of Shooting from Moving Carrier

The work is devoted to the development of software complex for modeling the dynamic characteristics of a moving carrier in burst firing mode and to the study of their impact on shooting accuracy. A mathematical model for mechanical system of moving carrier is given, which allows to take into account the movement and vibrations of the helicopter, as well as the mutual influence of the system “helicopter – rocket-gun armament”. The research results of the dispersion of projectiles and rockets in serial firing, depending on the parameters of the movement of moving carrier and the shooting mode, are presented. The paper gives a description and outlines working principles of the software complex for visualization of simulation results.

Sleep and Epilepsy Link by Plasticity.

We aimed to explore the link between NREM sleep and epilepsy. Based on human and experimental data we propose that a sleep-related epileptic transformation of normal neurological networks underlies epileptogenesis. Major childhood epilepsies as medial temporal lobe epilepsy (MTLE), absence epilepsy (AE) and human perisylvian network (PN) epilepsies - made us good models to study. These conditions come from an epileptic transformation of the affected functional systems. This approach allows a system-based taxonomy instead of the outworn generalized-focal classification. MTLE links to the memory-system, where epileptic transformation results in a switch of normal sharp wave-ripples to epileptic spikes and pathological high frequency oscillations, compromising sleep-related memory consolidation. Absence epilepsy (AE) and juvenile myoclonic epilepsy (JME) belong to the corticothalamic system. The burst-firing mode of NREM sleep normally producing sleep-spindles turns to an epileptic working mode ejecting bilateral synchronous spike-waves. There seems to be a progressive transition from AE to JME. Shared absences and similar bilateral synchronous discharges show the belonging of the two conditions, while the continuous age windows - AE affecting schoolchildren, JME the adolescents - and the increased excitability in JME compared to AE supports the notion of progression. In perisylvian network epilepsies - idiopathic focal childhood epilepsies and electrical status epilepticus in sleep including Landau-Kleffner syndrome - centrotemporal spikes turn epileptic, with the potential to cause cognitive impairment. Postinjury epilepsies modeled by the isolated cortex model highlight the shared way of epileptogenesis suggesting the derailment of NREM sleep-related homeostatic plasticity as a common step. NREM sleep provides templates for plasticity derailing to epileptic variants under proper conditions. This sleep-origin explains epileptiform discharges' link and similarity with NREM sleep slow oscillations, spindles and ripples. Normal synaptic plasticity erroneously overgrowing homeostatic processes may derail toward an epileptic working-mode manifesting the involved system's features. The impact of NREM sleep is unclear in epileptogenesis occurring in adolescence and adulthood, when plasticity is lower. The epileptic process interferes with homeostatic synaptic plasticity and may cause cognitive impairment. Its type and degree depends on the affected network's function. We hypothesize a vicious circle between sleep end epilepsy. The epileptic derailment of normal plasticity interferes with sleep cognitive functions. Sleep and epilepsy interconnect by the pathology of plasticity.

Experimentally-constrained biophysical models of tonic and burst firing modes in thalamocortical neurons.

Somatosensory thalamocortical (TC) neurons from the ventrobasal (VB) thalamus are central components in the flow of sensory information between the periphery and the cerebral cortex, and participate in the dynamic regulation of thalamocortical states including wakefulness and sleep. This property is reflected at the cellular level by the ability to generate action potentials in two distinct firing modes, called tonic firing and low-threshold bursting. Although the general properties of TC neurons are known, we still lack a detailed characterization of their morphological and electrical properties in the VB thalamus. The aim of this study was to build biophysically-detailed models of VB TC neurons explicitly constrained with experimental data from rats. We recorded the electrical activity of VB neurons (N = 49) and reconstructed morphologies in 3D (N = 50) by applying standardized protocols. After identifying distinct electrical types, we used a multi-objective optimization to fit single neuron electrical models (e-models), which yielded multiple solutions consistent with the experimental data. The models were tested for generalization using electrical stimuli and neuron morphologies not used during fitting. A local sensitivity analysis revealed that the e-models are robust to small parameter changes and that all the parameters were constrained by one or more features. The e-models, when tested in combination with different morphologies, showed that the electrical behavior is substantially preserved when changing dendritic structure and that the e-models were not overfit to a specific morphology. The models and their analysis show that automatic parameter search can be applied to capture complex firing behavior, such as co-existence of tonic firing and low-threshold bursting over a wide range of parameter sets and in combination with different neuron morphologies.

