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Oncotarget78222 Oncotarget, Vol. 7, No. 48
Serotonin and sleep-promoting neurons
Armelle Rancillac
Serotonin (5-HT) is a monoamine neurotransmitter
that plays major roles in several physiological functions
including circadian rhythmicity, thermoregulation,
emotion, cognition and nociception. The relationship
between 5-HT and sleep was demonstrated by several
experiments. In a particularly elegant one, cats were
rendered insomniac following the injection of a 5-HT
synthesis inhibitor. In this model, the preoptic area of
the hypothalamus containing the ventrolateral preoptic
area (VLPO) was the only brain region in which
microinjections of the 5-HT precursor could restore long
periods of sleep [1]. The VLPO being the main brain
structure inducing slow-wave sleep (SWS), it was then
hypothesized that 5-HT modulation of neuronal activity
in this structure is essential for sleep regulation. However,
the mechanisms involved in the physiological role of 5-HT
within the VLPO remained largely unknown.
The VLPO is a small cluster of neurons composed
of different neuronal populations. Five distinct neuronal
classes were recently electrophysiologically dened
[2]. These neuronal populations were morphologically
characterized and were shown to differently respond to
neurotransmitters such as noradrenaline (NA) and 5-HT.
Indeed, sleep-promoting neurons within the VLPO are
usually identied by their inhibitory response to NA,
suggesting that they are maintained silent during waking.
They are either inhibited (Type-1) or excited (Type-2) by
5-HT application [3].
In our paper, the mode of action and the effects
of 5-HT were determined in Type-1 and Type-2 sleep-
promoting neurons. In acute VLPO slices of mouse,
spontaneous and miniatures excitatory and inhibitory
postsynaptic currents were recorded in response to
bath application of 5-HT. We found that 5-HT reduces
frequencies of all these events to Type-1 neurons, whereas
5-HT selectively increases the frequencies of inhibitory
events to Type-2 VLPO neurons [4].
Furthermore, our data shows that Type-1 and
Type-2 sleep-promoting neurons present similar
morphological somatic hallmarks as measured on infrared
microphotography taken prior electrophysiological
recordings. However, we established that the area of
Type-1 neurons was signicantly smaller compared to
Type-2 neurons. Membrane properties of sleep-promoting
neurons were also investigated eletrophysiologically. We
found that the action potential threshold was signicantly
lower in Type-1 compared to Type-2 neurons. As Type-
2 neurons have been previously shown to selectively
respond to an A2A adenosine receptor agonist [3, 5], they
could likely integrate the homeostatic drive associated
with adenosine accumulation during wakefulness, and
rst respond to the serotonergic excitatory inputs. Then,
the activation of Type-2 neurons would decrease the
frequency of GABAergic inputs to Type-1 neurons and
favor their activation. Type-1 VLPO neurons would then
inhibit arousal systems and allow the maintenance of
slow-wave sleep.
Finally, we investigated the molecular diversity of
sleep-promoting neurons using the single-cell RT-PCR
technique to simultaneously detect the expression of the
Figure 1: Schematic drawing depicting the potential
mechanism of the regulation of afferent inputs to
sleep-promoting neurons by 5-HT.
13 serotonergic receptors. We established that 5-HT1
receptors mRNA were only detected in Type-1 neurons,
whereas mRNAs encoding 5-HT2A-C, 5-HT4 and 5-HT7
were equally distributed between Type-1 and Type-
2 VLPO neurons. To conrm the putative expression
of 5-HT1A and 5-HT2C receptors that were the most
frequently amplied mRNA, we applied potent agonist
of these receptors on sleep-promoting neurons. In loose-
patch recordings, we established that the selective 5-HT1A
receptor agonist, the 8-OH-DPAT, decreases the ring
frequency of Type-1 neurons, whereas a 5-HT2C receptor
agonist, PF03246799, enhances the ring frequency of
Type-2 neurons. Interestingly, we also observed that the
decreased ring rate induced by 5-HT application in Type-
1 neurons was subsequently followed by a small increased
of their ring rate and that PF03246799 application
could also increase the ring rate in a subset of Type-1
neurons. Physiologically, we hypothesize that afferent
serotonergic inputs to the VLPO could exert a complex
and ne control of sleep-promoting neurons. Nevertheless,
it appears from the literature that systemic injections of
a 5-HT agonist could produce opposite effects on sleep
amounts, depending on the concentration used and on the
time of the sleep-wake cycle during which the treatment
was administered [6, 7]. These studies suggest a circadian
modulation of serotonergic receptor function.
