Bursting of thalamic neurons and states of vigilance.

This article addresses the functional significance of the electrophysiological properties of thalamic neurons. We propose that thalamocortical activity, is the product of the intrinsic electrical properties of the thalamocortical (TC) neurons and the connectivity their axons weave. We begin with an overview of the electrophysiological properties of single neurons in different functional states, followed by a review of the phylogeny of the electrical properties of thalamic neurons, in several vertebrate species. The similarity in electrophysiological properties unambiguously indicates that the thalamocortical system must be as ancient as the vertebrate branch itself. We address the view that rather than simply relays, thalamic neurons have sui generis intrinsic electrical properties that govern their specific functional dynamics and regulate natural functional states such as sleep and vigilance. In addition, thalamocortical activity has been shown to be involved in the genesis of several neuropsychiatric conditions collectively described as thalamocortical dysrhythmia syndrome.

The reticular nucleus revisited: intrinsic and network properties of a thalamic pacemaker.

The intrinsic and network properties of thalamic reticular (RE) neurons, which release the potent inhibitory neurotransmitter gamma-aminobutyric acid (GABA), endow them with oscillatory properties within the frequency range of sleep spindles (7-15 Hz), a hallmark brain rhythm that characterizes early sleep stages. The original hypothesis that RE neurons are pacemakers of spindles, based on absence of this oscillation in thalamocortical (TC) systems after disconnection from RE nucleus and presence of spindle rhythmicity in the deafferented RE nucleus, is supported by new experimental results in vivo, in vitro and in computo showing that interactions through chemical synapses as well as electrical coupling among inhibitory RE neurons lead to generation and synchronization of spindle sequences within the nucleus. Besides their pacemaking role in spindle generation, RE neurons are crucially implicated in the inhibition of TC neurons during cortically generated spike-wave (absence) seizures, which may explain the obliteration of signals from the external world and unconsciousness during these epileptic fits.

The cortically evoked secondary depolarization affects the integrative properties of thalamic reticular neurons.

Corticothalamic terminals on thalamic reticular (RE) neurons account for most synapses from afferent pathways onto this nucleus and these inputs are more powerful than those from axon collaterals of thalamocortical neurons. Given the supremacy of cortical inputs, we analysed here the characteristics and possible mechanisms underlying a secondary component of the cortically elicited depolarization in RE neurons, recorded in cats under barbiturate anesthesia. Electrical stimulation of corticothalamic axons in the internal capsule evoked fixed and short-latency excitatory postsynaptic potentials (EPSPs) that, by increasing stimulation intensity and at hyperpolarized levels (< -70 mV), developed into low-threshold spikes and spindle oscillations. The threshold for spindle oscillations was 60% higher than that required for evoking minimal EPSPs. The evoked EPSPs included a secondary depolarizing component, which appeared approximately 5 ms after the peak of the initial component and was voltage dependent, i.e. most prominent between -70 mV and -85 mV, while being greatly reduced or absent at more hyperpolarized levels. The secondary depolarizing component was sensitive to QX-314 in the recording micropipette. We suggest that the secondary component of cortically evoked EPSPs in RE neurons is due to the dendritic activation of T-currents, with a probable contribution of the persistent Na+ current. This late component affected the integrative properties of RE neurons, including their spiking output and temporal summation of incoming cortical inputs.

Experimental evidence and modeling studies support a synchronizing role for electrical coupling in the cat thalamic reticular neurons in vivo.

Thalamic reticular (RE) neurons are crucially implicated in brain rhythms. Here, we report that RE neurons of adult cats, recorded and stained intracellularly in vivo, displayed spontaneously occurring spikelets, which are characteristic of central neurons that are coupled electrotonically via gap junctions. Spikelets occurred spontaneously during spindles, an oscillation in which RE neurons play a leading role, as well as during interspindle lulls. They were significantly different from excitatory postsynaptic potentials and also distinct from fast prepotentials that are presumably dendritic spikes generated synaptically. Spikelets were strongly reduced by halothane, a blocker of gap junctions. Multi-site extracellular recordings performed before, during and after administration of halothane demonstrated a role for electrical coupling in the synchronization of spindling activity within the RE nucleus. Finally, computational models of RE neurons predicted that gap junctions between these neurons could mediate the spread of low-frequency activity at great distances. These experimental and modeling data suggest that electrotonic coupling within the RE nucleus plays an important role in the generation and synchronization of low-frequency (spindling) activities in the thalamus.

