Neuropeptide VF neurons promote sleep via the serotonergic raphe.
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ABSTRACT:
SUBMITTER: Lee DA
PROVIDER: S-EPMC7748413 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
| S-EPMC6706304 | biostudies-literature
Project description:AimsGeneral anesthesia has been widely applied in surgical or nonsurgical medical procedures, but the mechanism behind remains elusive. Because of shared neural circuits of sleep and anesthesia, whether serotonergic system, which is highly implicated in modulation of sleep and wakefulness, regulates general anesthesia as well is worth investigating.MethodsImmunostaining and fiber photometry were used to assess the neuronal activities. Electroencephalography spectra and burst-suppression ratio (BSR) were used to measure anesthetic depth and loss or recovery of righting reflex to indicate the induction or emergence time of general anesthesia. Regulation of serotonergic system was achieved through optogenetic, chemogenetic, or pharmacological methods.ResultsWe found that both Fos expression and calcium activity were significantly decreased during general anesthesia. Activation of 5-HT neurons in the dorsal raphe nucleus (DRN) decreased the depth of anesthesia and facilitated the emergence from anesthesia, and inhibition deepened the anesthesia and prolonged the emergence time. Furthermore, agonism or antagonism of 5-HT 1A or 2C receptors mimicked the effect of manipulating DRN serotonergic neurons.ConclusionOur results demonstrate that 5-HT neurons in the DRN play a regulative role of general anesthesia, and activation of serotonergic neurons could facilitate emergence from general anesthesia partly through 5-HT 1A and 2C receptors.
| S-EPMC8265942 | biostudies-literature
Project description:Sleep is an essential and phylogenetically conserved behavioral state, but it remains unclear to what extent genes identified in invertebrates also regulate vertebrate sleep. RFamide-related neuropeptides have been shown to promote invertebrate sleep, and here we report that the vertebrate hypothalamic RFamide neuropeptide VF (NPVF) regulates sleep in the zebrafish, a diurnal vertebrate. We found that NPVF signaling and npvf-expressing neurons are both necessary and sufficient to promote sleep, that mature peptides derived from the NPVF preproprotein promote sleep in a synergistic manner, and that stimulation of npvf-expressing neurons induces neuronal activity levels consistent with normal sleep. These results identify NPVF signaling and npvf-expressing neurons as a novel vertebrate sleep-promoting system and suggest that RFamide neuropeptides participate in an ancient and central aspect of sleep control.
| S-EPMC5705210 | biostudies-literature
Project description:Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.
| S-EPMC4756479 | biostudies-literature
Project description:The serotonergic raphe nuclei of the midbrain are principal centers from which serotonin neurons project to innervate cortical and sub-cortical structures. The dorsal raphe nuclei receive light input from the circadian visual system and indirect input from the biological clock nuclei. Dysregulation of serotonin neurotransmission is implicated in neurobehavioral disorders, such as depression and anxiety, and alterations in the serotonergic phenotype of raphe neurons have dramatic effects on affective behaviors in rodents. Here, we demonstrate that day length (photoperiod) during development induces enduring changes in mouse dorsal raphe serotonin neurons—programming their firing rate, responsiveness to noradrenergic stimulation, intrinsic electrical properties, serotonin and norepinephrine content in the midbrain, and depression/anxiety-related behavior in a melatonin receptor 1 (MT1)-dependent manner. Our results establish mechanisms by which seasonal photoperiods may dramatically and persistently alter the function of serotonin neurons.
| S-EPMC4445239 | biostudies-literature
Project description:Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of serotonin signaling during critical periods is involved in developmental neurological disorders, such as schizophrenia and autism. In this study we focused on the consequences of defect reelin signaling for the development of the brainstem serotonergic raphe system. We observed that reelin signaling components are expressed by serotonergic neurons during the critical period of their lateral migration. Further, we found that reelin signaling is important for the normal migration of rostral, but not caudal hindbrain raphe nuclei and that reelin deficiency results in the malformation of the paramedian raphe nucleus and the lateral wings of the dorsal raphe nuclei. Additionally, we showed that serotonergic neurons projections to laminated brain structures were severely altered. With this study, we propose that the perturbation of canonical reelin signaling interferes with the orientation of tangentially, but not radially, migrating brainstem 5-HT neurons. Our results open the window for further studies on the interaction of reelin and serotonin and the pathogenesis of neurodevelopmental disorders.
| S-EPMC6042745 | biostudies-literature
Project description:Transient variations in pupil size (PS) under constant luminance are coupled to rapid changes in arousal state,1-3 which have been interpreted as vigilance,4 salience,5 or a surprise signal.6-8 Neural control of such fluctuations presumably involves multiple brain regions5,9-11 and neuromodulatory systems,3,12,13 but it is often associated with phasic activity of the noradrenergic system.9,12,14,15 Serotonin (5-HT), a neuromodulator also implicated in aspects of arousal16 such as sleep-wake transitions,17 motivational state regulation,18 and signaling of unexpected events,19 seems to affect PS,20-24 but these effects have not been investigated in detail. Here we show that phasic 5-HT neuron stimulation causes transient PS changes. We used optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) of head-fixed mice performing a foraging task. 5-HT-driven modulations of PS were maintained throughout the photostimulation period and sustained for a few seconds after the end of stimulation. We found no evidence that the increase in PS with activation of 5-HT neurons resulted from interactions of photostimulation with behavioral variables, such as locomotion or licking. Furthermore, we observed that the effect of 5-HT on PS depended on the level of environmental uncertainty, consistent with the idea that 5-HT could report a surprise signal.19 These results advance our understanding of the neuromodulatory control of PS, revealing a tight relationship between phasic activation of 5-HT neurons and changes in PS.
| S-EPMC7808753 | biostudies-literature
Project description:Appropriate choice about delayed reward is fundamental to the survival of animals. Although animals tend to prefer immediate reward, delaying gratification is often advantageous. The dorsal raphe (DR) serotonergic neurons have long been implicated in the processing of delayed reward, but it has been unclear whether or when their activity causally directs choice. Here, we transiently augmented or reduced the activity of DR serotonergic neurons, while mice decided between differently delayed rewards as they performed a novel odor-guided intertemporal choice task. We found that these manipulations, precisely targeted at the decision point, were sufficient to bidirectionally influence impulsive choice. The manipulation specifically affected choices with more difficult trade-off. Similar effects were observed when we manipulated the serotonergic projections to the nucleus accumbens (NAc). We propose that DR serotonergic neurons preempt reward delays at the decision point and play a critical role in suppressing impulsive choice by regulating decision trade-off.
| S-EPMC5691357 | biostudies-literature
Project description:During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2.
| S-EPMC7265411 | biostudies-literature
Project description:BACKGROUND:Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes. METHODS:We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout. Rats were allowed either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration to model moderate versus compulsive-like cocaine taking. RESULTS:SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced corticotropin-releasing factor (CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown. CONCLUSIONS:Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.
| S-EPMC5960600 | biostudies-literature