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Oncotarget78222
www.impactjournals.com/oncotarget
www.impactjournals.com/oncotarget/ 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
Editorial
Figure 1: Schematic drawing depicting the potential
mechanism of the regulation of afferent inputs to
sleep-promoting neurons by 5-HT.
Oncotarget78223
www.impactjournals.com/oncotarget
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
life.
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-
lac@college-de-france.fr
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
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4. Sangare A, et al. Neuropharmacology. 2016; 109:29-40.
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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]. ...
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  • 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.