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Serotonin Neurons in the Dorsal Raphe Mediate the Anticataplectic Action of Orexin Neurons by Reducing Amygdala Activity

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Serotonin Neurons in the Dorsal Raphe Mediate the Anticataplectic Action of Orexin Neurons by Reducing Amygdala Activity Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity Emi Hasegawaa,1, Takashi Maejimaa, Takayuki Yoshidab, Olivia A. Masseckc, Stefan Herlitzec, Mitsuhiro Yoshiokab, Takeshi Sakuraia,1, and Michihiro Miedaa,2 aDepartment of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan; bDepartment of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and cDepartment of General Zoology and Neurobiology, Ruhr-University Bochum, 44780 Bochum, Germany Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 20, 2017 (received for review August 31, 2016) Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)- Orexin neurons are distributed within the lateral hypothala- producing neurons and marked by excessive daytime sleepiness and a mus and send projections throughout the brain and spinal cord. sudden weakening of muscle tone, or cataplexy, often triggered by There are particularly dense innervations to nuclei containing strong emotions. In a mouse model for narcolepsy, we previously monoaminergic and cholinergic neurons that constitute the as- demonstrated that serotonin neurons of the dorsal raphe nucleus cending activating system in the brainstem and the hypothalamus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by (5, 6). We previously elucidated two critical efferent pathways of orexin neurons. Using an optogenetic tool, in this paper we show that orexin neurons; serotonin neurons in the dorsal raphe nucleus the acute activation of DRN serotonin neuron terminals in the amyg- (DRN) inhibit cataplexy-like episodes (CLEs), whereas norad- dala, but not in nuclei involved in regulating rapid eye-movement renergic neurons in the locus coeruleus (LC) stabilize wakeful- sleep and atonia, suppressed CLEs. Not only did stimulating serotonin ness episodes (8). In that study, we called direct transitions from nerve terminals reduce amygdala activity, but the chemogenetic in- wakefulness to REM sleep shown in EEG/EMG data CLEs, in hibition of the amygdala using designer receptors exclusively acti- reference to Scammell et al. (9), which were nearly equivalent to vated by designer drugs also drastically decreased CLEs, whereas murine cataplexy, although the mice were not videotaped to chemogenetic activation increased them. Moreover, the optogenetic confirm their immobility during such episodes. inhibition of serotonin nerve terminals in the amygdala blocked To further clarify the pathophysiology of narcolepsy and regulation the anticataplectic effects of orexin signaling in DRN serotonin of sleep/wakefulness by orexin neurons, we aimed to identify the neurons. Taken together, the results suggest that DRN serotonin downstream target that mediates the anticataplectic effects of sero- neurons, as a downstream target of orexin neurons, inhibit cata- tonin neurons in the DRN that also send widespread projections plexy by reducing the activity of amygdala as a center for throughout the brain (10–12). Based on evidence using electrophys- emotional processing. iological, neurochemical, genetic, and neuropharmacological ap- proaches, DRN serotonin neurons have long been implicated in sleep | narcolepsy | orexin | serotonin | amygdala promoting wakefulness and suppressing REM sleep (13, 14). Along with regulating sleep/wakefulness, serotonin in the brain has been arcolepsy type 1 (narcolepsy with cataplexy) is a debilitating Nsleep disorder caused by degenerative loss of neurons pro- Significance ducing the neuropeptides orexin A and orexin B (orexin neu- rons) (1–3). Its symptoms can be divided into two independent Although the neurodegeneration of orexin (hypocretin)-producing pathological phenomena (4, 5). The first phenomenon is dysre- neurons clearly causes the sleep disorder narcolepsy, the precise gulation of nonrapid eye-movement (NREM) sleep onset: the in- neural mechanisms by which orexin neurons prevent narcolepsy ability to maintain a consolidated awake period that is characterized remain unclear. We previously demonstrated that orexin neurons by abrupt transitions from wakefulness to NREM sleep. This phe- inhibit cataplexy-like episodes—cataplexy is a cardinal symptom of nomenon manifests itself clinically as excessive daytime sleepiness narcolepsy, characterized by a sudden weakening of muscle tone— or sleep attacks. The second phenomenon is dysregulation of rapid via serotonin neurons in the dorsal raphe nucleus (DRN). We thus eye-movement (REM) sleep onset: the pathological intrusion