Alterations in Oscillatory Behavior of Central Medial Thalamic Neurons Demonstrate a Key Role of CaV3.1 Isoform of T-Channels During Isoflurane-Induced Anesthesia.

Although the central medial nucleus (CeM) of the thalamus is an essential part of the arousal system for sleep and anesthesia initiation, the precise mechanisms that regulate its activity are not well studied. We examined the role of CaV3.1 isoform of T-type calcium channels (T-channels) in the excitability and rhythmic activity of CeM neurons during isoflurane (ISO)-induced anesthesia by using mouse genetics and selective pharmacology. Patch-clamp recordings taken from acute brain slices revealed that CaV3.1 channels in CeM are inhibited by prototypical volatile anesthetic ISO (250 and 500 μM) and selective T-channels blocker 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). Both TTA-P2 and ISO attenuated tonic and burst firing modes, and hyperpolarized CeM neurons from wild type (WT) mice. These effects were greatly diminished or abolished in CaV3.1 null mice. Our ensuing in vivo local field potential (LFP) recordings from CeM indicated that the ability of TTA-P2 and anesthetic concentrations of ISO to promote δ oscillation was substantially weakened in CaV3.1 null mice. Furthermore, escalating ISO concentrations induced stronger burst-suppression LFP pattern in mutant than in WT mice. Our results demonstrate for the first time the importance of CaV3.1 channels in thalamocortical oscillations from the non-specific thalamic nuclei that underlie clinically important effects of ISO.

Expertise, giftedness and insight in mathematics

Absence epilepsy (AE) and nocturnal frontal lobe epilepsy (NFLE) are system epilepsies of the sleep–wake system.1. Absence epilepsy is a well-known idiopathic childhood epilepsy. The spike–wake pattern of absence epilepsy and the non–rapid eye movement (NREM) sleep-related burst-firing mode of the corticothalamic system share the same functional structures in the brain. Absences occur when vigilance decreases, during the transition from waking to NREM sleep, whereas they are inhibited by wakefulness and rapid eye movement sleep. The sensory stimuli reaching the brain during the transition state [cyclic alternating pattern (CAP) A1 phase] elicit “reactive” slow-wave responses and may activate spike–wave responses, whereas those arriving in other states (CAP 2 or 3 NREM sleep) evoke “regular” desynchronization–arousal responses and do not trigger spike–waves.In other words, in terms of states and functions, absence epilepsy seems to be linked to the periods of initiation and shifts toward NREM sleep.2. Autosomal dominant nocturnal frontal lobe epilepsy, the genetic variation of NFLE, is underlain by mutations of the nicotinic acetylcholine receptor system.The acetylcholine receptor (AChE) gene mutations render the cholinergic ascending arousal system oversensitive to arousals during NREM sleep, resulting in arousal-linked seizure fragments and full-blown seizures with different degrees of behavioral manifestations, from plain arousal behaviors to alarm reactions with hypermotor features. The semiology and the occurrence pattern of seizures can be explained by an increased propensity to arousal and a dissociation between the partially activated brain and a sleeping (dysfunctional) dorsofrontal cortical system. The clinical semiology of the genetic variations and the sporadic cases does not differ.Therefore, NFLE seems to be linked to the epileptically facilitated cholinergic arousal system, underlain by a genetic or a suspected genetic origin.Arousal parasomnia (AP) manifests behaviors similar to those of NFLE, caused by a nonepileptic mechanism. The two conditions (AP and NFLE) show a familial clustering, with patients and families suffering in both conditions and probably sharing the pathomechanisms related to a dissociation background.We can see that NFLE and AP (the epileptic and nonepileptic counterparts) may both be linked to a disorder of the frontal part of the ascending arousal system.

