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Graphical Abstract

There is a long-standing division in memory research between hippocampus-dependent memory and non-hippocampus-dependent memory, as only the latter can be acquired and retrieved in the absence of normal hippocampal function1,2. Consolidation of hippocampus-dependent memory, in particular, is strongly supported by sleep3–5. Here we show that the formation of long-term representations in a rat model of non-hippocampus-dependent memory depends not only on sleep but also on activation of a hippocampus-dependent mechanism during sleep. Rats encoded non-hippocampus-dependent (novel-object recognition6–8) and hippocampus-dependent (object–place recognition) memories before a two-hour period of sleep or wakefulness. Memory was tested either immediately thereafter or remotely (after one or three weeks). Whereas object–place recognition memory was stronger for rats that had slept after encoding (rather than being awake) at both immediate and remote testing, novel-object recognition memory profited from sleep only three weeks after encoding, at which point it was preserved in rats that had slept after encoding but not in those that had been awake. Notably, inactivation of the hippocampus during post-encoding sleep by intrahippocampal injection of muscimol abolished the sleep-induced enhancement of remote novel-object recognition memory. By contrast, muscimol injection before remote retrieval or memory encoding had no effect on test performance, confirming that the encoding and retrieval of novel-object recognition memory are hippocampus-independent. Remote novel-object recognition memory was associated with spindle activity during post-encoding slow-wave sleep, consistent with the view that neuronal memory replay during slow-wave sleep contributes to long-term memory formation. Our results indicate that the hippocampus has an important role in long-term consolidation during sleep even for memories that have previously been considered hippocampus-independent.

Research in rats using preferences during exploration as a measure of memory has indicated that sleep is important for the consolidation of episodic-like memory, i.e., memory for an event bound into specific spatio-temporal context. How these findings relate to human episodic memory is unclear. We used spontaneous preferences during visual exploration and verbal recall as, respectively, implicit and explicit measures of memory, to study effects of sleep on episodic memory consolidation in humans. During encoding before 10-h retention intervals that covered nighttime sleep or daytime wakefulness, two groups of young adults were presented with two episodes that were 1-h apart. Each episode entailed a spatial configuration of four different faces in a 3 × 3 grid of locations. After the retention interval, implicit spatio-temporal recall performance was assessed by eye-tracking visual exploration of another configuration of four faces of which two were from the first and second episode, respectively; of the two faces one was presented at the same location as during encoding and the other at another location. Afterward explicit verbal recall was assessed. Measures of implicit and explicit episodic memory retention were positively correlated (r= 0.57, P< 0.01), and were both better after nighttime sleep than daytime wakefulness (P< 0.05). In the sleep group, implicit episodic memory recall was associated with increased fast spindles during nonrapid eye movement (NonREM) sleep (r= 0.62, P< 0.05). Together with concordant observations in rats our results indicate that consolidation of genuinely episodic memory benefits from sleep.

Mammalian sleep comprises the stages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Additionally, a transition state is often discriminated which in rodents is termed intermediate stage (IS). Although these sleep stages are thought of as unitary phenomena affecting the whole brain in a congruent fashion, recent findings have suggested that sleep stages can also appear locally restricted to specific networks and regions. Here, we compared in rats sleep stages and their transitions between neocortex and hippocampus. We simultaneously recorded the electroencephalogram (EEG) from skull electrodes over frontal and parietal cortex and the local field potential (LFP) from the medial prefrontal cortex and dorsal hippocampus. Results indicate a high congruence in the occurrence of sleep and SWS (>96.5%) at the different recording sites. Congruence was lower for REM sleep (>87%) and lowest for IS (<36.5%). Incongruences occurring at sleep stage transitions were most pronounced for REM sleep which in 36.6 per cent of all epochs started earlier in hippocampal LFP recordings than in the other recordings, with an average interval of 17.2 ± 1.1 s between REM onset in the hippocampal LFP and the parietal EEG (p < 0.001). Earlier REM onset in the hippocampus was paralleled by a decrease in muscle tone, another hallmark of REM sleep. These findings indicate a region-specific regulation of REM sleep which has clear implications not only for our understanding of the organization of sleep, but possibly also for the functions, e.g. in memory formation, that have been associated with REM sleep.