Intrinsic and synaptic mechanisms of cortical active states generation during slow wave sleep

Without any sensory input cortical networks may display spontaneous transitions between silent (hyperpolarized) and active (depolarized) states. These transitions may be periodic as observed during slow-wave sleep or irregular as spontaneous burst generation found in the isolated neocortical slabs. In this paper we will review intrinsic and synaptic mechanisms mediating properties of spontaneous active states. We will present different hypotheses regarding initiation and termination of active network states and we will discuss the possible role of transitions between silent and active network states in learning and memory. 1. Slow wave sleep oscillations and active network states in thalamocortical system A signature of the slow-wave sleep in the electroencephalogram (EEG) are large-amplitude fluctuations of field potential [1], which reflect alternating periods of activity and silence in the thalamocortical networks [27]. Similar patterns were recorded in neostriatal neurons by Wilson and Kawaguchi [8] who introduced now widely used terms of “Up state” for the depolarizing phases of slow oscillation and “Down state” for the hyperpolarizing phases of slow oscillation. Similar to neocortical neurons [4, 6] Up and Down states in neostriatal neurons occurred only during slow wave sleep (SWS) [9]. Cortically generated slow oscillation was also found to entrain the thalamus [5, 10, 11]. Similar to neocortical and neostriatal neurons, both the thalamic reticular and thalamocortical neurons are hyperpolarized during depth-positive EEG waves due to disfacilitation, i.e. an absence of spontaneous synaptic activities [4, 12-14]. During depth-negative EEG waves, cortical, neostriatal and inhibitory thalamic reticular neurons are depolarized and fire spikes, while thalamocortical neurons are primarily hyperpolarized, reveal rhythmic IPSPs and occasionally fire rebound spikebursts [5, 10]. Thus, in the dorsal thalamus, the intracellular activities occurring during depth-negative EEG waves cannot be characterized as either depolarizing or Up state. For the purposes of this article, we used the terms „active states‟ for processes occurring during EEG depth-negative waves and „silent states‟ for processes occurring during EEG depth-positive waves. We believe that such terminology better represents the functional state of the thalamocortical network during the slow oscillations. Cortical active states generation during sleep 3 Survival of slow oscillations after extensive thalamic lesions [3] and the absence of slow oscillations in the thalamus of decorticated cats [15] point to an intracortical origin for this rhythm. Recent studies show that following activation of the metabotropic glutamate receptor (mGluR), mGluR1a, cortical inputs can recruit cellular mechanisms that enable the generation of an intrinsic slow oscillation in thalamocortical neurons in vitro with frequencies similar to those observed in vivo [16, 17]. Intracellular studies on anesthetized and non-anesthetized cats have shown that the hyperpolarizing phase of the slow oscillation is associated with disfacilitation, a temporal absence of synaptic activity in all cortical, thalamocortical and reticular thalamic neurons [6, 14, 15]. Even a moderate spontaneous hyperpolarization of thalamocortical neurons during depth-positive EEG waves is sufficient to displace them from firing threshold, thereby affecting transmission of information toward the cerebral cortex and thus creating disfacilitation [15, 18]. Responses to peripheral sensory stimuli still may reach cerebral cortex during sleep or anesthesia [19-27], but the precision of cortical network to respond to peripheral volley during disfacilitation periods is lost [24, 26]. The spike timing is critical in cortical information processing [28] and a minimal time interval of stable thalamocortical activity is required to achieve conscious perceptions [29]. Thus, the conscious perception is impaired during sleep and anesthesia, likely, because the lost of precision in the sensory information transfer from periphery to the cerebral cortex and the presence of silent states. During sleep in humans, each cycle of the slow oscillation is a traveling wave originating at a definite site and traveling over the scalp at an estimated speed of 1.2-7.0 m/sec [30]. In anesthetized cats the active states originated from the border of area 5-7 and propagated in anterior and posterior directions [31]. In vertical dimension, the active states start in lower cortical layers and progressively involve superficial layers [32] (see also chapter by Chauvette et al). This finding is congruent with previous in vitro study in which active states were found to start in lower or infragranular layers and to propagate in vitro [33]. The conditions under which active states can propagate in vivo and specific mechanisms of their synchronization still remain to be investigated. 2. Mechanisms underlying the generation of slow oscillation in neocortex At least two distinct mechanisms for the origin of slow cortical oscillations were proposed based on what causes the transition to the active (Up) state of the slow-sleep oscillation: (a) spontaneous mediator release in a large population of neurons leading to occasional summation and firing [34] Bazhenov and Timofeev 4 and (b) spontaneous intrinsic activity in layer 5 intrinsically bursting neurons [33]. Below we will discuss these two mechanisms as well as some other processes contributing to the periodic transitions between silent and active states during slow sleep oscillations. 2.1. Spontaneous mediator release and transitions to active