Sleep is an evolutionarily conserved biological process observed in the animal kingdom. Invertebrates such as Drosophila, C. elegans, and even Hydra show sleep-like behavior (Cirelli et al., 2005; Koh et al., 2008; Raizen et al., 2008; Guo et al., 2016; Kanaya et al., 2020). In mammals, sleep stages can be subdivided into rapid eye movement (REM) sleep and non-REM (NREM) phases. During NREM sleep the activity of the skeletal muscle is reduced and the EEG is dominated by slow, high amplitude synchronous oscillations while in REM sleep the EEG activity is more similar to the awake brain state. There are also smaller building blocks of sleep stages. For instance, NREM sleep is often interrupted by brief epochs, which based on their EEG and EMG signatures, show remarkable reminiscence to awake states, thus, they are often referred to as microarousals (MAs). These events can be captured as brief motor bursts on the EMG signal and by abrupt alternations of low frequency oscillatory patterns in EEG recordings (Lo et al., 2004; Bartsch et al., 2012; dos Santos Lima et al., 2019). Even though MAs are natural parts of the sleep architecture, the function of these events is largely unknown.

Sleep is a fundamental biological process that plays a crucial role in many physiological functions. Studies using various model organisms have demonstrated that severe sleep loss or total sleep deprivation can even have fatal effects (Bentivoglio and Grassi-Zucconi, 1997; Rechtschaffen et al., 1983; Shaw et al., 2002). While the exact biological function of sleep is not fully understood, research has suggested that it plays a crucial role in memory consolidation, which is the process of converting newly acquired memories into a permanent form. The supportive evidence for this hypothesis is quite rich although far from consolidated. Current models suggest that slow wave sleep, which makes up deeper stages of NREM sleep, processes declarative memory and it requires the active participation of the hippocampus through the replay of episodic memory traces captured during waking hours (Buzsáki, 1989; Klinzing et al., 2019). While the role of hippocampal CA1 and CA3 subareas in this process is extensively studied, less is known about the contribution of the dentate gyrus (DG) which is the first station of the classic trisynaptic loop and located upstream from CA3. The main glutamatergic cell types of the DG are the granule cells (GCs) located in the granule cell layer and the mossy cells (MCs) which populate the hilus or polymorph layer between the upper and lower blades of the GC layers (Amaral, 1978). Experimental work has shown that GCs and MCs form a functional unit to perform pattern separation during active exploration (Senzai and Buzsáki, 2017; GoodSmith et al., 2017; Danielson et al., 2017), a neuronal mechanism by which distinct memory traces can be created even if the input pattern is highly overlapping. Furthermore, it has been also shown that in awake immobile mice, the DG generates sparse, synchronized activity patterns driven by inputs from the entorhinal cortex (Pofahl et al., 2021).

Sleep/wake cycles are regulated by various monoaminergic and peptidergic cell groups located throughout the hypothalamus and brainstem. Among the monoaminergic neuromodulators, the serotonin (5-HT) system has been shown to promote wakefulness and suppress REM sleep (Monti, 2011; Jouvet, 1999). It is widely accepted in the field that 5-HT release is reduced during NREM sleep, and 5-HT cells become entirely silent during REM sleep (Jouvet, 1999; Lee and Dan, 2012). Serotonin is also recognized as one of the primary neuromodulatory inputs to the DG and a substantial body of evidence implicates that genetic manipulation of 5-HT or 5-HT-related genes has a profound impact on a broad range of hippocampal processes, including anxiety behavior, learning and memory (Luchetti et al., 2020; Yoshida et al., 2019; Santarelli et al., 2003; Caspi et al., 2010; Holmes et al., 2003; Teixeira et al., 2018). Serotonin receptors are expressed throughout the dorsoventral axis of the hippocampus (Tanaka et al., 2012), with GCs expressing both the inhibitory Htr1a and excitatory Htr4 receptor subtypes and about a quarter of MCs expressing the excitatory Htr2a receptors (Tanaka et al., 2012). Furthermore, the mesopontine Median Raphe Nucleus plays a role in memory-related hippocampal ripple oscillations (Wang et al., 2015; Jelitai et al., 2021). Together these findings suggest that the 5-HTergic system has a strong impact on hippocampal functions.

In this study, we investigated the activity of GCs and MCs during sleep-wake cycles and their modulation by the 5-HT system. We found that both glutamatergic cell types – especially GCs – exhibit higher activity during specific sleep stages compared to wakefulness, and the calcium activity is organized to infraslow oscillatory (ISO) cycles during NREM sleep epochs. Our further findings obtained by recording from major 5-HTergic cell populations in the raphe and by manipulating specific 5-HT receptor subtypes suggest that the slow oscillatory activity in the DG is regulated by an ISO of the 5-HT system oscillating in the opposite phase during NREM which is also tightly coupled to MA events. Genetic knockdown of Htr1a receptors in the DG impairs the ISOs and contextual fear memory, suggesting a key role for this inhibitory 5-HT receptor in governing the oscillatory effect.

