Anatomical and electrophysiological development of the hypothalamic orexin neurons from embryos to neonates

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Sleep/wake is one of indispensable behaviors in mammals to maintain vital functions (Marks, Shaffery, Oksenberg, Speciale, & Roffwarg, 1995; Frank, Issa, & Stryker, 2001; Peirano, Algarı'n, & Uauy, 2003; Dumoulin Bridi et al., 2015). Sleep/wake states, namely wake, rapid‐eye movement (REM) sleep, and non‐REM sleep are defined by electroencephalography (EEG) and electromyography, sometimes supplemented or substituted by other indices such as ocular movement, respiration rate, heart rate, and high‐resolution ultrasound imaging in utero (Mirmiran, Maas, & Ariagno, 2003). By using these readouts, sleep/wake‐like states are detected at prenatal stages in humans and other mammals; gestation day 115–120 (0.8 term) sheep in utero showed sleep/wake transition (Szeto & Hinman, 1985), while REM and non‐REM‐like states can be distinguished in human fetuses between 28 and 31 weeks of gestation (Okai, Kozuma, Shinozuka, Kuwabara, & Mizuno, 1992).
The amount, quality, and diurnal pattern of sleep change greatly during development. For example, a prominent difference in sleep/wake architecture between fetuses/neonates and adults is the total amount of REM sleep; fetuses/neonates spend more than 60% of the day in REM sleep, while adults spend less than 10% of the day (Garcia‐Rill, Charlesworth, Heister, Ye, & Hayar, 2008; Hobson 2009). The quality of sleep in fetuses/neonates is quite different from that of adults; REM and non‐REM sleep in fetuses/neonates are called active and quiet sleep, respectively, and their EEG waveforms are mixed (Mirmiran et al., 2003; Peirano et al., 2003). Fetuses also have some unclassified period, so their sleep/wake can be considered undifferentiated. The amount of REM sleep gradually decreases with concomitant increase of non‐REM sleep and wake amount, while the duration of individual episodes gradually lengthens with development. In other words, sleep/wake states are severely fragmented at early postnatal stages and gradually consolidated through development. Notably, the trends of wake, REM and non‐REM sleep development are common in humans and other mammals (Jouvet‐Mounier, Astic, & Lacote, 1970; Szeto & Hinman, 1985; Garcia‐Rill et al., 2008; Hobson 2009). In rodents, the sleep/wake architecture matures by three weeks after birth (Jouvet‐Mounier et al., 1970; Vogel, Feng, & Kinney, 2000; Blumberg, Gall, & Todd, 2014).
The sleep/wake architecture is regulated by neuronal networks among a number of nuclei located in the hypothalamus, midbrain, and pons (Saper, Fuller, Pedersen, Lu, & Scammell, 2010). The regulatory mechanism is characterized by the flip‐flop model (Saper, Chou, & Scammell, 2001): during wake, monoaminergic neurons, that is, histaminergic tuberomammillary nucleus (TMN), noradrenergic locus coeruleus (LC), and serotonergic dorsal raphe (DR) neurons as well as peptidergic orexin neurons, are active and inhibit sleep‐active GABAergic neurons in the preoptic area (Hobson, McCarley, & Wyzinski, 1975; McGinty & Harper, 1976; Trulson & Jacobs 1979; Gallopin et al., 2000; Sakai & Crochet, 2001; Takahashi, Lin, & Sakai, 2006). Once the system switches to sleep state, preoptic neurons release GABA to repress monoaminergic and orexinergic neuronal activities, resulting in a suppression of wake state (Sakurai et al., 2005; Saito et al., 2013). Orexin neurons in the lateral hypothalamic area show tonic discharge mainly in wake (Mileykovskiy, Kiyashchenko, & Siegel, 2005; Lee, Hassani, & Jones, 2005; Takahashi, Lin, & Sakai, 2008). The orexin system is considered to be a stabilizer in the flip‐flop model that promotes and maintains wake states (Saper et al., 2001; Schöne et al., 2012). Deficiency of either orexin or orexin receptors (OX1R/OX2R) results in narcolepsy in humans and animal models, characterized by severe destabilization of sleep/wake states (Chemelli et al., 1999; Lin et al., 1999; Willie et al., 2003).
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