Ablation of Central Serotonergic Neurons Decreased REM Sleep and Attenuated Arousal Response.

Kanako Iwasaki,Hiromasa Funato,Miyo Kakizaki,Chika Miyoshi,Manabu Abe,Masashi Yanagisawa,Haruna Komiya,Kenji Sakimura

doi:10.3389/fnins.2018.00535

Abstract

Sleep/wake behavior is regulated by distinct groups of neurons, such as dopaminergic, noradrenergic, and orexinergic neurons. Although monoaminergic neurons are usually considered to be wake-promoting, the role of serotonergic neurons in sleep/wake behavior remains inconclusive because of the effect of serotonin (5-HT)-deficiency on brain development and the compensation for inborn 5-HT deficiency by other sleep/wake-regulating neurons. Here, we performed selective ablation of central 5-HT neurons in the newly developed Rosa-diphtheria toxin receptor (DTR)-tdTomato mouse line that was crossed with Pet1Cre/+ mice to examine the role of 5-HT neurons in the sleep/wake behavior of adult mice. Intracerebroventricular administration of diphtheria toxin completely ablated tdTomato-positive cells in Pet1Cre/+; Rosa-DTR-tdTomato mice. Electroencephalogram/electromyogram-based sleep/wake analysis demonstrated that central 5-HT neuron ablation in adult mice decreased the time spent in rapid eye movement (REM) sleep, which was associated with fewer transitions from non-REM (NREM) sleep to REM sleep than in control mice. Central 5-HT neuron-ablated mice showed attenuated wake response to a novel environment and increased theta power during wakefulness compared to control mice. The current findings indicated that adult 5-HT neurons work to support wakefulness and regulate REM sleep time through a biased transition from NREM sleep to REM sleep.

Highlights

Sleep/wake behavior is regulated by distinct groups of neurons located from the forebrain to the medulla (Luppi et al, 2011; Weber and Dan, 2016; Scammell et al, 2017)
Rosa26-DTRtdTomato mice were crossed with Pet1Cre mice (Scott et al, 2005; Liu et al, 2010), in which Cre is expressed in 5-HT neurons, intestinal epithelial cells and pancreatic islet cells in adult mice (Scott et al, 2005)
The present study demonstrated that the ablation of central 5-HT neurons in adult mice resulted in a reduction in total rapid eye movement (REM) sleep time that was associated with fewer transitions from NREM sleep to REM sleep

Summary

Introduction

Sleep/wake behavior is regulated by distinct groups of neurons located from the forebrain to the medulla (Luppi et al, 2011; Weber and Dan, 2016; Scammell et al, 2017). Serotonin (5-HT)-containing neurons are regarded as wake-promoting neurons (Saper et al, 2005; Scammell et al, 2017), the role of serotonergic neurons on sleep/wake behavior remains inconclusive (Ursin, 2002; Monti, 2011). The administration of pchlorophenylalanine (PCPA), which is an irreversible inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in the synthesis of 5-HT, induced insomnia, suggesting a role of the ascending serotonergic system in sleep enhancement (Mouret et al, 1968; Jouvet, 1999). Hypothermia after PCPA treatment may lead to insomnia (Murray et al, 2015)

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Results

Conclusion