In this study, we demonstrated that major glutamatergic cell types of the DG, the GCs and MCs, display ISO activity (1–2 cycles/min or 0.02–0.03 Hz) during NREM sleep (Figures 1 and 2) but not during awake or REM periods. Our two-photon calcium imaging data shows that this oscillation is mainly driven by NREM-active glutamatergic cells (about 50% of GCs and 28% of MCs, Figure 3). Furthermore, we found that the ISO is negatively correlated with phasic 5-HT release in raphe nuclei during NREM sleep (Figures 4 and 5). Finally, we showed that local genetic ablation of Htr1a receptors in GCs impaired the ISO and fear memory recall a week after contextual fear conditioning (Figure 6). Taken together, our findings demonstrate that the serotonin system plays a pivotal role in modulating DG activity during NREM sleep.

MCs and GCs are two major cell populations of DG which are thought to be involved in pattern separation and other cognitive functions in awake animals (Senzai and Buzsáki, 2017; GoodSmith et al., 2017; Danielson et al., 2017; Kim et al., 2020). The activity of GCs and MCs has been investigated with both electrophysiological and imaging tools and the available data suggests that both cell types are significantly more active during sleep (Senzai and Buzsáki, 2017; Pofahl et al., 2021; Jung and McNaughton, 1993) than wakefulness. However, to our knowledge, ours is the first report showing that the population activity is dynamically rendered to ISO pattern during NREM sleep which is organized by at least one of the neuromodulatory systems, the 5-HT.

Two-site photometry recordings revealed a tight coupling between the activity of the raphe and the DG. During awake periods we detected a strong positive correlation between the two regions, whereas during NREM intervals this activity became strongly anticorrelated. In REM sleep, we detected a greater variability of correlation across animals, which cannot be attributed to serotonin, as most neuromodulatory systems are silent during REM sleep. Rather, varied DG activity during REM sleep across recording sessions may contribute to this variability.

There is much less available data on the activity pattern of MCs and GCs during MA episodes. Here, we showed that about 50% of putative GCs and 28% of putative MCs are upregulated during NREM and their activity is abruptly terminated by MAs.

We also observed that local downregulation of Htr1a receptors disrupts the ISO, suggesting that the 5-HT is directly involved in the regulatory mechanisms of this oscillatory process. Htr1a receptors are expressed by GCs which suggest that the inhibitory effect is mediated via this cell type. Since MCs are driven by GCs via highly efficient ‘detonator’ type of synapses, our current working hypothesis is that MC excitation is driven by GCs during NREM. We speculate that the drop of the calcium activity in MCs during the ISO is not mediated by serotonin but rather it is the result of the lack of excitation from GCs during the phasic 5-HT release. This hypothesis is supported by the difference in the delay preceding MAs in GCs and MCs (5.89+/-0.28 s in GCs vs. 4.89+/-0.40 s in MCs) which shows that GC inactivity is followed by MC inactivity. Simultaneous recording of MCs and GCs with two-photon calcium imaging in Htr1a knockout mice will further test this hypothesis.

ISOs have been observed in multiple brain regions during sleep-wake cycles (Hughes et al., 2011). Polysomnographic recordings have revealed a 0.02 Hz ISO pattern recorded from cortical areas (Lecci et al., 2017; Vanhatalo et al., 2004) which frequency is on the same time scale as the ISO we recorded from the DG. The cortical ISO is dominant in the sigma (10–15 Hz) power range in both mice and humans (Lecci et al., 2017) which is the most prominent frequency band that contains neural rhythms associated with the gating of sensory information during sleep. A follow-up study by the same group demonstrated that the ISO from cortical EEG sigma band is correlated with MAs (Cardis et al., 2021). Our data with others (Kato et al., 2022) show that 5-HT concentration slowly oscillates in the hippocampus and in the raphe during NREM, thus it would be intriguing to conclude that peaks of the phasic 5-HT bursts act as the gating signal when the animal is more receptive to external stimulation and this can lead to awakening. However, we also need to point out that there are multiple other systems that can be active in parallel and contribute to the shaping of the sleep microarchitecture (Kjaerby et al., 2022). Several recent publications from different laboratories have shown rhythmic release of norepinephrine (NE) (~0.03 Hz) in the medial prefrontal cortex, the thalamus, and in the locus coeruleus (LC), and similar rhythmic activity of glutamatergic neurons in the preoptic area during sleep-wake cycles (Kjaerby et al., 2022; Antila et al., 2022; Osorio-Forero et al., 2021). The recording techniques used in these studies are highly similar to ours and the analyses arrive at the same conclusion, that is, about 30% of the phasic neuromodulator bursts lead to MAs while NREM sleep is maintained about 60% of the time. Furthermore, their work also demonstrated a correlation between LC-NE signal and EEG sigma power during NREM sleep, a characteristic EEG frequency band of sleep spindles. We performed a correlation analysis between DG activity and EEG sigma power and found a positive correlation between them during NREM sleep (Figure 1—figure supplement 1C–E). The available data obtained with other novel neuromodulatory sensors suggests, that several other neuromodulatory and peptidergic systems (i.e. histaminergic, cholinergic, oxytocinergic) (Dong et al., 2023; Jing et al., 2020; Zhang et al., 2024; Smith et al., 2024; Osorio-Forero et al., 2025) also display this phasic ISO activity during NREM sleep which raises the question of how the individual components of the ascending reticular activating system shapes sleep microarchitecture. Increase in the infraslow oscillatory frequency of NE during NREM leads to increased frequency of MAs (Kjaerby et al., 2022; Antila et al., 2022). However, increasing the extracellular 5-HT level by acute SSRI (selective serotonin reuptake inhibitors) administration does not seem to change the frequency of these events (Kato et al., 2022). This suggests that the 5-HT system might have different neuromodulatory functions from the NE system during sleep.

