Dual function of thalamic low-vigilance state oscillations: rhythm-regulation and plasticity.

During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamus cooperatively engage in rhythmic activities that are exquisitely reflected in the electroencephalogram as distinctive rhythms spanning a range of frequencies from <1 Hz slow waves to 13 Hz alpha waves. In the thalamus, these diverse activities emerge through the interaction of cell-intrinsic mechanisms and local and long-range synaptic inputs. One crucial feature, however, unifies thalamic oscillations of different frequencies: repetitive burst firing driven by voltage-dependent Ca2+ spikes. Recent evidence reveals that thalamic Ca2+ spikes are inextricably linked to global somatodendritic Ca2+ transients and are essential for several forms of thalamic plasticity. Thus, we propose herein that alongside their rhythm-regulation function, thalamic oscillations of low-vigilance states have a plasticity function that, through modifications of synaptic strength and cellular excitability in local neuronal assemblies, can shape ongoing oscillations during inattention and NREM sleep and may potentially reconfigure thalamic networks for faithful information processing during attentive wakefulness.

A distinct class of slow (~0.2-2 Hz) intrinsically bursting layer 5 pyramidal neurons determines UP/DOWN state dynamics in the neocortex.

During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at ~0.2-2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca(2+) medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states.

Differential spike timing and phase dynamics of reticular thalamic and prefrontal cortical neuronal populations during sleep spindles.

The 8-15 Hz thalamocortical oscillations known as sleep spindles are a universal feature of mammalian non-REM sleep, during which they are presumed to shape activity-dependent plasticity in neocortical networks. The cortex is hypothesized to contribute to initiation and termination of spindles, but the mechanisms by which it implements these roles are unknown. We used dual-site local field potential and multiple single-unit recordings in the thalamic reticular nucleus (TRN) and medial prefrontal cortex (mPFC) of freely behaving rats at rest to investigate thalamocortical network dynamics during natural sleep spindles. During each spindle epoch, oscillatory activity in mPFC and TRN increased in frequency from onset to offset, accompanied by a consistent phase precession of TRN spike times relative to the cortical oscillation. In mPFC, the firing probability of putative pyramidal cells was highest at spindle initiation and termination times. We thus identified "early" and "late" cell subpopulations and found that they had distinct properties: early cells generally fired in synchrony with TRN spikes, whereas late cells fired in antiphase to TRN activity and also had higher firing rates than early cells. The accelerating and highly structured temporal pattern of thalamocortical network activity over the course of spindles therefore reflects the engagement of distinct subnetworks at specific times across spindle epochs. We propose that early cortical cells serve a synchronizing role in the initiation and propagation of spindle activity, whereas the subsequent recruitment of late cells actively antagonizes the thalamic spindle generator by providing asynchronous feedback.

Identification of the mechanism mediating genioglossus muscle suppression in REM sleep.

RATIONALE: Inhibition of pharyngeal motoneurons accompanies REM sleep and is a cause of hypoventilation and obstructive sleep apnea in humans. One explanation posits that the neurotransmitters glycine and γ-aminobutyric acid are responsible for REM sleep motor inhibition. However, blockade of that mechanism at cranial motor nuclei increases motor activity in all sleep-wake states, and least of all in REM sleep, arguing against it as a major mechanism of REM sleep pharyngeal motor inhibition. OBJECTIVES: To identify the mechanism of REM sleep inhibition at the hypoglossal motor pool. METHODS: Genioglossus and diaphragm activities were recorded in 34 rats across sleep-wake states. Microdialysis probes were implanted into the hypoglossal motor pool. MEASUREMENTS AND MAIN RESULTS: Here we show that muscarinic receptor antagonism at the hypoglossal motor pool prevents the inhibition of genioglossus activity throughout REM sleep; likewise, with G-protein-coupled inwardly rectifying potassium (GIRK) channel blockade. Importantly, the genioglossus activating effects of these interventions were largest in REM sleep and minimal or often absent in other sleep-wake states. Finally, we showed that muscarinic inhibition of the genioglossus is functionally linked to GIRK channel activation. CONCLUSIONS: We identify a powerful cholinergic-GIRK channel mechanism operating at the hypoglossal motor pool that has its largest inhibitory influence in REM sleep and minimal or no effects in other sleep-wake states. This mechanism is the major cause of REM sleep inhibition at a pharyngeal motor pool critical for effective breathing.