of used optogenetic and chemogenetic approaches to demonstrate REM sleep or REM atonia at sleep onset or into wakefulness. It is that DRN serotonin neurons suppress cataplexy-like episodes by during these periods that patients may experience hypnagogic hal- reducing the activity of the amygdala that plays an important role lucinations, sleep paralysis, and cataplexy. Cataplexy manifests as in emotional processing, as consistent with the fact that strong sudden episodes of muscle weakness without consciousness im- emotions often trigger cataplexy. We therefore propose that the pairment triggered by strong emotions of positive valence, including orexin neuron–DRN serotonin neuron–amygdala pathway is a crit- laughter, joking, and delight. ical circuit for preventing cataplexy. Similarly, mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy type 1 phenotypes to fur- Author contributions: E.H., T.M., and M.M. designed research; E.H., T.M., T.Y., M.Y., and ther highlight the critical role that orexin signaling plays in the M.M. performed research; T.M., O.A.M., S.H., and T.S. contributed new reagents/analytic – tools; E.H., T.M., T.Y., M.Y., and M.M. analyzed data; and E.H., T.M., and M.M. wrote maintenance of wakefulness (5 7). The mice demonstrate markedly the paper. decreased duration of wakefulness episodes during the dark phase The authors declare no conflict of interest. (i.e., inability to maintain a long awake period, or sleepiness), abrupt This article is a PNAS Direct Submission. behavioral arrests with muscle atonia that manifest as direct tran- 1Present address: International Institute for Integrative Sleep Medicine, University of sitions from wakefulness to REM sleep in electroencephalogram/ Tsukuba, Tsukuba 305-8575, Japan. electromyogram (EEG/EMG) recordings (i.e., cataplexy), decreased 2To whom correspondence should be addressed. Email: [email protected]. REM sleep latency, and increased REM sleep time during the This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. dark phase. 1073/pnas.1614552114/-/DCSupplemental. E3526–E3535 | PNAS | Published online April 10, 2017 www.pnas.org/cgi/doi/10.1073/pnas.1614552114 Downloaded by guest on September 28, 2021 implicated in various sensorimotor, affective, and cognitive behaviors activity of serotonin neurons directly or indirectly, if not both, as PNAS PLUS (15–18). Therefore, identifying the action site of DRN serotonin consistent with the role of orexin signaling in DRN serotonin neurons in preventing CLEs can shed additional light on the multiple neurons in inhibiting CLEs. functions of the serotonin system. Knowing that DRN serotonin neurons send projections throughout the brain (10–12), we aimed to determine the site of Results the anticataplectic action of those neurons: that is, the down- Optogenetic Activation of Serotonin Neurons in the DRN Suppresses stream targets of DRN serotonin neurons in suppressing CLEs. CLEs in Narcoleptic orexin-ataxin3 Mice. We previously demon- To that end, we used channelrhodopsin-2 (ChR2) to activate the strated that serotonin neurons of the DRN mediate an anti- neurons because axonal projections of ChR2-expressing neurons cataplectic action of orexin neurons (8). To further confirm the can be selectively activated at each target site (20). To minimize physiological importance of orexinergic activation in DRN se- light illumination, we used a variant of ChR2—namely, the sta- rotonin neurons, we compared the activity of DRN serotonin bilized step-function opsin (SSFO) (21)—whose activation with a neurons between control and orexin neuron-deficient (orexin- single blue-light pulse increases the excitability of targeted cells ataxin3) mice (7) by measuring Fos protein expression. To in- during depolarization sustained for more than 30 min. Accord- crease cataplexy, we gave chocolate to the mice beginning at the ingly, we expressed SSFO in serotonin neurons of the DRN by onset of the dark phase (19), as shown in Fig. S1. Fos expres- stereotaxically microinjecting a Cre-inducible adeno-associated sion in the tryptophan hydroxylase 2 (TPH2)-positive serotonin virus (AAV) vector (20) AAV-EF1α-DIO-SSFO-EYFP (DIO: neurons of the DRN after 90 min of chocolate feeding was sig- double-floxed inverted open-reading-frame) in the DRN of nificantly lower in orexin-ataxin3 mice than in control mice (Fig. orexin-ataxin3 mice crossed with Sert-Cre mice (22), which ex- 1). That result suggests that orexin neurons indeed enhance the presses Cre recombinase specifically in serotonin neurons (Sert- Cre;orexin-ataxin3 mice). In those mice, SSFO-EYFP was + + expressed in 92.3 ± 3.62% of TPH2 cells, and 100% of EYFP + cells were TPH2 (n = 5), which confirms the targeted expres- sion of SSFO
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