In our experiments we wanted to minimize the impact of the surgical procedures on the behavior, thus we used separate cohorts to record the photometry signals and carry out the behavior experiments, therefore, we are unable to correlate the magnitude changes in the serotonergic ISO and memory performance. However, in a recent paper published by Kjaerby et al. there seemed to be a direct correlation between the magnitude of the norepinephrine pulses and sleep behavior (Kjaerby et al., 2022). Gradual decrease of norepinephrine during NREM led to a fragmented sleep phenotype characterized by increased MA occurrence, decreased REM, and reduced spindle activity. The memory performance was also tested in a novel object recognition task and found to be diminished in the manipulation group. Serotonin has multiple roles in the brain, many of them show overlap with proposed functions of the noradrenergic system including regulation of plasticity, signaling reward or fearful stimuli (Teixeira et al., 2018; Paquelet et al., 2022). Therefore, we speculate that the modification of serotonin dynamics during sleep will most likely interfere with memory performance, however, further experiments are required to test this hypothesis.

Our data demonstrated that phasic release of 5-HT during sleep acts as an inhibitory input to the neuronal activity in DG via Htr1a receptors, thus it serves as a pacemaker signal. In addition, we speculate that there could be an excitatory input which is responsible for the elevated activity of GC and MC subpopulations during NREM. The DG is the main input node of the hippocampal tri-synaptic loop receiving glutamatergic inputs from distant brain areas such as the entorhinal cortex or the supramammillary nucleus (Farrell et al., 2021). Recent data have shown a similar ISO in the medial entorhinal cortex in head-fixed mice while moving on a rotating wheel (Gonzalo Cogno et al., 2024) which also transcended immobility epochs, but further data would be needed to confirm that they exist during NREM sleep as well.

A recent work from Pofahl et al. have used in vivo two-photon microscopy and showed that GCs display synchronous activity patterns during immobility Pofahl et al., 2021 which might be related to the phenomenon we observed. However, the authors were not able to break down the immobility intervals to sleep stages due to the lack of simultaneous EEG/EMG recordings, nor did they assess the activity of the MCs in their work. Our results demonstrated the dynamic activity of DG cells during sleep (Figure 3). Interestingly, we did not observe the ISO at the single-cell level under two-photon microscope. One possibility is that this was due to different sleep patterns between head-restricted and freely moving animals. We hypothesize that deep sleep is needed for the ISO. Even though we habituated our mice extensively to our two-photon setup to minimize stress, head-fixed posture may still result in differences in sleep behavior due to the slightly increased stress response caused by head-fixation (Juczewski et al., 2020). Another possibility is that the ISO mainly has a dendritic origin and manifests less at the somatic level. Future dendritic imaging in sleeping mice can test this possibility.

In summary, here we showed that calcium activity in the DG is highly increased during NREM sleep periods, and population activity is entrained to ISO. The activity of the serotonergic system is highly correlated with this oscillation, and rhythmic bursts of 5-HT maintain the oscillatory activity, via Htr1a receptors expressed by GCs. While our study highlights the role of neuromodulation in organizing neuronal activity during sleep, the direct relationship between these effects and sleep-dependent memory functions, such as memory consolidation, remains to be explicitly demonstrated.

Source data supporting the findings of this study are provided in Source data 1.

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Author details

1. Gergely F Turi

   1. New York State Psychiatric Institute, Division of Systems Neuroscience New York, New York, United States
   2. Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Sasa Teng

   For correspondence

   gt2253@cumc.columbia.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5651-9459

2. Sasa Teng

   1. Institute for Genomic Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States
   2. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Gergely F Turi

   Competing interests

   No competing interests declared

3. Xinyue Chen

   1. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States
   2. Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0264-1488

4. Emily CY Lim

   Columbia College, Columbia University, New York, United States

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Carla Dias

   1. New York State Psychiatric Institute, Division of Systems Neuroscience New York, New York, United States
   2. Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

6. Ruining Hu

   Institute for Genomic Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

7. Ruizhi Wang

   Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

8. Fenghua Zhen

   Institute for Genomic Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Present address

   National Institute of Allergy and Infectious Diseases, Bethesda, United States

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

9. Yueqing Peng

   1. Institute for Genomic Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States
   2. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States
   3. Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   yp2249@cumc.columbia.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3488-0670

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