The application of auditory clicks during non‐rapid eye movement (NREM) sleep phase‐locked to the up state of the slow oscillation (closed‐loop stimulation) has previously been shown to enhance the consolidation of declarative memories. We designed and applied sequences of three clicks during deep NREM sleep to achieve a quasi‐phase‐dependent open‐loop stimulation. This stimulation was successful in eliciting slow oscillation power in the stimulation period. Although fast and slow spindle power were markedly decreased during the stimulation period, memory consolidation did not differ from control. During putative up states fast spindle power remained, however, at control levels. We conclude that concurrence of slow oscillations and fast spindles suffices to maintain memory consolidation at control levels despite an overall decreased spindle activity.

Time locking between neocortical sleep slow oscillations, thalamo-cortical spindles, and hippocampal sharp-wave ripples has convincingly been shown to be a key element of systems consolidation. Here we investigate the role of monosynaptic projections from ventral/intermediate hippocampus to medial prefrontal cortex (mPFC) in sleep-dependent memory consolidation in male mice. Following acquisition learning in the Barnes maze, we optogenetically silenced the axonal terminals of hippocampal projections within mPFC during slow-wave sleep. This silencing during SWS selectively impaired recent but not remote memory in the absence of effects on error rate and escape latencies. Furthermore, it prevented the development of the most efficient search strategy and sleep spindle time-locking to slow oscillation. An increase in post-learning sleep sharp-wave ripple (SPWR) density and reduced time locking of learning-associated SPWR activity to sleep spindles may be a less specific response. Our results demonstrate that monosynaptic projections from hippocampus to mPFC contribute to sleep-dependent memory consolidation, potentially by affecting the temporal coupling of sleep-associated electrophysiological events. SIGNIFICANCE STATEMENT Convincing evidence supports the role of slow-wave sleep (SWS), and the relevance of close temporal coupling of neuronal activity between brain regions for systems consolidation. Less attention has been paid so far to the specific neuronal pathways underlying these processes. Here, we optogenetically silenced the direct monosynaptic projection from ventral/intermediate hippocampus (HC) to medial prefrontal cortex (mPFC) during SWS in male mice following repeated learning trials in a weakly aversive spatial task. Our results confirm the concept that the monosynaptic projection between HC and mPFC contributes to memory consolidation and support an important functional role of this pathway in shaping the temporal precision among sleep-associated electrophysiological events.

Few models exist that accurately reproduce the complex rhythms of the thalamocortical system that are apparent in measured scalp EEG and at the same time, are suitable for large-scale simulations of brain activity. Here, we present a neural mass model of the thalamocortical system during natural non-REM sleep, which is able to generate fast sleep spindles (12–15 Hz), slow oscillations (<1 Hz) and K-complexes, as well as their distinct temporal relations, and response to auditory stimuli. We show that with the inclusion of detailed calcium currents, the thalamic neural mass model is able to generate different firing modes, and validate the model with EEG-data from a recent sleep study in humans, where closed-loop auditory stimulation was applied. The model output relates directly to the EEG, which makes it a useful basis to develop new stimulation protocols. Sleep plays a pivotal role for the consolidation of memory. While REM sleep had originally been the focus of research due to its similarity with wakefulness, more recent studies suggest that different sleep stages are responsible for the consolidation of different types of memory. To better understand the changes in neuronal dynamics between the different sleep stages, neural mass models are a valuable tool, as they relate directly to the large-scale dynamics measured by an EEG. Here, we present a model of the sleeping thalamocortical system. We first show that the isolated thalamic submodule is able to generate different oscillatory behavior found in vivo. Furthermore, the full thalamocortical model reproduces the EEG of sleep stages N2 and N3 and preserves the temporal relationship between cortical K-complexes/slow oscillations and thalamic sleep spindles. A comparison with event related potential data from a recent sleep study in humans demonstrates its possible application in predicting the outcome of external stimulation on EEG rhythms. Our study shows, that a neural mass model incorporating few key mechanisms is sufficient to reproduce the complex brain dynamics observed during sleep.

Newly acquired memory traces are spontaneously reactivated during slow-wave sleep (SWS), leading to the consolidation of recent memories. Empirical studies found that sensory stimulation during SWS can selectively enhance memory consolidation with the effect depending on the phase of stimulation. In this new study, we aimed to understand the mechanisms behind the role of sensory stimulation on memory consolidation using computational models implementing effects of neuromodulators to simulate transitions between awake and SWS sleep, and synaptic plasticity to allow the change of synaptic connections due to the training in awake or replay during sleep. We found that when closed-loop stimulation was applied during the Down states of sleep slow oscillation, particularly right before the transition from Down to Up state, it significantly affected the spatiotemporal pattern of the slow waves and maximized memory replay. In contrast, when the stimulation was presented during the Up states, it did not have a significant impact on the slow waves or memory performance after sleep. For multiple memories trained in awake, presenting stimulation cues associated with specific memory trace could selectively augment replay and enhance consolidation of that memory and interfere with consolidation of the others (particularly weak) memories. Our study proposes a synaptic-level mechanism of how memory consolidation is affected by sensory stimulation during sleep.SIGNIFICANCE STATEMENTStimulation, such as training-associated cues or auditory stimulation, during sleep can augment consolidation of the newly encoded memories. In this study, we used a computational model of the thalamocortical system to describe the mechanisms behind the role of stimulation in memory consolidation during slow-wave sleep. Our study suggests that stimulation preferentially strengthens memory traces when delivered at a specific phase of the slow oscillation, just before the Down to Up state transition when it makes the largest impact on the spatiotemporal pattern of sleep slow waves. In the presence of multiple memories, presenting sensory cues during sleep could selectively strengthen selected memories. Our study proposes a synaptic-level mechanism of how memory consolidation is affected by sensory stimulation during sleep.

Sleep is one of the most ubiquitous but also complex animal behaviors. It is regulated at the global, systems level scale by circadian and homeostatic processes. Across the 24-h day, distribution of sleep/wake activity differs between species, with global sleep states characterized by defined patterns of brain electric activity and electromyography. Sleep patterns have been most intensely investigated in mammalian species. The present review begins with a brief overview on current understandings on the regulation of sleep, and its interaction with aging. An overview on age-related variations in the sleep states and associated electrophysiology and oscillatory events in humans as well as in the most common laboratory rodents follows. We present findings observed in different studies and meta-analyses, indicating links to putative physiological changes in the aged brain. Concepts requiring a more integrative view on the role of circadian and homeostatic sleep regulatory mechanisms to explain aging in sleep are emerging.