Key concepts

Figure 1. Synaptic and systems levels of memory consolidation. In the first hours following acquisition, a memory trace is represented in specific neural circuits (in this example, within the hippocampus, highlighted in grey, (a)). The memory trace is then gradually integrated into a broader neuronal network, including areas not involved in acquisition (in this example, in the neocortex, (b)), and distributed over time throughout the neocortex (c). Synaptic consolidation (schematized in (d)) involves activation of NMDAR- and kinase-dependent signalling cascades which promote de novo mRNA and protein synthesis. NMDAR activation increases calcium (Ca²⁺) influx, whereas neurotransmitter-mediated activation of G protein-coupled receptors stimulate cyclic adenosine monophosphate (cAMP) production. These intracellular signals in turn promote the phosphorylation-dependent activation of kinases (e.g. PKA, CaMKII and extracellular signal-regulated kinase (ERK)) (Wang et al., 2006). These kinases activate cAMP response element-binding (CREB) protein-dependent immediate early gene (IEG) expression (e.g. zif268, arc/arg3.1, c-fos) (Abel and Lattal, 2001). Products of these transcripts are then translated, together with additional effectors of synaptic potentiation or depression (e.g. glutamate receptor subunits, and CaMKII). Systems consolidation (schematized in (e)) requires subsequent activation of CaMKII and synthetic pathways over a period of days to months (Wang et al., 2006), as memory traces expand through more broadly distributed brain areas.

Figure 2. Potential roles of sleep in synaptic and systems consolidation. (a) Representative changes in release of acetylcholine (ACh) and noradrenaline (NA) in the cortex (relative to waking) during REM and NREM sleep. Representative EEG traces for the two sleep states show cortical activity similar to that of waking during REM sleep, and high-amplitude EEG oscillations – including sleep spindles and slow-wave activity (SWA) – during NREM sleep. (b) Sequence of events showing the transfer over time of the memory trace from hippocampus to neocortical distributed network (see Figure 1a–c for detailed description). (c)–(e) Potential cellular mechanisms underlying sleep facilitation of consolidation. Functions demonstrated to occur specifically during sleep are shown in colour; mechanisms correlated with sleep (i.e. known to be active at the time when sleep is required for consolidation) are indicated with a question mark. Mechanisms that have not been studied with respect to sleep are shown in gray. (c) Mechanisms implicated in sleep facilitation of synaptic consolidation are schematized in a neuron within the circuits activated by prior learning (in this example, a neuron in the hippocampus). NMDAR activation during sleep may be necessary for some early forms of consolidation (Gais et al., 2008), whereas PKA, CaMKII and CREB activation and protein synthesis are correlated with the time-dependent requirement for sleep in other forms of learning (Bourtchouladze et al., 1998; Horn, 2004; Saha and Datta, 2005). Increased expression of the IEG zif268 occurs during REM sleep following some forms of learning (Ribeiro et al., 1999), whereas arc/arg3.1 and c-fos expression are correlated in time with the requirement for sleep following other learning paradigms (Horn, 2004; Bock et al., 2005). (d) The same signalling pathways may be activated in additional neural circuits during subsequent systems consolidation (schematized as a neuron in the neocortex which is synaptically connected with the original hippocampal neuron). Changes in neurotransmission or activity during sleep (e.g. synchronized bursting activity produced by SWA and spindles) could promote intercellular communication between these brain areas (represented by red arrows). During subsequent stages of systems consolidation (e), these same sleep-dependent mechanisms may promote further expansion of memory traces throughout the neocortex (indicated by red arrows).