Rhythmic dendritic Ca2+ oscillations in thalamocortical neurons during slow non-REM sleep-related activity in vitro.

The distribution of T-type Ca2+ channels along the entire somatodendritic axis of sensory thalamocortical (TC) neurons permits regenerative propagation of low threshold spikes (LTS) accompanied by global dendritic Ca2+ influx. Furthermore, T-type Ca2+ channels play an integral role in low frequency oscillatory activity (<1­4 Hz) that is a defining feature of TC neurons. Nonetheless, the dynamics of T-type Ca2+ channel-dependent dendritic Ca2+ signalling during slow sleep-associated oscillations remains unknown. Here we demonstrate using patch clamp recording and two-photon Ca2+ imaging of dendrites from cat TC neurons undergoing spontaneous slow oscillatory activity that somatically recorded δ (1­4 Hz) and slow (<1 Hz) oscillations are associated with rhythmic and sustained global oscillations in dendritic Ca2+. In addition, our data reveal the presence of LTS-dependent Ca2+ transients (Δ[Ca2+]) in dendritic spine-like structures on proximal TC neuron dendrites during slow (<1 Hz) oscillations whose amplitudes are similar to those observed in the dendritic shaft. We find that the amplitude of oscillation associated Δ[Ca2+] do not vary significantly with distance from the soma whereas the decay time constant (τdecay) of Δ[Ca2+] decreases significantly in more distal dendrites. Furthermore, τdecay of dendritic Δ[Ca2+] increases significantly as oscillation frequency decreases from δ to slow frequencies where pronounced depolarised UP states are observed. Such rhythmic dendritic Ca2+ entry in TC neurons during sleep-related firing patterns could be an important factor in maintaining the oscillatory activity and associated biochemical signalling processes, such as synaptic downscaling, that occur in non-REM sleep.

Activity of cortical and thalamic neurons during the slow (<1 Hz) rhythm in the mouse in vivo.

During NREM sleep and under certain types of anaesthesia, the mammalian brain exhibits a distinctive slow (<1 Hz) rhythm. At the cellular level, this rhythm correlates with so-called UP and DOWN membrane potential states. In the neocortex, these UP and DOWN states correspond to periods of intense network activity and widespread neuronal silence, respectively, whereas in thalamocortical (TC) neurons, UP/DOWN states take on a more stereotypical oscillatory form, with UP states commencing with a low-threshold Ca(2+) potential (LTCP). Whilst these properties are now well recognised for neurons in cats and rats, whether or not they are also shared by neurons in the mouse is not fully known. To address this issue, we obtained intracellular recordings from neocortical and TC neurons during the slow (<1 Hz) rhythm in anaesthetised mice. We show that UP/DOWN states in this species are broadly similar to those observed in cats and rats, with UP states in neocortical neurons being characterised by a combination of action potential output and intense synaptic activity, whereas UP states in TC neurons always commence with an LTCP. In some neocortical and TC neurons, we observed 'spikelets' during UP states, supporting the possible presence of electrical coupling. Lastly, we show that, upon tonic depolarisation, UP/DOWN states in TC neurons are replaced by rhythmic high-threshold bursting at ~5 Hz, as predicted by in vitro studies. Thus, UP/DOWN state generation appears to be an elemental and conserved process in mammals that underlies the slow (<1 Hz) rhythm in several species, including humans.

Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo.

Motoneurons are the final output pathway for the brain's influence on behavior. Here we identify properties of hypoglossal motor output to the tongue musculature. Tongue motor control is critical to the pathogenesis of obstructive sleep apnea, a common and serious sleep-related breathing disorder. Studies were performed on mice expressing a light sensitive cation channel exclusively on cholinergic neurons (ChAT-ChR2(H134R)-EYFP). Discrete photostimulations under isoflurane-induced anesthesia from an optical probe positioned above the medullary surface and hypoglossal motor nucleus elicited discrete increases in tongue motor output, with the magnitude of responses dependent on stimulation power (P < 0.001, n = 7) and frequency (P = 0.002, n = 8, with responses to 10 Hz stimulation greater than for 15-25 Hz, P < 0.022). Stimulations during REM sleep elicited significantly reduced responses at powers 3-20 mW compared to non-rapid eye movement (non-REM) sleep and wakefulness (each P < 0.05, n = 7). Response thresholds were also greater in REM sleep (10 mW) compared to non-REM and waking (3 to 5 mW, P < 0.05), and the slopes of the regressions between input photostimulation powers and output motor responses were specifically reduced in REM sleep (P < 0.001). This study identifies that variations in photostimulation input produce tunable changes in hypoglossal motor output in-vivo and identifies REM sleep specific suppression of net motor excitability and responsivity.