Altogether, our results established
electrophysiological, morphological and molecular
differences between these two neuronal types of sleep-
promoting neurons. Type-2 neurons being more excitable,
they could likely integrate the homeostatic drive of sleep
and be involved in the preparation and initiation of sleep
(permissive neurons). Then, their activation could decrease
the frequency of inhibitory inputs to Type-1 neurons to
favor their activation. Type-1 VLPO neurons would then
inhibit arousal systems and allow the maintenance of SWS
(executive neurons, Figure 1).
Our work provides new insights regarding sleep
regulation by 5-HT and propose distinct roles for Type-
1 and Type-2 neurons. Furthermore, we established that
sleep-promoting neurons frequently express 5-HT2C
receptors that could represent a molecular target for the
development of safer and more effective sleep-promoting
medication to treat insomnia and to improve quality of
Armelle Rancillac: Neuroglial Interactions in Cerebral
Physiopathology, CIRB, Rouach’s team, CNRS UMR /
Inserm, Collège de France, place Marcelin Berthelot, Paris
Correspondence to: Armelle Rancillac, email armelle.rancil-
Keywords: VLPO, slow-wave sleep (SWS), non-rapid eye
movement sleep (NREM), 5-HT2C receptor, 5-HT1A receptor
Received: November 08, 2016
Published: November 16, 2016
1. Denoyer M, et al. Neuroscience. 1989; 28:83-94.
2. Dubourget R, et al. Brain Structure and Function. 2016;
3. Gallopin T, et al. Neuroscience. 2005; 134:1377-1390.
4. Sangare A, et al. Neuropharmacology. 2016; 109:29-40.
5. Scharbarg E, et al. Scientic Report. 2016; 6:19107.
6. Monti JM, Sleep Medicine Reviews. 2011; 15:269-281.
7. Morrow JD, et al. Sleep. 2008; 31:21-33.
... Activation of the dorsal raphe nucleus promotes wakefulness [73]. The ventrolateral preoptic area (VLPO) is the main brain area that promotes SWS [74]. It has been reported that serotonergic modulation of neuronal activity in the VLPO is essential for sleep regulation [75]. ...
... The VLPO is a small cluster of neurons that is consisted of various neuronal populations. Electrophysiological reports have shown five distinct neuronal populations in the VLPO [74]. Furthermore, it has been shown that these neuronal populations are morphologically different and induce different responses to neurotransmitters such as noradrenaline and serotonin. ...
... Furthermore, it has been shown that these neuronal populations are morphologically different and induce different responses to neurotransmitters such as noradrenaline and serotonin. In fact, sleep-promoting neurons in the VLPO are usually identified by their inhibitory responses to noradrenaline [74]. These neuronal population are inhibited (Type-1) or excited (Type-2) by serotonin [76]. ...
Serotonin is an important neurotransmitter with various receptors and wide-range effects on physiological processes and cognitive functions including sleep, learning, and memory. In this review study, we aimed to discuss the role of serotonergic receptors in modulating sleep–wake cycle, and learning and memory function. Furthermore, we mentioned to sleep deprivation, its effects on memory function, and the potential interaction with serotonin. Although there are thousands of research articles focusing on the relationship between sleep and serotonin; however, the pattern of serotonergic function in sleep deprivation is inconsistent and it seems that serotonin has not a certain role in the effects of sleep deprivation on memory function. Also, we found that the injection type of serotonergic agents (systemic or local), the doses of these drugs (dose-dependent effects), and up- or down-regulation of serotonergic receptors during training with various memory tasks are important issues that can be involved in the effects of serotonergic signaling on sleep–wake cycle, memory function, and sleep deprivation-induced memory impairments. This comprehensive review was conducted in the PubMed, Scopus, and ScienceDirect databases in June and July 2021, by searching keywords sleep, sleep deprivation, memory, and serotonin.
