Typical human sleep profile and sleep-related signals. A: sleep is characterized by the cyclic occurrence of rapid-eye-movement (REM) sleep and non-REM sleep. Non-REM sleep includes slow-wave sleep (SWS) corresponding to N3, and lighter sleep stages N1 and N2 (). According to an earlier classification system by Rechtschaffen and Kales (), SWS was divided into stage 3 and stage 4 sleep. The first part of the night (early sleep) is dominated by SWS, whereas REM sleep prevails during the second half (late sleep). B: the most prominent electrical field potential oscillations during SWS are the neocortical slow oscillations (∼0.8 Hz), thalamocortical spindles (waxing and waning activity between 10–15 Hz), and the hippocampal sharp wave-ripples (SW-R), i.e., fast depolarizing waves that are generated in CA3 and are superimposed by high-frequency (100–300 Hz) ripple oscillation. REM sleep, in animals, is characterized by ponto-geniculo-occipital (PGO) waves, which are associated with intense bursts of synchronized activity propagating from the pontine brain stem mainly to the lateral geniculate nucleus and visual cortex, and by hippocampal theta (4–8 Hz) activity. In humans, PGO and theta activity are less readily identified. C: sleep is accompanied by a dramatic change in activity levels of different neurotransmitters and neuromodulators. Compared with waking, cholinergic activity reaches a minimum during SWS, whereas levels during REM sleep are similar or even higher than those during waking. A similar pattern is observed for the stress hormone cortisol. Aminergic activity is high during waking, intermediate during SWS, and minimal during REM sleep. [Modified from Diekelmann and Born ().]

Effects of sleep and wake intervals of different length after learning on memory for senseless syllables. Sleep after learning leads to superior recall of syllables after the 1-, 2-, 4-, and 8-h retention interval, compared with wake intervals of the same length. Two subjects (H. and Mc.) participated in this classic study by Jenkins and Dallenbach (). For each data point, each participant completed 6–8 trials, with the different retention intervals performed in random order. The study took ∼2 mo during which the participants lived in the laboratory and were tested almost every day and night. Data are based on Table 3 in Reference , as the original figure contains an erroneous exchange of data points at the 4-h wake retention interval. Values are means ± SE. **P ≤ 0.01; ***P ≤ 0.001.

A model of active system consolidation during sleep. A: during SWS, memories newly encoded into a temporary store (i.e., the hippocampus in the declarative memory system) are repeatedly reactivated, which drives their gradual redistribution to the long-term store (i.e., the neocortex). B: system consolidation during SWS relies on a dialogue between neocortex and hippocampus under top-down control by the neocortical slow oscillations (red). The depolarizing up phases of the slow oscillations drive the repeated reactivation of hippocampal memory representations together with sharp wave-ripples (green) and thalamo-cortical spindles (blue). This synchronous drive allows for the formation of spindle-ripple events where sharp wave-ripples and associated reactivated memory information becomes nested into succeeding troughs of a spindle (shown at larger scale). In the black-and-white version of the figure, red, green, and blue correspond to dark, middle, and light gray, respectively. [Modified from Born and Wilhelm ().]

Odor-induced reactivations during SWS benefit memory consolidation. A: procedures: participants learned a visuospatial memory task (card-pair locations) in the presence of an odor. During subsequent SWS, they were either reexposed to the same odor serving as a cue to induce memory reactivations, or received an odorless vehicle. After sleep, retrieval was tested (in the absence of the odor). B: odor-induced reactivation of memories during SWS distinctly increased memory for card-pair locations, compared with vehicle condition. In a control experiment, retention of card-pairs remained unchanged when the odor was not administered during learning, excluding unspecific effects of odor exposure on memory processing during sleep. [Modified from Rasch et al. (), with permission from American Association for the Advancement of Science.] C: only reexposure during SWS to the same odor as during learning effectively enhanced card-pair memory (congruent odor condition), whereas an odor different from that administered during learning (incongruent condition) was not effective. (Data from Rihm et al., unpublished observation). D: odor-induced reactivations during SWS immediately stabilized memories against interference (induced by learning an interference card-pair task shortly after reactivations during SWS). In contrast and consistent with reconsolidation theory, odor-induced reactivations during wakefulness destabilized memories, as indicated by an impaired card-pair recall when reactivations during waking were followed by learning an interference card-pair task. [Data from Diekelmann et al. ().] E: odor-induced reactivations of memories during SWS activated the left hippocampus as revealed by functional magnetic resonance imaging (fMRI). Values are means ± SE: *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. [Modified from Rasch and Born (), with permission from Elsevier.]