Cellular dynamics of cholinergically induced alpha (8-13 Hz) rhythms in sensory thalamic nuclei in vitro.

Although EEG alpha (8-13 Hz) rhythms are traditionally thought to reflect an "idling" brain state, they are also linked to several important aspects of cognition, perception, and memory. Here we show that reactivating cholinergic input, a key component in normal cognition and memory operations, in slices of the cat primary visual and somatosensory thalamus, produces robust alpha rhythms. These rhythms rely on activation of muscarinic receptors and are primarily coordinated by activity in the recently discovered, gap junction-coupled subnetwork of high-threshold (HT) bursting thalamocortical neurons. By performing extracellular field recordings in combination with intracellular recordings of these cells, we show that (1) the coupling of HT bursting cells is sparse, with individual neurons typically receiving discernable network input from one or very few additional cells, (2) the phase of oscillatory activity at which these cells prefer to fire is readily modifiable and determined by a combination of network input, intrinsic properties and membrane polarization, and (3) single HT bursting neurons can potently influence the local network state. These results substantially extend the known effects of cholinergic activation on the thalamus and, in combination with previous studies, show that sensory thalamic nuclei possess powerful and dynamically reconfigurable mechanisms for generating synchronized alpha activity that can be engaged by both descending and ascending arousal systems.

Are corticothalamic 'up' states fragments of wakefulness?

The slow (<1 Hz) oscillation, with its alternating 'up' and 'down' states in individual neurons, is a defining feature of the electroencephalogram (EEG) during slow-wave sleep (SWS). Although this oscillation is well preserved across mammalian species, its physiological role is unclear. Electrophysiological and computational evidence from the cortex and thalamus now indicates that slow-oscillation 'up' states and the 'activated' state of wakefulness are remarkably similar dynamic entities. This is consistent with behavioural experiments suggesting that slow-oscillation 'up' states provide a context for the replay, and possible consolidation, of previous experience. In this scenario, the T-type Ca(2+) channel-dependent bursts of action potentials that initiate each 'up' state in thalamocortical (TC) neurons might function as triggers for synaptic and cellular plasticity in corticothalamic networks. This review is part of the INMED/TINS special issue Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com).

Cellular mechanisms of the slow (<1 Hz) oscillation in thalamocortical neurons in vitro.

The slow (<1 Hz) rhythm is a defining feature of the electroencephalogram during sleep. Since cortical circuits can generate this rhythm in isolation, it is assumed that the accompanying slow oscillation in thalamocortical (TC) neurons is largely a passive reflection of neocortical activity. Here we show, however, that by activating the metabotropic glutamate receptor (mGluR), mGluR1a, cortical inputs can recruit intricate cellular mechanisms that enable the generation of an intrinsic slow oscillation in TC neurons in vitro with identical properties to those observed in vivo. These mechanisms rely on the "window" component of the T-type Ca(2+) current and a Ca(2+)-activated, nonselective cation current. These results suggest an active role for the thalamus in shaping the slow (<1 Hz) sleep rhythm.

Synchronized oscillations at alpha and theta frequencies in the lateral geniculate nucleus.

In relaxed wakefulness, the EEG exhibits robust rhythms in the alpha band (8-13 Hz), which decelerate to theta (approximately 2-7 Hz) frequencies during early sleep. In animal models, these rhythms occur coherently with synchronized activity in the thalamus. However, the mechanisms of this thalamic activity are unknown. Here we show that, in slices of the lateral geniculate nucleus maintained in vitro, activation of the metabotropic glutamate receptor (mGluR) mGluR1a induces synchronized oscillations at alpha and theta frequencies that share similarities with thalamic alpha and theta rhythms recorded in vivo. These in vitro oscillations are driven by an unusual form of burst firing that is present in a subset of thalamocortical neurons and are synchronized by gap junctions. We propose that mGluR1a-induced oscillations are a potential mechanism whereby the thalamus promotes EEG alpha and theta rhythms in the intact brain.

