Abstract
Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep–wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep–wake regulatory network.
Highlights
Hypocretin-1 and -2 (Hcrts; known as orexin-A and -B), excitatory neuropeptides synthesized in neurons located in the tuberal hypothalamus, are involved in metabolism, feeding, reward, addiction, and sleep–wake control (Ohno and Sakurai, 2008)
We find that eliminating either Hcrt receptor 1 (HcrtR1) signaling in the locus coeruleus (LC) or HcrtR2 signaling in the tuberomammillary nuclei (TMN) yields similar effects on ALM-induced REM sleep without affecting NREM sleep time
In DBH-SAP-injected rats, only a few scattered DBHpositive neurons were visible in the LC (Fig. 1C); bilateral counts in the LC revealed 15.75 Ϯ 4.2 DBH-positive cells in SAP-treated rats, ranging from 2 to 38 neurons remaining in individual animals
Summary
Hypocretin-1 and -2 (Hcrts; known as orexin-A and -B), excitatory neuropeptides synthesized in neurons located in the tuberal hypothalamus, are involved in metabolism, feeding, reward, addiction, and sleep–wake control (Ohno and Sakurai, 2008). Hcrt administration (Bourgin et al, 2000; Morairty et al, 2011) or optogenetic stimulation of Hcrt neurons (Adamantidis et al, 2007; Carter et al, 2010) is wake-promoting. Optogenetic inhibition or activation of LC norepinephrine (NE) neurons increases or decreases the likelihood of sleep, respectively (Carter et al, 2010). The LC expresses Hcrt receptor 1 (HcrtR1; Marcus et al, 2001) and Hcrt-1/ orexin-A infusion into the LC increases LC neuron firing and promotes wakefulness (Hagan et al, 1999; Bourgin et al, 2000) in a HcrtR1-dependent manner (Soffin et al, 2002; Choudhary et al, 2014). Optogenetic LC inactivation blocks transitions to wakefulness following Hcrt neuron activation (Carter et al, 2012), indicating that the LC is important for Hcrt-induced wakefulness
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