Synaptic interactions between thalamic and cortical inputs onto cortical neurons in vivo.

To study the interactions between thalamic and cortical inputs onto neocortical neurons, we used paired-pulse stimulation (PPS) of thalamic and cortical inputs as well as PPS of two cortical or two thalamic inputs that converged, at different time intervals, onto intracellularly recorded cortical and thalamocortical neurons in anesthetized cats. PPS of homosynaptic cortico-cortical pathways produced facilitation, depression, or no significant effects in cortical pathways, whereas cortical responses to thalamocortical inputs were mostly facilitated at both short and long intervals. By contrast, heterosynaptic interactions between either cortical and thalamic, or thalamic and cortical, inputs generally produced decreases in the peak amplitudes and depolarization area of evoked excitatory postsynaptic potentials (EPSPs), with maximal effect at approximately 10 ms and lasting from 60 to 100 ms. All neurons tested with thalamic followed by cortical stimuli showed a decrease in the apparent input resistance (R(in)), the time course of which paralleled that of decreased responses, suggesting that shunting is the factor accounting for EPSP's decrease. Only half of neurons tested with cortical followed by thalamic stimuli displayed changes in R(in). Spike shunting in the thalamus may account for those cases in which decreased synaptic responsiveness of cortical neurons was not associated with decreased R(in) because thalamocortical neurons showed decreased firing probability during cortical stimulation. These results suggest a short-lasting but strong shunting between thalamocortical and cortical inputs onto cortical neurons.

Local gating of information processing through the thalamus.

Inhibitory sculpting of afferent signals in the thalamus is exerted by two types of neurons using gamma-amino butyric acid (GABA) as neurotransmitter. Of them, local-circuit neurons exert their functions via two outputs: axons and presynaptic dendrites. In this issue of Neuron, Govindaiah and Cox reveal that synaptic activation of metabotropic glutamate receptors selectively increases the output of presynaptic dendrites of local interneurons in rat visual thalamus, without affecting the axonal output.

The corticothalamic system in sleep.

The transition from wakefulness to NREM sleep is associated with typical signs of brain electrical activity, characterized by prolonged periods of hyperpolarization and increased membrane conductance in thalamocortical (TC) neurons, with the consequence that incoming messages are inhibited and the cerebral cortex is deprived of signals from the outside world. There are three major oscillations during NREM sleep. Spindles are generated within the thalamus, due to thalamic reticular (RE) neurons that impose rhythmic inhibitory sequences onto TC neurons, but the widespread synchronization of this rhythm is governed by corticothalamic projections. There are two types of delta activity: clock-like waves generated in TC neurons by the interplay between two hyperpolarization-activated inward currents; and cortical waves that survive extensive thalamectomy. The hallmark of NREM sleep activity is the slow oscillation, generated intracortically, which has the virtue of grouping the other types of sleep activities, thus leading to a coalescence of different rhythms that can only be observed in intact-brain animals and humans. Far from being epiphenomena, with no functional role, NREM sleep oscillations, particularly spindles and their experimental model augmenting responses, produce synaptic plasticity in target cortical neurons and resonant activity in corticothalamic loops, as in "memory" processes. Upon brain arousal, spindles are blocked by inhibition of RE neurons, the spindles' pacemakers; clock-like delta rhythm is obliterated by depolarization of TC neurons; and the cortically generated slow oscillation is abolished by selective erasure of its hyperpolarizing components. Fast (beta and gamma) oscillations are roduced by the depolarizing effects of mesopontine cholinergic neurons acting on TC neurons and nucleus basalis neurons acting on cortical neurons.

Electrophysiological properties and input-output organization of callosal neurons in cat association cortex.