NeuReal: an interactive simulation system for implementing artificial dendrites and large hybrid networks.

The dynamic clamp is a technique which allows the introduction of artificial conductances into living cells. Up to now, this technique has been mainly used to add small numbers of 'virtual' ion channels to real cells or to construct small hybrid neuronal circuits. In this paper we describe a prototype computer system, NeuReal, that extends the dynamic clamp technique to include (i) the attachment of artificial dendritic structures consisting of multiple compartments and (ii) the construction of large hybrid networks comprising several hundred biophysically realistic modelled neurons. NeuReal is a fully interactive system that runs on Windows XP, is written in a combination of C++ and assembler, and uses the Microsoft DirectX application programming interface (API) to achieve high-performance graphics. By using the sampling hardware-based representation of membrane potential at all stages of computation and by employing simple look-up tables, NeuReal can simulate over 1000 independent Hodgkin and Huxley type conductances in real-time on a modern personal computer (PC). In addition, whilst not being a hard real-time system, NeuReal still offers reliable performance and tolerable jitter levels up to an update rate of 50kHz. A key feature of NeuReal is that rather than being a simple dedicated dynamic clamp, it operates as a fast simulation system within which neurons can be specified as either real or simulated. We demonstrate the power of NeuReal with several example experiments and argue that it provides an effective tool for examining various aspects of neuronal function.

Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons.

It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies. For example, both metabotropic glutamate receptor (mGluR) and muscarinic Ach receptor (mAchR) activation can cause rhythmic bursting at alpha/theta frequencies. Interestingly, key differences exist between mGluR- and mAchR-induced bursting, with the former involving extensive dendritic Ca2+ electrogenesis and being mimicked by a non-specific block of K+ channels with Ba2+, whereas the latter appears to be more reliant on proximal Na+ channels and a prominent spike afterdepolarization (ADP). This likely relates to the differential somatodendritic distribution of mGluRs and mAChRs and may have important functional consequences. We also show here that in similarity to some neocortical neurons, inhibiting large-conductance Ca2+-activated K+ channels in TC neurons can lead to fast rhythmic bursting (FRB) at approximately 40 Hz. This activity also appears to rely on a Na+ channel-dependent spike ADP and may occur in vivo during natural wakefulness. Taken together, these results show that TC neurons are considerably more flexible than generally thought and strongly endorse a role for the thalamus in promoting a range of cognitively-relevant brain rhythms.

Neuronal basis of the slow (<1 Hz) oscillation in neurons of the nucleus reticularis thalami in vitro.

During deep sleep and anesthesia, the EEG of humans and animals exhibits a distinctive slow (<1 Hz) rhythm. In inhibitory neurons of the nucleus reticularis thalami (NRT), this rhythm is reflected as a slow (<1 Hz) oscillation of the membrane potential comprising stereotypical, recurring "up" and "down" states. Here we show that reducing the leak current through the activation of group I metabotropic glutamate receptors (mGluRs) with either trans-ACPD [(+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid] (50-100 microM) or DHPG [(S)-3,5-dihydroxyphenylglycine] (100 microM) instates an intrinsic slow oscillation in NRT neurons in vitro that is qualitatively equivalent to that observed in vivo. A slow oscillation could also be evoked by synaptically activating mGluRs on NRT neurons via the tetanic stimulation of corticothalamic fibers. Through a combination of experiments and computational modeling we show that the up state of the slow oscillation is predominantly generated by the "window" component of the T-type Ca2+ current, with an additional supportive role for a Ca2+-activated nonselective cation current. The slow oscillation is also fundamentally reliant on an Ih current and is extensively shaped by both Ca2+- and Na+-activated K+ currents. In combination with previous work in thalamocortical neurons, this study suggests that the thalamus plays an important and active role in shaping the slow (<1 Hz) rhythm during deep sleep.