Probing the functional relevance of slow oscillatory activity for memory processes by transcranial direct current stimulation (tDCS). A: procedures: participants learned declarative and nondeclarative tasks before sleep and recall was tested in the next morning. During early postlearning non-REM sleep, tDCS oscillating at different frequencies was applied via electrodes attached bilaterally over the prefrontal cortex and to the mastoids. In a sham control condition, no current was applied. B and C: effects of tDCS depend on frequency of the oscillating stimulation. B: tDCS during non-REM sleep oscillating at the 0.75 Hz slow oscillation frequency (SO-tDCS) increased endogenous slow oscillation activity (0.5–1 Hz) at all recording sites and slow frontal spindle activity (8–12 Hz), and these effects were associated with an enhanced retention (consolidation) of declarative memory (for word pairs) across sleep, compared with the sham condition. [Data from Marshall et al. ().] C: in contrast, tDCS oscillating at 5 Hz (theta-tDCS) decreased slow oscillation activity at all recording sites and slow frontal spindle activity, and these effects were associated with an impaired retention of declarative memory across sleep. [Data from Marshall et al. ().] D: effects of SO-tDCS depend on brain state: when applied during waking (rather than during non-REM sleep), tDCS induced a widespread increase in 4–8 Hz theta and 16–14 Hz beta activity, rather than slow oscillation activity, and these increases were associated with an enhanced encoding of declarative memory (for words), particularly in later learning trials (R5, R6), whereas consolidation across the wake retention interval remained unaffected (not shown). Values are means ± SE: *P ≤ 0.05; **P ≤ 0.01. [Data from Kirov et al. ().]

Influence of cholinergic activity on memory consolidation during wakefulness and sleep. A: concept: during active waking, acetylcholine (ACh) levels are high. Information encoded by neocortical structures flows through the entorhinal cortex and dentate gyrus (DG) into hippocampal region CA3 (connections less sensitive to modulation by ACh; thick arrows). Connections suppressed by ACh modulation (dashed arrows) to region CA1, entorhinal cortex, and association cortex are strong enough to mediate immediate retrieval, but do not overwhelm the feed-forward connectivity, ensuring efficient encoding. In contrast, during SWS, ACh levels are low, and memories are reactivated in region CA3 during sharp wave-ripples (SW-Rs). These waves of activity flow back through region CA1 to entorhinal cortex and neocortex, enabling an efficient redistribution of memory representation (system consolidation) underlying long term memory storage. [Adapted from Hasselmo (), with permission from Elsevier.] B: in accordance with the model, increasing cholinergic tone in humans by administration of the acetylcholineesterase inhibitor physostigmine during postlearning SWS impairs consolidation of declarative memory (word pairs) during sleep, compared with placebo. In contrast, combined blockade of muscarinic and nicotinic cholinergic receptors during a postlearning wake interval (by administration of scopolamine and mecamylamine) enhanced consolidation of declarative memory (word pairs) during this wake interval. Simultaneously, the combined receptor blockade impaired new encoding (of numbers). Values are means ± SE: *P ≤ 0.05; **P ≤ 0.01. [Data from Gais and Born () and Rasch et al. ().]