... It is currently accepted that serotonin promotes wakefulness, inhibits REM sleep, and induces slow wave sleep (Monti, 2011;Rancillac, 2016). Serotonin is predominantly synthesized in the raphe nuclei of the brainstem and is projected extensively into multiple cortical and subcortical structures in a sprinkler-type fashion to arouse wakefulness (Daubert and Condron, 2010). ...
... In fact, considering the complex innervation of serotonergic neurons, based on the available evidence, it is difficult to distinctly illustrate the role of serotonin decline in age-related sleep disturbances. Still, existing evidence, such as serotonin activating sleep-promoting neurons in VLPO in mice (Rancillac, 2016), local blockage of serotonergic transmission in the forebrain/preoptic areas disrupting the circadian clocks of mice (Miyamoto et al., 2012), and serotonin-enhancing circadian responses to light in hamsters (Smith et al., 2015) partially explain the underlying mechanisms. ...
With aging, various factors deteriorate the normal sleep process that is essential for the restoration of functional and physical performance. Due to aging-related diseases, life changes, or aging itself, disturbances in normal sleep cycles can profoundly affect healthy aging. To understand the interconnections between aging and the factors influencing sleep, with emerging evidence accumulated in recent years, this study elaborates on the roles of aging in sleep from four perspectives: cortical thinning, white matter degeneration, neurotransmitter dysregulation, and circadian disorganization. In brief, with aging, cortical thinning can be induced by the deposition of neurotoxic substances, and white matter degeneration can be induced by vascular abnormalities. These alterations emerging in the brain jointly disrupt sleep spindles and slow waves, leading to sleep disturbances. Age-related dysregulation in neurotransmitters (including galanin, orexin, serotonin, and adenosine) directly impairs the sleep modulation system. Disorganization in the circadian system consisting of suprachiasmatic nucleus dysfunction, reduced light transmission, and local circadian clock disruption collectively interrupts circadian rhythms, also causing sleep disturbances in the older. Of note is the bidirectional relationship between aging and sleep, which required us to examine this issue from different perspectives.
... DNA methylation associated with childhood trauma has been found to alter serotonin activity [62]. Serotonin affects appetite [63], memory [64], mood [65], sleep [66], social behavior [67], and sexual interest and function [68]. ...
... As reported in Table 1 and Figure 1, we would expect drugs that increase concentrations of the catecholamines (noradrenaline and dopamine) or histamine to induce or enhance wakefulness, and those that increase GABA concentration to induce or enhance sleep. Serotonergic stimulation yields complex and seemingly opposing effects on the sleep-wake cycle (244), possibly due to circadian modulation of serotonergic receptor function (253), and hence, drugs that increase concentrations of serotonin, or both catecholamines and serotonin, like some antidepressants, might have mixed effects. As summarized in Table 2, the gabapentinoids, which reduce excitatory catecholamines, enhance sleep. ...
We review the known physiological mechanisms underpinning all of pain processing, sleep regulation, and pharmacology of analgesics prescribed for chronic pain. In particular, we describe how commonly prescribed analgesics act in sleep-wake neural pathways, with potential unintended impact on sleep and/or wake function. Sleep disruption, whether pain- or drug-induced, negatively impacts quality of life, mental and physical health. In the context of chronic pain, poor sleep quality heightens pain sensitivity and may affect analgesic function, potentially resulting in further analgesic need. Clinicians already have to consider factors including efficacy, abuse potential, and likely side effects when making analgesic prescribing choices. We propose that analgesic-related sleep disruption should also be considered. The neurochemical mechanisms underlying the reciprocal relationship between pain and sleep are poorly understood, and studies investigating sleep in those with specific chronic pain conditions (including those with comorbidities) are lacking. We emphasize the importance of further work to clarify the effects (intended and unintended) of each analgesic class to inform personalized treatment decisions in patients with chronic pain. © 2021 American Physiological Society. Compr Physiol 11:1-31, 2021.