Just a phase they're going through: the complex interaction of intrinsic high-threshold bursting and gap junctions in the generation of thalamic alpha and theta rhythms.

Rhythms in the alpha frequency band (8-13 Hz) are a defining feature of the human EEG during relaxed wakefulness and are known to be influenced by the thalamus. In the early stages of sleep and in several neurological and psychiatric conditions alpha rhythms are replaced by slower activity in the theta (3-7 Hz) band. Of particular interest is how these alpha and theta rhythms are generated at the cellular level. Recently we identified a subset of thalamocortical (TC) neurons in the lateral geniculate nucleus (LGN) which exhibit rhythmic high-threshold (>-55 mV) bursting at approximately 2-13 Hz and which are interconnected by gap junctions (GJs). These cells combine to generate a locally synchronized continuum of alpha and theta oscillations, thus providing direct evidence that the thalamus can act as an independent pacemaker of alpha and theta rhythms. Interestingly, GJ coupled pairs of TC neurons can exhibit both in-phase and anti-phase synchrony and will often spontaneously alternate between these two states. This dictates that the local field oscillation amplitude is not simply linked to the extent of cell recruitment into a single synchronized neuronal assembly but also to the degree of destructive interference between dynamic, spatially overlapping, competing anti-phase groups of continuously bursting neurons. Thus, the waxing and waning of thalamic alpha/theta rhythms should not be assumed to reflect a wholesale increase and reduction, respectively, in underlying neuronal synchrony. We argue that these network dynamics might have important consequences for relating changes in the amplitude of EEG alpha and theta rhythms to the activity of thalamic networks.

Thalamic T-type Ca2+ channels and NREM sleep.

T-type Ca2+ channels play a number of different and pivotal roles in almost every type of neuronal oscillation expressed by thalamic neurones during non-rapid eye movement (NREM) sleep, including those underlying sleep theta waves, the K-complex and the slow (<1 Hz) sleep rhythm, sleep spindles and delta waves. In particular, the transient opening of T channels not only gives rise to the 'classical' low threshold Ca2+ potentials, and associated high frequency burst of action potentials, that are characteristically present during sleep spindles and delta waves, but also contributes to the high threshold bursts that underlie the thalamic generation of sleep theta rhythms. The persistent opening of a small fraction of T channels, i.e. I(Twindow), is responsible for the large amplitude and long lasting depolarization, or UP state, of the slow (<1 Hz) sleep oscillation in thalamic neurones. These cellular findings are in part matched by the wake-sleep phenotype of global and thalamic-selective CaV3.1 knockout mice that show a decreased amount of total NREM sleep time. T-type Ca2+ channels, therefore, constitute the single most crucial voltage-dependent conductance that permeates all activities of thalamic neurones during NREM sleep. Since I(Twindow) and high threshold bursts are not restricted to thalamic neurones, the cellular neurophysiology of T channels should now move away from the simplistic, though historically significant, view of these channels as being responsible only for low threshold Ca2+ potentials.

GABAA receptor-mediated tonic inhibition in thalamic neurons.

Tonic GABAA receptor-mediated inhibition is typically generated by delta subunit-containing extrasynaptic receptors. Because the delta subunit is highly expressed in the thalamus, we tested whether thalamocortical (TC) neurons of the dorsal lateral geniculate nucleus (dLGN) and ventrobasal complex exhibit tonic inhibition. Focal application of gabazine (GBZ) (50 microM) revealed the presence of a 20 pA tonic current in 75 and 63% of TC neurons from both nuclei, respectively. No tonic current was observed in GABAergic neurons of the nucleus reticularis thalami (NRT). Bath application of 1 microM GABA increased tonic current amplitude to approximately 70 pA in 100% of TC neurons, but it was still not observed in NRT neurons. In dLGN TC neurons, the tonic current was sensitive to low concentrations of the delta subunit-specific receptor agonists allotetrahydrodeoxycorticosterone (100 nM) and 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol (THIP) (100 nM) but insensitive to the benzodiazepine flurazepam (5 microM). Bath application of low concentrations of GBZ (25-200 nM) preferentially blocked the tonic current, whereas phasic synaptic inhibition was primarily maintained. Under intracellular current-clamp conditions, the preferential block of the tonic current with GBZ led to a small depolarization and increase in input resistance. Using extracellular single-unit recordings, block of the tonic current caused the cessation of low-threshold burst firing and promoted tonic firing. Enhancement of the tonic current by THIP hyperpolarized TC neurons and promoted burst firing. Thus, tonic current in TC neurons generates an inhibitory tone. Its modulation contributes to the shift between different firing modes, promotes the transition between different behavioral states, and predisposes to absence seizures.