Brain stimulation patterns emulating endogenous thalamocortical input to parvalbumin-expressing interneurons reduce nociception in mice

BackgroundThe bursting pattern of thalamocortical (TC) pathway dampens nociception. Whether brain stimulation mimicking endogenous patterns can engage similar sensory gating processes in the cortex and reduce nociceptive behaviors remains uninvestigated. ObjectiveWe investigated the role of cortical parvalbumin expressing (PV) interneurons within the TC circuit in gating nociception and their selective response to TC burst patterns. We then tested if transcranial magnetic stimulation (TMS) patterned on endogenous nociceptive TC bursting modulate nociceptive behaviors. MethodsThe switching of TC neurons between tonic (single spike) and burst (high frequency spikes) firing modes may be a critical component in modulating nociceptive signals. Deep brain electrical stimulation of TC neurons and immunohistochemistry were used to examine the differential influence of each firing mode on cortical PV interneuron activity. Optogenetic stimulation of cortical PV interneurons assessed a direct role in nociceptive modulation. A new TMS protocol mimicking thalamic burst firing patterns, contrasted with conventional continuous and intermittent theta burst protocols, tested if TMS patterned on endogenous TC activity reduces nociceptive behaviors in mice. ResultsImmunohistochemical evidence confirmed that burst, but not tonic, deep brain stimulation of TC neurons increased the activity of PV interneurons in the cortex. Both optogenetic activation of PV interneurons and TMS protocol mimicking thalamic burst reduced nociceptive behaviors. ConclusionsOur findings suggest that burst firing of TC neurons recruits PV interneurons in the cortex to reduce nociceptive behaviors and that neuromodulation mimicking thalamic burst firing may be useful for modulating nociception.

The Cacna1h mutation in the GAERS model of absence epilepsy enhances T-type Ca2+ currents by altering calnexin-dependent trafficking of Cav3.2 channels

Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3.2 channel to modulate the sorting of the channel to the cell surface. We demonstrate that the GAERS missense mutation located in the Cav3.2 III-IV linker alters the Cav3.2/calnexin interaction, resulting in an increased surface expression of the channel and a concomitant elevation in calcium influx. Our study reveals a novel mechanism that controls the expression of T-type channels, and provides a molecular explanation for the enhancement of T-type calcium conductance in GAERS.

Sleep and Serotonin Modulate Paracapsular Nitric Oxide Synthase Expressing Neurons of the Amygdala.

Unraveling the roles of distinct neuron types is a fundamental challenge to understanding brain function in health and disease. In the amygdala, a brain structure regulating emotional behavior, the diversity of GABAergic neurons has been only partially explored. We report a novel population of GABAergic amygdala neurons expressing high levels of neuronal nitric oxide synthase (nNOS). These cells are predominantly localized along basolateral amygdala (BLA) boundaries. Performing ex vivo patch-clamp recordings from nNOS+ neurons in Nos1-CreER;Ai9 mice, we observed that nNOS+ neurons located along the external capsule display distinctive electrophysiological properties, axonal and dendritic arborization, and connectivity. Examining their c-Fos expression, we found that paracapsular nNOS+ neurons are activated during a period of undisturbed sleep following sleep deprivation, but not during sleep deprivation. Consistently, we found that dorsal raphe serotonin [5-hydroxytryptamine (5-HT)] neurons, which are involved in sleep–wake regulation, innervate nNOS+ neurons. Bath application of 5-HT hyperpolarizes nNOS+ neurons via 5-HT1A receptors. This hyperpolarization produces a reduction in firing rate and, occasionally, a switch from tonic to burst firing mode, thereby contrasting with the classic depolarizing effect of 5-HT on BLA GABAergic cells reported so far. Thus, nNOS+ cells are a distinct cell type of the amygdala that controls the activity of downstream neurons in both amygdaloid and extra-amygdaloid regions in a vigilance state-dependent fashion. Given the strong links among mood, sleep deprivation, and 5-HT, the recruitment of paracapsular nNOS+ neurons following high sleep pressure may represent an important mechanism in emotional regulation.

Electroresponsive properties of rat central medial thalamic neurons.