... Once thought to be the primary neurotransmitter of sleep (88), the role of serotonin in the sleep-wake cycle is now understood as more complex, being involved in various processes necessary for both sleep and wake. Serotonin has been hypothesized to regulate neuronal activity in the ventrolateral preoptic area of the brain, the main structure responsible for inducing slow-wave sleep (SWS) (91). High levels of neuronal activity in this region during sleep suggest a role of serotonin in the induction of the sleep cycle. ...
Two factors intrinsic to health are diet and sleep. These two behaviors may well influence one another. Indeed, that insufficient sleep adversely impacts dietary intakes is well documented. On the other hand, diet may influence sleep via melatonin and its biosynthesis from tryptophan. Experimental data exist indicating that provision of specific foods rich in tryptophan or melatonin can improve sleep quality. Whole diets rich in fruits, vegetables, legumes, and other sources of dietary tryptophan and melatonin have been shown to predict favorable sleep outcomes. Although clinical trials are needed to confirm a causal impact of dietary patterns on sleep and elucidate underlying mechanisms, available data illustrate a cyclical relation between these lifestyle factors. We recommend adopting a healthful diet to improve sleep, which may further promote sustained favorable dietary practices. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see for revised estimates.
... Таким чином, таламус є провідною структурою, що активує сон. Cеротонін, впливаючи на циркадність, терморегуляційну, емоційно-пізнавальну і ноцицептивну функції, виконує регуляторну функцію в циклі сну -неспання [3,16]. Зміни концентрації норадреналіну в циклі сну -неспання і фазі швидкого сну не тільки беруть участь у когнітивних процесах, але й регулюють стан перекисного окиснення у нейронах та глії, діючи на альфа-1-адренорецептори і за допомогою ініціалізації внутрішнього шляху мітохондрій [17]. ...
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Para-chlorophenylalanine, a blocker of serotonin biosynthesis by inhibiting tryptophan hydroxylase, induced total insomnia which was accompanied in cat by a permanent discharge of ponto-geniculo-occipital activity. L-5-Hydroxytryptophan microinjection (1-4 micrograms/0.5 microliters) in the anterior hypothalamus 72 h after para-chlorophenylalanine administration, restored both slow wave sleep and paradoxical sleep with variable latencies for each state of sleep. On the contrary, ponto-geniculo-occipital activity was never suppressed. The hypnogenic effects of L-5-hydroxytryptophan were always followed by a return of the para-chlorophenylalanine-induced insomnia. On the other hand, the temperature recording did not show any alteration of the cerebral temperature after para-chlorophenylalanine treatment but the subsequent L-5-hydroxytryptophan microinjection was followed by hyperthermia. Using immunohistochemistry for serotonin after intrahypothalamic L-5-hydroxytryptophan microinjection in parachlorophenylalanine-pretreated cat, we defined a restricted region of the anterior hypothalamus possibly responsible for the hypnogenic effect. This region included the lateral hypothalamus and the anterior hypothalamic area. It is suggested that the reversible hypersomnia after L-5-hydroxytryptophan microinjection in the anterior hypothalamus in para-chlorophenylalanine-pretreated cat is due to a neurohormonal action of serotonin: serotonin could act upon the anterior hypothalamus which secondarily inhibits a waking system located in the ventrolateral hypothalamus leading to the appearance of paradoxical sleep.
  • A Sangare
Sangare A, et al. Neuropharmacology. 2016; 109:29-40.
  • E Scharbarg
Scharbarg E, et al. Scientific Report. 2016; 6:19107.
  • J M Monti
Monti JM, Sleep Medicine Reviews. 2011; 15:269-281.
  • R Dubourget
Dubourget R, et al. Brain Structure and Function. 2016; 1-15.