Pathway-specific action of gamma-hydroxybutyric acid in sensory thalamus and its relevance to absence seizures.

The systemic injection of gamma-hydroxybutyric acid (GHB) elicits spike and wave discharges (SWDs), the EEG hallmark of absence seizures, and represents a well established, widely used pharmacological model of this nonconvulsive epilepsy. Despite this experimental use of GHB, as well as its therapeutic use in narcolepsy and its increasing abuse, however, the precise cellular mechanisms underlying the different pharmacological actions of this drug are still unclear. Because sensory thalamic nuclei play a key role in the generation of SWDs and sleep rhythms, and because direct injection of GHB in the ventrobasal (VB) thalamus elicits SWDs, we investigated GHB effects on corticothalamic EPSCs and GABAergic IPSCs in VB thalamocortical (TC) neurons. GHB (250 microm-10 mm) reversibly decreased the amplitude of electrically evoked EPSCs and GABAA IPSCs via activation of GABAB receptors; however, approximately 60% of the IPSCs were insensitive to low (250 microm-1.0 mm) GHB concentrations. The putative GHB receptor antagonist NSC 382 applied alone had a number of unspecific effects, whereas it either had no action on, or further increased, the GHB-elicited effects on synaptic currents. Low GHB concentrations (250 microm) were also effective in increasing absence-like intrathalamic oscillations evoked by cortical afferent stimulation. These results indicate that low concentrations of GHB, similar to the brain concentrations that evoke SWDs in vivo, differentially affect excitatory and inhibitory synaptic currents in TC neurons and promote absence-like intrathalamic oscillations. Furthermore, the present data strengthen previous suggestions on the GHB mechanism of sleep promotion and will help focus future studies on the cellular mechanisms underlying its abuse.

Thalamic mechanisms of EEG alpha rhythms and their pathological implications.

During relaxed wakefulness, the human brain exhibits pronounced rhythmic electrical activity in the alpha frequency band (8-13 Hz). This activity consists of 3 main components: the classic occipital alpha rhythm, the Rolandic mu rhythm, and the so-called third rhythm. In recent years, the long-held belief that alpha rhythms are strongly influenced by the thalamus has been confirmed in several animal models and, in humans, is well supported by numerous noninvasive imaging studies. Of specific importance is the emergence of 2 key cellular thalamic mechanisms, which come together to generate locally synchronized alpha activity. First, a novel form of rhythmic burst firing, termed high-threshold (HT) bursting, which occurs in a specialized subset of thalamocortical (TC) neurons, and second, the interconnection of this subset via gap junctions (GJs). Because repetitive HT bursting in TC neurons occurs in the range of 2 to 13 Hz, with the precise frequency increasing with increasing depolarization, the same cellular components that underlie thalamic alpha rhythms can also lead to theta (2-7 Hz) rhythms when the TC neuron population is less depolarized. As such, this scenario can explain both the deceleration of alpha rhythms that takes place during early sleep and the chronic slowing that characterizes a host of neurological and psychiatric disorders.

The thalamocortical network as a single slow wave-generating unit.

During non-REM sleep the EEG is dominated by slow waves which result from synchronized UP and DOWN states in the component neurons of the thalamocortical network. This review focuses on four areas of recent progress in our understanding of these events. Thus, it has now been conclusively demonstrated that the full expression of slow waves, both of natural sleep and anesthesia, requires an essential contribution by the thalamus. Furthermore, the modulatory role of brainstem transmitters, the function of cortical inhibition and the relative contribution of single neocortical neurons to EEG slow waves have started to be carefully investigated. Together, these new data confirm the view that a full understanding of slow waves can only be achieved by considering the thalamocortical network as a single functional and dynamic unit for the generation of this key EEG rhythm.