The central medial thalamic (CMT) nucleus is a poorly known component of the middle thalamic complex that relays nociceptive inputs to the basolateral amygdala and cingulate cortex and plays a critical role in the control of awareness. The present study was undertaken to characterize the electroresponsive properties of CMT neurons. Similar to relay neurons found throughout the dorsal thalamus, CMT cells assumed tonic or burst-firing modes, depending on their membrane potentials (Vm). However, they showed little evidence of the hyperpolarization-activated mixed cationic conductance (IH)-mediated inward rectification usually displayed by dorsal thalamic relay cells at hyperpolarized Vm Two subtypes of CMT neurons were identified when comparing their responses with depolarization applied from negative potentials. Some cells generated a low-threshold spike burst followed by tonic firing, whereas others remained silent after the initial burst, irrespective of the amount of depolarizing current injected. Equal proportions of the two cell types were found among neurons retrogradely labeled from the basolateral amygdala. Their morphological properties were heterogeneous but distinct from the classical bushy relay cell type that prevails in most of the dorsal thalamus. We propose that the marginal influence of IHin CMT relative to other dorsal thalamic nuclei has significant network-level consequences. Because IHpromotes the genesis of highly coherent delta oscillations in thalamocortical networks during sleep, these oscillations may be weaker or less coherent in CMT. Consequently, delta oscillations would be more easily disrupted by peripheral inputs, providing a potential mechanism for the reported role of CMT in eliciting arousal from sleep or anesthesia.

Dopamine System Dysregulation and the Pathophysiology of Schizophrenia: Insights From the Methylazoxymethanol Acetate Model

Data from numerous studies have strongly implicated the dopamine (DA) system in the pathophysiology of schizophrenia. The data are particularly robust for the positive or the psychotic symptoms of schizophrenia, which can be mimicked by DA agonists and attenuated by D2 antagonist antipsychotic drugs. Nonetheless, there is little evidence for a major dysfunction within the DA system itself; instead, current research has focused on a disruption in the regulation of the DA system. One region in particular that has shown correlations with DA dysfunction is the limbic portion of the hippocampus, which comprises the ventralmost segment in rats analogous to the anterior aspect in humans. Thus, studies in patients with schizophrenia have shown hyperactivity in the hippocampus that correlates with psychosis as well as a loss of parvalbumin gamma-aminobutyric acid–ergic (GABAergic) inhibitory neurons (1). To examine the pathophysiology of schizophrenia, we employed a developmental disruption model that uses the mitotoxin methylazoxymethanol acetate (MAM). This drug is administered to pregnant rats at gestational day 17 to mimic the second trimester in humans, during which insults have a higher impact on inducing schizophrenia births. The offspring are then examined peripubertally for developmental changes and as adults to test for dysfunctions that correspond to schizophrenia in humans. The adult offspring of MAM-treated rats display many characteristics consistent with schizophrenia (2,3), including neuroanatomic changes (thinning of limbic cortices with an increase in cell packing density, loss of parvalbumin interneurons), behavioral deficits (prepulse inhibition of startle, reversal learning, extradimensional shift, latent inhibition, social interaction), and pharmacologic responses (hyperresponsivity to phencyclidine, increased locomotion to amphetamine). Furthermore, as in humans, there is hyperactivity in the ventral hippocampus (vHipp) and a disruption of rhythmic activity including delta and gamma rhythms (3). There was also a substantial increase in DA neuron population activity. In anesthetized and awake rats, DA neurons exhibit several activity states that are regulated by different systems and differentially affect system function (Figure 1). In the basal state, DA neurons discharge in a slow, irregular tonic firing pattern. However, if the organism is exposed to a behaviorally salient stimulus, DA neurons transition to a rapid burst-firing mode. Thus, burst firing is considered to be the behaviorally relevant phasic response to stimuli. Burst firing is driven by a glutamatergic input arising primarily from the brainstem pedunculopontine tegmentum (PPTg) acting on N-methyl-D-aspartate

Are Absence Epilepsy and Nocturnal Frontal Lobe Epilepsy System Epilepsies of the Sleep/Wake System?

