Changing concepts on the role of serotonin in the regulation of sleep and waking

Ursin, Reidun

doi:10.1007/978-3-7643-8561-3_1

Cited by 10 publications

(4 citation statements)

References 102 publications

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“…Several questions regarding serotonergic mechanisms in sleep-wake regulation remain. One long-lasting dichotomous debate regarding the role of serotonin is that it is sleep promoting rather than wake promoting (Ursin, 2008;see above, Introduction). Sleep/wake-promoting roles were originally designated by long-term loss-of-function studies; for example, ablation, and the designation sleep promoting meant that the proportion of sleep bouts was enhanced by serotonin.…”

Section: Discussionmentioning

confidence: 99%

Oscillatory Population-Level Activity of Dorsal Raphe Serotonergic Neurons Is Inscribed in Sleep Structure

et al. 2022

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Dorsal raphe (DR) 5-HT neurons regulate sleep-wake transitions. Previous studies demonstrated that single-unit activity of DR 5-HT neurons is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and ceases during rapid eye movement (REM) sleep. However, characteristics of the population-level activity of DR 5-HT neurons, which influence the entire brain, are largely unknown. Here, we measured population activities of 5-HT neurons in the male and female mouse DR across the sleep-wake cycle by ratiometric fiber photometry. We found a slow oscillatory activity of compound intracellular Ca 21 signals during NREM sleep. The trough of the concave 5-HT activity increased across sleep progression, but 5-HT activity always returned to that seen during the wake period. When the trough reached a minimum and remained there, REM sleep was initiated. We also found a unique coupling of the oscillatory 5-HT activity and wideband EEG power fluctuation. Furthermore, optogenetic activation of 5-HT neurons during NREM sleep triggered a high EMG power and induced wakefulness, demonstrating a causal role of 5-HT neuron activation. Optogenetic inhibition induced REM sleep or sustained NREM, with an EEG power increase and EEG fluctuation, and pharmacological silencing of 5-HT activity using a selective serotonin reuptake inhibitor led to sustained NREM, with an EEG power decrease and EEG fluctuation. These inhibitory manipulations supported the association between oscillatory 5-HT activity and EEG fluctuation. We propose that NREM sleep is not a monotonous state, but rather it contains dynamic changes that coincide with the oscillatory population-level activity of DR 5-HT neurons.

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Section: Discussionmentioning

confidence: 99%

Oscillatory Population-Level Activity of Dorsal Raphe Serotonergic Neurons Is Inscribed in Sleep Structure

et al. 2022

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“…The serotonergic RN were first implicated in sleep-wake regulation over 50 years ago, but it has long been disputed whether they act to promote sleep or wakefulness (Ursin, 2008). We and others recently addressed this controversy in both mammals and zebrafish by providing both gain- and loss-of-function evidence using genetic, pharmacological, optogenetic and chemogenetic approaches to demonstrate that the serotonergic RN promote sleep (Oikonomou et al, 2019; Venner et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, in mice, ablation of the RN results in increased wakefulness and an impaired homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation of the RN at a rate similar to their baseline pattern of activity induces NREM sleep. These complementary results in zebrafish and mice (Oikonomou et al, 2019), along with classical ablation and pharmacological studies (Ursin, 2008), indicate an evolutionarily conserved role for the serotonergic system in promoting vertebrate sleep. However, it is unclear how the RN are themselves regulated to promote sleep.…”

