M-current modulation of cortical slow oscillations: Network dynamics and computational modeling

摘要

The slow oscillation is a synchronized network activity expressed by the cortical network in slow wave sleep and under anesthesia. Waking up requires a transition from this synchronized brain state to a desynchronized one. Cholinergic innervation is critical for the transition from slow-wave-sleep to wakefulness, and muscarinic action is largely exerted through the muscarinic-sensitive potassium current (M-current) block. We investigated the dynamical impact of blocking the M-current on slow oscillations, both in cortical slices and in a cortical network computational model. Blocking M-current resulted in an elongation of Up states (by four times) and in a significant firing rate increase, reflecting an increased network excitability, albeit no epileptiform discharges occurred. These effects were replicated in a biophysical cortical model, where a parametric reduction of the M-current resulted in a progressive elongation of Up states and firing rate. All neurons, and not only those modeled with M-current, increased their firing rates due to network recurrency. Further increases in excitability induced even longer Up states, approaching the microarousals described in the transition towards wakefulness. Our results bridge an ionic current with network modulation, providing a mechanistic insight into network dynamics of awakening. Author summaryDuring slow wave sleep we are unconscious and disconnected from the outside world, while when we wake we are conscious of ourselves and the world around us. These two different brain states, slow wave sleep and wakefulness, are rather different from a network dynamics perspective: highly synchronous and desynchronized, respectively. Furthermore, spatiotemporal complexity of activity patterns is low for slow wave sleep and high for wakefulness. What are the mechanisms driving the transition between these very different functional brain states? In the current study we investigated one mechanism that is critical for the sleep to wake transition to occur in the cerebral cortex network: the blockade of M-current by cholinergic action, and we did this both in experiments (in vitro) and in a computational model (in silico). We observed that the slow oscillations that dominate the synchronous activity are largely transformed by M-current blockade, the periods of activity or Up states becoming longer, and eventually generating microarousals that lead into wakefulness. In this study we bridge ionic channels, network dynamics, and brain states to understand how microscopic mechanisms determine macroscopic brain states and information processing capabilities.