Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: A study using a knockout mouse model
Introduction
Neurons containing histamine (HA) are located in the tuberomamillary nucleus and the adjacent posterior hypothalamus. They send widespread inputs to most cerebral areas. In freely-moving cats and behaving mice, these neurons fire tonically and exclusively during wakefulness (W) (Sakai et al., 1990, Vanni-Mercier et al., 2003, Takahashi et al., 2006), a pattern of activity that is the most wake-selective one among the brain activating systems identified to date. This wake-selective activity enhances cellular excitability and activity of a wide range of target cells via different HA receptor subtypes (reviewed in Schwartz et al., 1991, Lin, 2000, Brown et al., 2001, Haas et al., 2008, Vu et al., 2015, Panula et al., 2015), contributing to a general cortical activation during W. Hence, impairment of the brain histaminergic transmission using pharmacological interventions or knockout (KO) mouse models causes somnolence and wake deficits, whereas enhancement of transmission promotes cortical arousal and W (Lin et al., 1986, Monti et al., 1991, Lin, 2000, Lin et al., 2011a). HA neurons make multiple interactions with other brain arousal systems such as cholinergic aminergic and orexinergic neurons (reviewed in McCormick, 1992, Lin, 2000, Haas et al., 2008, Haas and Lin, 2012). The latter ones send particularly dense inputs to HA cells and excite them by direct depolarization through orexin-2 receptors (Eriksson et al., 2001). Mice selectively lacking the orexin-2 receptors show signs of chronic sleepiness, a phenotype rescued by restoration of orexin-2 receptors on neurons in the tuberomamillary areas (Mochizuki et al., 2011). Recently, the wake-promoting effects of HA were shown to be balanced by its co-neurotransmitter GABA (Yu et al., 2015).
Using KO mice lacking the HA-synthesizing enzyme, histidine decarboxylase (HDC), we have previously shown that long-term abolition of HA impairs cortical EEG, deteriorates both sleep and waking quality, causing sleepiness and behavioral deficits. Consequently, these mice are unable to remain awake in crucial situations, such as at lights-off or when faced with an environmental change (Parmentier et al., 2002, Anaclet et al., 2009, Lin et al., 2011b).
Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for its wake-promoting effects. The importance of the H1-receptor has long been suggested because brain–penetrating H1-receptor antagonists cause sedation and drowsiness in man and increase in slow wave sleep in animals (Douglas, 1985, Nicholson and Stone, 1986, Schwartz et al., 1991, Yanai et al., 1999, Lin, 2000, Panula et al., 2015). However, whether the long-term loss of H1-receptors causes similar genotypes of HDC KO mice in terms of EEG, behavioral states and how the brain remains awake during deficiency of a brain activating system remains unknown. We have therefore studied and compared the cortical EEG and sleep-wake cycle under baseline conditions and after behavioral challenges in littermate wild type and H1-receptor knockout mice. In order to assess brain plasticity involved in wake maintenance during deficiency of an activating system, we also compared in those mice pharmacological responses to ligands of the aminergic and cholinergic systems known for their role in controlling cortical activities and the sleep-wake cycle.
Section snippets
Detection of the histamine H1-receptor gene using PCR and in situ hybridization
At 3 weeks of age, tail biopsies were taken from all mice and analyzed by PCR for genotyping. The WT allele was amplified using primers located within the H1 gene and the KO allele was amplified with one primer within the neomycin resistance cassette. These primers were 5′-TGA AGT ATC TGG CTC TGA GTG G-3′ (5′-primer 5′-upstream of H1R gene) and 5′- CCA TCG ATG GCT CCC TCC CTG GGA G -3′ (H1R gene 5′-primer complementary to H1R gene), the expected product size being 1100 base pairs. The mutant
Genotyping by PCR and in situ hybridization
We performed PCR on genomic DNA from tail biopsies from all mice. As shown in Fig. 1A, a strong H1 receptor signal, corresponding to a 1100 base pair band, was detected in the H1+/+ mice (animals 1–14 in Fig. 1), and a strong Neor signal, corresponding to a 900 base pair band, was detected in the H1−/− mice (animals 15–28), proof that, in the KO animals, the H1-receptor gene had been disrupted and the Neor gene inserted.
The deletion of H1-receptor gene was further confirmed by in situ
Major sleep-wake phenotypes of H1-receptor−/− mice
We showed here that the sleep-wake cycle in H1−/− mice was affected both quantitatively and qualitatively. On the one hand, these mice exhibited a deficit of W just after lights-off in spite of an unaffected daily amount. On the other hand, their cortical EEG showed a reduced SWS/W power ratio and a significant deficit of θ rhythms (3–9 Hz) during W. These changes likely impacted the animal's behavior, as they presented signs of sleepiness, uncovered through a significant decrease in sleep
Acknowledgments
This work was supported by INSERM U480, U628, U1028-Waking team, Claude Bernard University and by the European Contract No. QLRT-2001-00826 (5th PCRDT). The doctoral fellowship of R. Parmentier was provided by the Ministère de l’éducation nationale, de la recherche et de la technologie (France). The fellowship of Y. Zhao was provided by the Institut Franco-Chinois (Lyon, France). We thank the late Dr. Jean-Louis Valatx for help at the start of the project and Dr. Luc Gentet for critical reading
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- 1
Equal contribution.
- 2
Present Institution: Forgetting Team, CRNL, INSERM-U1028, CNRS-UMR5292, Cl. Bernard University, Lyon, France.
- 3
Present Institution: University of Turku and Turku University Hospital, Finland.