Different time courses of plasticity in the hippocampus and neocortex. A: concept: the hippocampus undergoes a few plasticity waves before fading out. These plasticity waves are probably enough for memories to remain in the hippocampus for weeks or months. In contrast, the cerebral cortex undergoes plasticity waves for a much longer period of time, leading to many more cycles of memory reinforcement and years-old memories. B: in single neuron recordings in rats, long-lasting firing rate increases after novel spatio-tactile stimulation (EXP) occurred during SWS in primary somatosensory cortex (S1), but not in the hippocampus (HP) or primary visual cortex (V1). Increased neuronal activity persisted for hours after experience offset during SWS in S1. Shown are the normalized firing rates during concatenated SWS episodes spanning an entire representative experiment. Ticks at the bottom indicate SWS episode boundaries. C: model of memory propagation from hippocampus to neocortex during sleep. Via thalamo-cortical inputs (not shown), episodic and spatial memories are acquired during waking as new synaptic changes (red) distributed over hippocampocortical networks of neurons (top panel). The recurrence of cortical plasticity during subsequent sleep causes the stabilization and propagation of new synaptic changes in the neocortex. Conversely, the fast decay of sleep-dependent plasticity in the hippocampus generates a net outflow of information, gradually flushing memories to associated cortical networks over time. [Modified from Ribeiro et al. ().]

Sleep-dependent formation and reactivation of song memory in birds. A: the measure of Wiener entropy variance (EV) of song structures reveals a continuous improvement in song structure in young birds over the 45-day developmental period starting with the first exposure to the tutor song (start of training). In spite of this overall improvement, during early development (day 46, middle panel) overnight sleep induces an acute decrease in song performance as indicated by a stronger deviation in song structure in the morning after sleep compared with presleep performance. This overnight decrease is not any more present in the end of the learning period (day 89, right panel). Bottom panel indicates continuous tracking of EV values over the 45-day period. [Modified from Derégnaucourt et al. (), with permission from Nature Publishing Group.] B: neuronal trace of an arcopallium (RA) neuron emitting 10 distinct bursts of 2–7 spikes/burst (”singing“). The bursts are precisely timed to when the bird sang a song whose motif consisted of a sequence of five syllables (see spectrograph, frequency vs. time representation; top). For each song bout, the sequence of syllables and the structure of each spike burst (timing of spikes and numbers of spikes) were highly reliable. The same pattern of spike-bursts reoccurred during recording during sleep. [Modified from Dave and Margoliash (), with permission from American Association for the Advancement of Science.]

Sleep supports the initiation of an adaptive immune response. A: concept: the invading antigen is taken up and processed by antigen presenting cells (APC) which present fragments of the antigen to T helper (Th) cells, with the two kinds of cells forming an “immunological synapse.” The concomitant release of interleukin (IL)-12 by APC induces a Th1 response that supports the function of antigen-specific cytotoxic T cells and initiates production of antibodies by B cells. This response finally generates long-lasting immunological memory for the antigen. Sleep, in particular slow wave sleep (SWS), and the circadian system act in concert to generate a proinflammatory hormonal milieu with enhanced growth hormone and prolactin release and reduced levels of the anti-inflammatory stress hormone cortisol. The hormonal changes in turn support the early steps in the generation of an adaptive immune response in the lymph nodes. In analogy to neurobehavioral memory formed in the central nervous system, the different phases of immunological memory might be divided in an encoding, a consolidation, and a recall phase. In both the central nervous system and the immune system, sleep specifically supports the consolidation stage of the respective memory types. [Modified from Besedovsky et al. ().] B: sleep enhances the hepatitis A virus (HAV)-specific T helper (Th) cell response to vaccination (three shots at weeks 0, 8, and 16, vertical syringes) in two groups of human subjects who either slept (black circle, thick line) or stayed awake (white circle, thin line) in the night following inoculations. The immune response as indicated by the frequency of CD40L+ HAV-specific Th cells (percentage of total Th cells) at weeks 18–20 (left panel) and particularly at week 52 (right panel) is strongly predicted by the amount of slow wave activity (averaged across the three postinoculation nights). Values are means ± SE: *P ≤ 0.1; **P ≤ 0.05; ***P ≤ 0.01. [Data from Lange et al. ().]