System epilepsy is an emerging concept interpreting major nonlesional epilepsies as epileptic dysfunctions of physiological systems. I extend here the concept of reflex epilepsy to epilepsies linked to input dependent physiological systems. Experimental and clinical reseach data were collected to create a coherent explanation of underlying pathomechanism in AE and NFLE. We propose that AE should be interpreted as epilepsy linked to the corticothalamic burst-firing mode of NREM sleep, released by evoked vigilance level oscillations characterized by reactive slow wave response. In the genetic variation of NFLE the ascending cholinergic arousal system plays an essential role being in strong relationship with a gain mutation of the nicotinic acethylcholin receptors, rendering the arousal system hyperexcitable. I try to provide a more unitary interpretation for the variable seizure manifestation integrating them as different degree of pathological arosuals and alarm reactions. As a supporting hypothesis the similarity between arousal parasomnias and FNLE is shown, underpinned by overlaping pathomechanism and shared familiarity, but without epileptic features. Lastly we propose that both AE and NFLE are system epilepsies of the sleep-wake system representing epileptic disorders of the antagonistic sleep/arousal network. This interpretation may throw new light on the pathomechanism of AE and NFLE.

Neuronal excitability level transition induced by electrical stimulation

In experimental studies, electrical stimulation (ES) has been applied to induce neuronal activity or to disrupt pathological patterns. Nevertheless, the underlying mechanisms of these activity pattern transitions are not clear. To study these phenomena, we simulated a model of the hippocampal region CA1. The computational simulations using different amplitude levels and duration of ES revealed three states of neuronal excitability: burst-firing mode, depolarization block and spreading depression wave. We used the bifurcation theory to analyse the interference of ES in the cellular excitability and the neuronal dynamics. Understanding this process would help to improve the ES techniques to control some neurological disorders.

Elevated striatal dopamine attenuates nigrothalamic inputs and impairs transthalamic cortico-cortical communication in schizophrenia: A hypothesis

Schizophrenia has been found to involve source-monitoring deficits, whereby perceptions that result from self-initiated motor output become attributed to outside sources. One example of this phenomenon are the so called passivity experiences, such as delusions of control, during which the individual feels that own actions are controlled remotely by someone else. To explain these phenomena, it has been proposed that this illness involves efference copy failure. In other words, brain mechanism that prepare perceptual processes for the sensory consequences of self-initiated actions are impaired leading to their misattribution and to psychosis. In earlier work, it was argued that efference copy failure in schizophrenia is related to thalamic abnormalities. Namely, the thalamus can be thought of as a hub for cortico-cortical interactions, and these transthalamic cortico-cortical interactions were found to play a part in internal motor monitoring. Cortico-cortical communication via the thalamus can be impaired in a number of ways. For example, one way to impair these interactions is by interfering with the ability of the thalamus to display bursts of firing. As the burst firing mode in the thalamus requires a preceding period of prolonged hyperpolarization (100ms), one way to reduce the burst propensity of thalamic neurons is to interfere with the ability to display prolonged hyperpolarizations. In this paper, we argue that elevated striatal dopaminergic activity in schizophrenia attenuates nigrothalamic GABAergic inputs, and thereby reduces burst propensity of the mediodorsal (MD) thalamic nucleus in schizophrenia, with the ultimate result of reduced transthalamic cortico-cortical communication, relative disconnection between functionally associated cortical areas and to psychosis. Conversely, dopamine D2 receptor blockers (antipsychotics) may help restore nigrothalamic GABAergic inputs, thereby increasing the burst propensity in the thalamus.

Firing Modes of Dopamine Neurons Drive Bidirectional GIRK Channel Plasticity

G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons, including dopamine (DA) neurons in the ventral tegmental area (VTA). VTA DA neurons are bistable, firing in two modes: one characterized by bursts of action potentials, the other by tonic firing at a lower frequency. Here we provide evidence that these firing modes drive bidirectional plasticity of GIRK channel-mediated currents. In acute midbrain slices of mice, we observed that in vitro burst activation of VTA DA neurons potentiated GIRK currents whereas tonic firing depressed these currents. This plasticity was not specific to the metabotropic receptor activating the GIRK channels, as direct activation of GIRK channels by nonhydrolyzable GTP also potentiated the currents. The plasticity of GIRK currents required NMDA receptor and CaMKII activation, and involved protein trafficking through specific PDZ domains of GIRK2c and GIRK3 subunit isoforms. Prolonged tonic firing may thus enhance the probability to switch into burst-firing mode, which then potentiates GIRK currents and favors the return to baseline. In conclusion, activity-dependent GIRK channel plasticity may represent a slow destabilization process favoring the switch between the two firing modes of VTA DA neurons.