Intracellular recordings from association cortical areas 5 and 7 were performed in cats under barbiturate or ketamine-xylazine anesthesia to investigate the activities of different classes of neurons involved in callosal pathways, which were electrophysiologically characterized by depolarizing current steps. Excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs), and/or antidromic responses were elicited by stimulating homotopic sites in the contralateral cortical areas. Differential features of EPSPs related to latencies, amplitudes, and slopes were detected in closely located (50 microm or less) neurons recorded in succession along the same electrode track. In contrast to synchronous thalamocortical volleys that excited most neurons within a cortical column, stimuli applied to homotopic sites in the contralateral cortex activated neurons at restricted cortical depths. Median latencies of callosally evoked EPSPs were 1.5 to 4 ms in various cortical cell-classes. Fast-rhythmic-bursting neurons displayed EPSPs whose amplitudes were threefold larger, and latencies two- or threefold shorter, than those found in the three other cellular classes. Converging callosal and thalamic inputs were recorded in the same cortical neuron. EPSPs or IPSPs were elicited by stimulating foci spaced by <1 mm in the contralateral cortex. In the overwhelming majority of neurons, latencies of antidromic responses were between 1.2 and 3.1 ms; however, some callosal neurons had much longer latencies,

Neuronal plasticity in thalamocortical networks during sleep and waking oscillations.

Spontaneous brain oscillations during states of vigilance are associated with neuronal plasticity due to rhythmic spike bursts and spike trains fired by thalamic and neocortical neurons during low-frequency rhythms that characterize slow-wave sleep and fast rhythms occurring during waking and REM sleep. Intracellular recordings from thalamic and related cortical neurons in vivo demonstrate that, during natural slow-wave sleep oscillations or their experimental models, both thalamic and cortical neurons progressively enhance their responsiveness. This potentiation lasts for several minutes after the end of oscillatory periods. Cortical neurons display self-sustained activity, similar to responses evoked during previous epochs of stimulation, despite the fact that thalamic neurons remain under a powerful hyperpolarizing pressure. These data suggest that, far from being a quiescent state during which the cortex and subcortical structures are globally inhibited, slow-wave sleep may consolidate memory traces acquired during wakefulness in corticothalamic networks. Similar phenomena occur as a consequence of fast oscillations during brain-activated states.

Model of thalamocortical slow-wave sleep oscillations and transitions to activated States.

During natural slow-wave sleep (SWS) in nonanesthetized cats, silent (down) states alternate with active (up) states; the down states are absent during rapid-eye-movement sleep and waking. Oscillations (<1 Hz) in SWS and transformation to an activated awake state were investigated with intracellular recordings in vivo and with computational models of the corticothalamic system. Occasional summation of the miniature EPSPs during the hyperpolarized (silent) phase of SWS oscillation activated the persistent sodium current and depolarized the membrane of cortical pyramidal (PY) cells sufficiently for spike generation. In the model, this triggered the active phase, which was maintained by lateral PY-PY excitation and persistent sodium current. Progressive depression of the excitatory interconnections and activation of Ca2+-dependent K+ current led to termination of the 20-25 Hz activity after 500-1000 msec. Including thalamocortical (TC) and thalamic reticular neurons in the model increased the duration of the active epochs up to 1-1.5 sec and introduced waning spindle sequences. An increase in acetylcholine activity, which is associated with activated states, was modeled by the reduction in the K+ leak current in PY and TC cells and by a decrease in intracortical PY-PY synaptic conductances. These changes eliminated the hyperpolarizing phases of network activity and transformed cortical neurons to tonic firing at 15-20 Hz. During the transition from SWS to the activated state, the input resistance of cortical neurons gradually increased and, in a fully activated state, reached the same or even higher values as during silent phases of SWS oscillations. The model describes many essential features of SWS and activated states in the thalamocortical system as well as the transition between them.

Frequency-selective augmenting responses by short-term synaptic depression in cat neocortex.

Thalamic stimulation at frequencies between 5 and 15 Hz elicits incremental or 'augmenting' cortical responses. Augmenting responses can also be evoked in cortical slices and isolated cortical slabs in vivo. Here we show that a realistic network model of cortical pyramidal cells and interneurones including short-term plasticity of inhibitory and excitatory synapses replicates the main features of augmenting responses as obtained in isolated slabs in vivo. Repetitive stimulation of synaptic inputs at frequencies around 10 Hz produced postsynaptic potentials that grew in size and carried an increasing number of action potentials resulting from the depression of inhibitory synaptic currents. Frequency selectivity was obtained through the relatively weak depression of inhibitory synapses at low frequencies, and strong depression of excitatory synapses together with activation of a calcium-activated potassium current at high frequencies. This network resonance is a consequence of short-term synaptic plasticity in a network of neurones without intrinsic resonances. These results suggest that short-term plasticity of cortical synapses could shape the dynamics of synchronized oscillations in the brain.