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 slow (<1 Hz) rhythm, the most significant EEG signature of non-rapid eye movement (NREM) sleep, is generally viewed as originating exclusively from neocortical networks. Here we argue that the full manifestation of this fundamental sleep oscillation within a corticothalamic module requires the dynamic interaction of three cardinal oscillators: a predominantly synaptically-based cortical oscillator and two intrinsic, conditional thalamic oscillators. The functional implications of this hypothesis are discussed in relation to other key EEG features of NREM sleep, with respect to coordinating activities in local and distant neuronal assemblies and in the context of facilitating cellular and network plasticity during slow wave sleep.Although membrane potential fluctuations at a low frequency had already been observed in neurons of the rat cortex in vivo 1 , the discovery of the slow (<1 Hz) rhythm in the EEG, and of its cellular counterpart, the slow (<1 Hz) oscillation, rests with the pioneering work of Mircea Steriade and his coworkers 2 -4 . In 1993, using intracellular microelectrode recordings from morphologically identified neurons in different layers of the sensory, motor and association cortex of anesthetized cats (Fig. 1a), these authors described the presence of a slow oscillation of the membrane potential, consisting of regularly repeating sequences of depolarizations (most often with firing) and hyperpolarizations (with no firing) at a low (0.2 -0.9 Hz) frequency 2 , 3 , which are nowadays commonly referred to as UP and DOWN states, respectively (Figs. 1b and 2a) (Supplementary Note A). The slow oscillation was also present in the glutamatergic thalamocortical (TC) neurons of various thalamic nuclei and in the GABAergic neurons of the nucleus reticularis thalami (NRT), with the respective UP and DOWN states showing good temporal correlation with the corresponding cortical states and with the respective negative and positive depth-EEG waves 4 (Figs. 1b and 2b,c). Other key findings from that original series of studies were that the slow oscillation could group together periods of sleep spindles and delta waves during its UP and DOWN states 2 , 3 , respectively, and that it was present in a cerveau isolé preparation 3 . Moreover, the slow oscillation in cortex was shown to survive electrolytic lesions of extensive thalamic territories or destruction of TC neurons by kainic acid 3 , leading to the conclusion that this rhythm is generated in the neocortex and then imposed on recipient thalamic territories 4 .In the intervening 16 years, extensive and ground-breaking investigations of the slow (<1 Hz) rhythm/oscillation, both in humans and in experimental animals, have now have provided us with a remarkably detailed picture of the salient features of this brain activity 5 -14 , powerful insights into its intricate mechanisms 15 -25 and a clear window into its potential physiological significance 26 -33 . However, despite the presence of compelling evidence to the contrary 4 , 15 , 18 , 20 , 34 -...

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.

Tonic GABA A receptor-mediated inhibition is typically generated by ␦ subunit-containing extrasynaptic receptors. Because the ␦ 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 M) 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 M GABA increased tonic current amplitude to ϳ70 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 ␦ 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 M). 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.