Section: Introductionmentioning

confidence: 90%

Neuropeptide VF neurons promote sleep via the serotonergic raphe

Lee

Oikonomou

Cammidge

et al. 2019

Preprint

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15Although several sleep-regulating neurons have been identified, little is known about how they 16 interact with each other for sleep/wake control. We previously identified neuropeptide VF (NPVF) 17 and the hypothalamic neurons that produce it as a sleep-promoting system (Lee et al., 2017). 18Here we use zebrafish to describe a neural circuit in which neuropeptide VF (npvf)-expressing 19 neurons control sleep via the serotonergic raphe nuclei (RN), a hindbrain structure that promotes 20 sleep in both diurnal zebrafish and nocturnal mice. Using genetic labeling and calcium imaging, 21we show that npvf-expressing neurons innervate and activate serotonergic RN neurons. We 22 additionally demonstrate that optogenetic stimulation of npvf-expressing neurons induces sleep 23 in a manner that requires NPVF and is abolished when the RN are ablated or lack serotonin. 24Finally, genetic epistasis demonstrates that NPVF acts upstream of serotonin in the RN to 25 maintain normal sleep levels. These findings reveal a novel hypothalamic-hindbrain circuit for 26 sleep/wake control. 28While several sleep-and wake-promoting neuronal populations have been identified (reviewed in 30 (Bringmann, 2018; Liu and Dan, 2019; Saper and Fuller, 2017; Scammell et al., 2017)), 31 characterizing and understanding the functional and hierarchical relationships between these 32 populations is essential for understanding how the brain regulates sleep and wake states 33 (Oikonomou and Prober, 2017). Recent evidence from zebrafish and mice demonstrate that the 34 serotonergic raphe nuclei (RN) are critical for the initiation and maintenance of sleep (Oikonomou 35 et al., 2019), in contrast with previous models suggesting a wake-promoting role for the RN that 36 were largely based on their wake-active nature (Saper and Fuller, 2017; Scammell et al., 2017; 37Weber and Dan, 2016). In zebrafish, mutation of tryptophan hydroxylase 2 (tph2), which is 38 required for serotonin (5-HT) synthesis in the RN, results in reduced sleep, sleep depth, and 39 homeostatic response to sleep deprivation (Oikonomou et al., 2019). Pharmacological inhibition 40 of 5-HT synthesis or ablation of the RN also results in reduced sleep. Consistent with a sleep-41 promoting role for the raphe, optogenetic stimulation of raphe neurons results in increased sleep.42 Similarly, in mice, ablation of the RN results in increased wakefulness and an impaired 43 homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation of the RN at a 44 rate similar to their baseline pattern of activity induces NREM sleep. These complementary results 45 in zebrafish and mice (Oikonomou et al., 2019), along with classical ablation and pharmacological 46 studies (Ursin, 2008), indicate an evolutionarily conserved role for the serotonergic system in 47 promoting vertebrate sleep. However, it is unclear how the RN are themselves regulated to 48 promote sleep. 50Trans-synaptic retrograde viral tracing studies have identified substantial inputs to the RN from 51 hypothalamic ...

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“…Furthermore, changes in 5-HT levels have been causally linked to brain state changes, though some controversy over the direction of such changes remains. While some studies suggest a wake-promoting role for 5-HT, others propose that 5-HT increases sleep drive over the course of waking (3,4). In either case, state-dependent changes in 5-HT levels can be seen to reorganize brain networks in response to ongoing functional demands.…”

Section: Introductionmentioning

confidence: 99%

Ultraslow serotonin oscillations in the hippocampus delineate substates across NREM and waking

Cooper,

Parthier,

Sibille

et al. 2024

Preprint

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Beyond the vast array of functional roles attributed to serotonin (5-HT) in the brain, changes in 5-HT levels have been shown to accompany changes in behavioral states, including WAKE, NREM and REM sleep. Whether 5-HT dynamics at shorter time scales can be seen to delineate substates within these larger brain states remains an open question. Here, we performed simultaneous recordings of extracellular 5-HT using a recently-developed G Protein–Coupled Receptor-Activation–Based 5-HT sensor (GRAB5-HT3.0) and local field potential (LFP) in the hippocampal CA1, which revealed the presence of prominent ultraslow (<0.05 Hz) 5-HT oscillations both during NREM and WAKE states. Interestingly, the phase of these ultraslow 5-HT oscillations was found to distinguish substates both within and across larger behavioral states. Hippocampal ripples occurred preferentially on the falling phase of ultraslow 5-HT oscillations during both NREM and WAKE, with higher power ripples concentrating near the peak specifically during NREM. By contrast, hippocampal-cortical coherence was strongest and microarousals and EMG peaks were most prevalent during the rising phase in both wake and NREM. Overall, ultraslow 5-HT oscillations delineate substates within the larger behavioral states of NREM and WAKE, thus potentially temporally segregating internal memory consolidation processes from arousal-related functions.

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Changing concepts on the role of serotonin in the regulation of sleep and waking

Cited by 10 publications

References 102 publications

Oscillatory Population-Level Activity of Dorsal Raphe Serotonergic Neurons Is Inscribed in Sleep Structure

Oscillatory Population-Level Activity of Dorsal Raphe Serotonergic Neurons Is Inscribed in Sleep Structure

Neuropeptide VF neurons promote sleep via the serotonergic raphe

Ultraslow serotonin oscillations in the hippocampus delineate substates across NREM and waking

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