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.

Spindle oscillations are commonly observed during stage 2 of non-rapid eye movement sleep. During sleep spindles, the cerebral cortex and thalamus interact through feedback connections. Both initiation and termination of spindle oscillations are thought to originate in the thalamus based on thalamic recordings and computational models, although some in vivo results suggest otherwise. Here, we have used computer modeling and in vivo multisite recordings from the cortex and the thalamus in cats to examine the involvement of the cortex in spindle oscillations. We found that although the propagation of spindles depended on synaptic interaction within the thalamus, the initiation and termination of spindle sequences critically involved corticothalamic influences.

Epileptic seizures are characterized by periods of recurrent, highly synchronized activity that spontaneously terminates, followed by postictal state when neuronal activity is generally depressed. The mechanisms for spontaneous seizure termination and postictal depression remain poorly understood. Using a realistic computational model, we demonstrate that termination of seizure and postictal depression state may be mediated by dynamics of the intracellular and extracellular ion concentrations. Spontaneous termination was linked to progressive increase of intracellular sodium concentration mediated by activation of sodium channels during highly active epileptic state. In contrast, an increase of intracellular chloride concentration extended seizure duration making possible long-lasting epileptic activity characterized by multiple transitions between tonic and clonic states. After seizure termination, the extracellular potassium was reduced below baseline, resulting in postictal depression. Our study suggests that the coupled dynamics of sodium, potassium, and chloride ions play a critical role in the development and termination of seizures. Findings from this study could help identify novel therapeutics for seizure disorder.

Key points: A signature of deep sleep in the EEG is large‐amplitude fluctuation of field potential, which reflects alternating periods of activity and silence in the thalamocortical network. Transitions between active and silent states of sleep slow oscillation are well synchronous between remote populations of neurons with the onsets of silent states synchronized better than the onsets of activity. We found that synaptic inhibition plays a major role in terminating active cortical states; strong synaptic inhibition is necessary to synchronize onsets of silent states during normal sleep slow oscillation. We further show that when synaptic inhibition is significantly reduced, active state termination is mediated by intrinsic hyperpolarizing conductances. Our study suggests that inhibitory interaction in the cortical network actively mediates the patterns of neural activity during slow‐wave sleep and may, therefore, contribute to various brain functions developed during deep sleep. Abstract  The signature of slow‐wave sleep in the electroencephalogram (EEG) is large‐amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron‐mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure‐like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms.