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Inactivation of the Tuberomammillary Nucleus by GABAA Receptor Agonist Promotes Slow Wave Sleep in Freely Moving Rats and Histamine-Treated Rats

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Abstract

A prominent hypothesis, the “flip–flop switch” model, predicts that histaminergic (HAergic) neurons in the tuberomammillary nucleus (TMN), an important component of the ascending arousal system, are inactivated by GABA mainly from the ventrolateral preoptic nucleus to allow the appearance and maintenance of sleep. However, which sleep state and the band of EEG activity induced by GABAergic inactivation of the TMN are unclear. In this study, alterations of sleep-wake states and cortical EEG power spectral density were investigated following muscimol, a GABAA-receptor agonist, microinjected bilaterally into the TMN in freely moving rats and HA pretreated rats, respectively. Muscimol dosed at 0.25 and 0.50 μg/side into the TMN during dark period dose-dependently increased slow wave sleep (SWS) accompanied by an increase in cortical EEG delta (0.5–4 Hz) and spindle (8.2–12 Hz) activities. In the meanwhile, wakefulness and EEG beta (12.2–30 Hz) activity were decreased significantly, while paradoxical sleep and EEG theta (4.2–8 Hz) activity were not changed. The increase of muscimol-induced SWS was because of prolonged SWS bout duration and not to an increased bout number. Muscimol (0.50 μg/side) administration 2 h after HA (0.125 μg/side) treatment during light period reversed the HA-induced wakefulness and EEG beta 2 (20.2–30 Hz) activity into SWS and EEG delta activity. These results demonstrate that the GABAergic inactivation of the TMN in freely moving rats and HA-treated rats promotes SWS and slow activity of cortical EEG, suggesting that the potential function of the GABAA receptor in the TMN is to dampen vigilant arousal.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (30670677, 81071076, 81171254 and 81471347 to YPH; 31500853 to YFS) and the Fundamental Research Funds for the Central University (lzujbky-2015-167 and lzujbky-2015-277 to YFS). The authors declare no conflicts of interest in this manuscript.

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    1. Department of Neuroscience, Anatomy, Histology and Embryology, Key laboratory of preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 199 Donggang Xi Road, Lanzhou, 730000, People’s Republic of China

      Jun-Fan Xie, Kun Fan, Can Wang, Peng Xie, Min Hou, Le Xin, Guang-Fu Cui, Lin-Xin Wang, Yu-Feng Shao & Yi-Ping Hou

    2. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Gansu University of Chinese Medicine, 35 Dingxi Dong Road, Lanzhou, 730000, People’s Republic of China

      Min Hou

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    Xie, JF., Fan, K., Wang, C. et al. Inactivation of the Tuberomammillary Nucleus by GABAA Receptor Agonist Promotes Slow Wave Sleep in Freely Moving Rats and Histamine-Treated Rats. Neurochem Res 42, 2314–2325 (2017). https://doi.org/10.1007/s11064-017-2247-3

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