Research Article: Phospholipase C-β4 Is Essential for the Progression of the Normal Sleep Sequence and Ultradian Body Temperature Rhythms in Mice

Date Published: November 9, 2009

Publisher: Public Library of Science

Author(s): Masayuki Ikeda, Moritoshi Hirono, Takashi Sugiyama, Takahiro Moriya, Masami Ikeda-Sagara, Naomi Eguchi, Yoshihiro Urade, Tohru Yoshioka, Shin Yamazaki. http://doi.org/10.1371/journal.pone.0007737

Abstract: The sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Phospholipase C (PLC) mediates the signaling of numerous metabotropic receptors, including orexin receptors. Among the several PLC subtypes, the β4 subtype is uniquely localized in the geniculate nucleus of thalamus which is hypothesized to have a critical role in the transition and maintenance of sleep stages. In fact, we have reported irregular theta wave frequency during REM sleep in PLC-β4-deficient mutant (PLC-β4−/−) mice. Daily behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-β4−/− mice, however.

Partial Text: The behavioral state of sleep consists of two basic stages: (1) rapid-eye-movement (REM) sleep with typical theta electroencephalogram (EEG) waves and (2) restful non-REM sleep, with slow EEG waves. The sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, with REM sleep consistently following non-REM sleep. While understanding of the REM-regulating network remains incomplete, it is known that in general, the occurrence of REM sleep follows the generation of ponto-geniculo-occipital waves that arise in the pons and are transmitted to the thalamic lateral geniculate nucleus (LGN) and visual occipital cortex. The REM-On neurons in the laterodorsal and pedunculopontine tegmental nuclei under the regulation of serotonergic dorsal raphe neurons and noradrenergic locus coeruleus neurons may be critical for the activation of the pontine reticular formation (PRF) and ultimately contribute to the shift to REM sleep [1], [2]. However, understanding of the REM-regulating network is incomplete due to the large network size.

The results of the present study demonstrate that PLC-β4−/− mice exhibited increased REM sleep during the night and unusual wake-to-REM sleep transitions. Immunoreactivity to PLC-β4 was detected in the thalamus, superior colliculus, and cerebellum in mouse brain, with the highest expression levels in the thalamus observed in the LGNd and MGN (Fig. 3). To our knowledge, there is currently no evidence that suggests that either the cerebellum or MGN are involved in sleep regulation. Based on aspiration lesion data, Miller and colleagues suggested that the superior-colliculus-pretectum complex was involved in light-regulated REM-sleep episodes [25], but their more recent studies using more specific lesions demonstrated that it is the pretectum-geniculate complex that is important in this sleep regulation [26]. LGNd relay neurons are part of a glutamatergic corticothalamic feedback loop, which is hypothesized to have a critical role in the transition and maintenance of sleep stages [17]–[19]. Therefore, of the PLC-β4 immunoreactive brain areas, the LGNd is the most likely site of functional change underlying the irregular REM sleep observed in PLC-β4−/− mice.

Source:

http://doi.org/10.1371/journal.pone.0007737

 

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