Sleep slow oscillation and inhibition

When we fall asleep, fast electrical brain activities are progressively replaced by slower rhythms. The major sleep rhythm is the slow oscillation, the cortically generated brain rhythm with a frequency around 1 Hz. This rhythm coordinates activities of multiple other cortical rhythms. The slow oscillation was initially described and investigated by Steriade and his co-workers in the early 1990s. They describe the slow oscillation (<1 Hz) in anaesthetized cats as an alternation of depolarizing and hyperpolarizing states of cortical neurons. A follow-up study that used simultaneous local field potential (LFP) and intracellular recordings in anaesthetized cats demonstrated that cortical hyperpolarization and silence correspond to depth-positive (surface-negative) waves of LFP and cortical depolarization corresponds to depth-negative (surface-positive) waves of LFP (Contreras & Steriade, 1995). The depolarizing components of the slow oscillation are essentially composed of excitatory and inhibitory synaptic events, and dendritic Ca2+ spikes occurring in both excitatory and inhibitory cortical neurons from all cortical layers; they are therefore often called active or UP states. During cortical active states, inhibitory activities dominate over excitation. By contrast, hyperpolarizing states are periods of disfacilitation, the network state at which synaptic activities are largely absent. Therefore, they are called silent or DOWN states. The slow oscillation originates in neocortex. It exists not only during slow-wave sleep, but also in isolated cortical slabs in vivo, in neocortical slices and in cortical cell cultures in vitro. The cortical slow oscillation has multiple subcortical controllers that influence its overall frequency or duration of active or silent states. Activation of neuromodulatory systems blocks the slow oscillation and after such activation the neocortex goes to permanent active states, which is characteristic of waking or rapid eye movement sleep. Blockage of thalamic inputs to the cortex dramatically increases the duration of cortical silent states (Lemieux et al. 2014). A recent study demonstrated that claustrum neurons provide a very efficient global control of cortical slow wave activity (Narikiyo et al. 2020). Not only do claustrum neurons increase their firing prior to the onset of silent state, but they effectively trigger the firing of parvalbumin-expressing GABAergic neurons immediately before the onset of silent state. Taken together with several previous findings of possible thalamic activation of cortical inhibitory interneurons, one can conclude that the subcortical control of the slow oscillation is primarily mediated via an activation of inhibition that precedes the onset of silent states. A vast majority of previous studies have demonstrated that GABAA (Cl−)-dependent inhibition was critically involved. In this issue of The Journal of Physiology, Perez-Zabalza et al. (2020) provide evidence for a strong involvement of GABAB inhibition in control of the cortical slow oscillation. The study consists of two major experimental approaches: electrophysiology in vitro, and computational modelling. Slices of ferret brain placed in an artificial cerebrospinal solution displayed slow oscillation patterns. The authors provide clear and strong evidence that blockage of GABAB receptors consistently prolongs duration of UP states, suggesting that activation of GABAB receptors helps to terminate UP states in agreement with the findings of Mann et al. (2009). Effects on DOWN state duration were variable. In about 75% of cases (typical network), blockage of GABAB receptors increased the duration of DOWN states, but in the remaining cases (atypical network), the same procedure decreased the duration of DOWN states, showing that the same effect in UP states is compatible with opposite changes in the subsequent DOWN states. The blockage of GABAB receptors also resulted in an increase in the regularity of slow oscillation, suggesting that the physiological activation of GABAB receptors introduces irregularity and richness in the temporal patterns. Similar changes occurred in both superficial and deep cortical layers. The possible mechanisms of the network effects of GABAB receptor blockage were investigated in a computational model. In the model, progressively growing excitation led to the onset of UP states. Fast inhibition was followed by excitation with millisecond precision. The adaptation current led to the termination of UP states, generating a rather regular cycle. In these conditions, adding GABAB current invariantly increased the total inhibitory drive and the network went to the DOWN state faster, because the balance was shifted toward inhibition and dominating inhibition terminated self-sustained activity during UP states. The difference between typical and atypical network was modelled by manipulations of NMDA conductance and the adaptation current. In a typical network, the NMDA current was stronger, but to maintain the overall duration of the UP state, it was compensated by a larger adaptation current. Blockage of GABAB inhibition increased the overall adaptation current. Because the adaptation current is less stochastic than synaptic activities, it also decreased the variability of DOWN state duration. The overall stronger excitatory drive during the UP state increased the duration of following DOWN states. The conclusions of the study are clear and very straightforward. What remains to be done in future is to demonstrate that GABAB inhibition indeed plays a significant role in the generation of slow oscillation during sleep. Indeed, in this study, the UP states lasted roughly up to 0.5 s and DOWN states lasted somewhere between 2 and 3 s. However, there is a large range of variability of UP/DOWN durations depending on the brain state: e.g. slow-wave sleep, type of anaesthesia or anaesthesia