Research report
Circadian rhythms in behavior and clock gene expressions in the brain of mice lacking histidine decarboxylase

https://doi.org/10.1016/j.molbrainres.2004.02.015Get rights and content

Abstract

To clarify functional roles of histamine in the circadian clock system, circadian rhythms of behavior and clock gene expression in the brain were examined in the mouse lacking histidine decarboxylase (HDC−/− mouse). Wheel-running and spontaneous locomotion were recorded under light–dark cycle (LD) and constant darkness (DD). mPer1, mPer2 and mBMAL1 mRNA expression rhythms under LD and DD were measured in the suprachiasmatic nucleus (SCN), cerebral cortex and striatum by in situ hybridization. The activity levels under LD and DD in the HDC−/− mice were lower than that in the wild type regardless of activity types (wheel-running and spontaneous locomotion). The free-running period under DD was significantly longer in the HDC−/− mice than in the wild type. The 24-h profiles of mPer1, mPer2 and mBMAL1 mRNA expressions in the SCN were not different between the two genotypes. By contrast, the mPer1 and mPer2 mRNA rhythms in the other brain areas such as the cortex and striatum were significantly disrupted in the HDC−/− mice. These results suggest that histamine is involved in the circadian system especially in the output pathway or feedback route from behavior to the pacemaker in the SCN, and that mPer genes in the brain areas outside the SCN play an important role in the expression of behavioral rhythm.

Introduction

A functional correlate has been suggested between the circadian system and physical activity. Previously, Aschoff et al. [4] demonstrated significant effects of types of actograph on the free-running period of behavioral rhythm. More recently, induced physical activity by novel running-wheel was shown to phase-shift the locomotor rhythm in hamsters [28]. Free-running periods in rats under constant darkness (DD) were reported to be changed by changing an actograph from the running-wheel to Animex, which measures spontaneous activity [40]. These findings suggest a feedback from behavior or arousal state to the circadian pacemaker.

Histamine has been suggested to play an important role in the arousal mechanism [6]. Injections of histamine into the brain caused arousal reactions in electroencephalograph (EEG) [23], [24], [26]. Inhibition of histamine synthesis by α-fluoromethylhistidine (α-FMH) led to a reduction of the wakefulness in cats and rats [19], [22], [27]. In addition, recent studies demonstrated that orexin increased histamine release in the anterior hypothalamus and frontal cortex, which was accompanied by an increase in the electrical activity of histaminergic neurons in the tuberomammilary nucleus (TM) in parallel with arousal induction [9], [14]. These results indicate that histamine acts as an arousal factor in the brain.

On the other hand, histamine was suggested to be involved in the regulation of mammalian circadian rhythm. Application of histamine induced phase-shifts in the circadian rhythm of rat's locomotor activity [17], [18] and of neuronal activity in the suprachiasmatic nucleus (SCN), a site of the mammalian circadian pacemaker [7], in a phase-dependent manner. The α-FMH disrupts the free-running circadian activity rhythm in rats [17]. Morphologically, the SCN receives rich histaminergic innervations from the TM [38], and exhibits high density of histamine H1 receptor in rats [32]. These two aspects of histamine raise the hypothesis that histamine is involved in the feedback pathway from behavior to the circadian pacemaker.

A transcription/translation autoregulatory loop of Period genes (Per1 and Per2) is thought to generate the circadian oscillation in mammals [8], [34]. Recently, the clock genes in the areas outside the SCN were demonstrated to associate with behavioral outputs of the circadian system in rats treated with methamphetamine [25], in CS mice, a spontaneous rhythm splitting inbred strain [2], [3], and in mice under restricted feeding schedule [37]. These findings suggest that the Per gene expression rhythms outside the SCN are functionally associated with enhanced or altered behavior rhythms and a close relation between the arousal and circadian systems.

One of the authors produced histamine deficient mice by homologous recombination targeting the whole gene of l-histidine decarboxylase (HDC), an enzyme for histamine synthesis from histidine [30]. These mice have been used to clarify the mechanisms of histamine effects on several known phenotypes, i.e., gastric acid secretion [35], contraction of smooth muscles [20] and vascular permeability [31], and also used to explore new effects of histamine [12], [21]. In order to understand roles of histamine in the circadian system more directly, we analyzed the circadian behavior rhythms and rhythms of clock gene expression (mPer1, mPer2 and mBMAL1) in and outside the SCN in the HDC-deficient (HDC−/−) mice.

Section snippets

Animals

This study was performed in compliance with Rules and Regulations of the Animal Care and Use Committee, Hokkaido University Graduate School of Medicine, and followed the Guide for the Care and Use of Laboratory Animals, Hokkaido University Graduate School of Medicine.

Homozygous HDC−/− and wild-type mice were provided by Department of Cellular Pharmacology, Tohoku University Graduate School of Medicine, and were maintained in our laboratory. The HDC−/− mice were generated according to previously

Body weight and food and water intakes

The mean body weights of HDC−/− and wild-type mice were 31.44±0.62 and 30.43±0.89 g (mean±S.E.M.), respectively. The mean daily food intake was 4.09±0.12 g for HDC−/− and 3.71±0.33 g for wild type. The mean daily water intake was 5.53±0.21 g for HDC−/− and 5.61±0.47 g for wild type. There were no significant differences between the two genotypes in these parameters (t test).

Behavioral rhythms

Fig. 1 shows representative circadian rhythms in wheel-running activity and spontaneous locomotion in wild-type and HDC−/−

Discussion

The present study demonstrates several phenotypes of homozygous HDC−/− mice in behavior and clock gene expressions in the brain; low physical activity under LD and DD, a lengthening of free-running period under DD, and damped circadian rhythms in mPer1 and mPer2 expressions in the brain areas outside the SCN. These findings suggest that histamine is involved in the expression of circadian behavioral rhythm in mice. Neither body weight nor daily food and water intakes in HDC−/− were different

Acknowledgements

This research was supported by the Grant-in-Aid from the Ministry of Education, Science, Sports and Culture (14570054 and 11233201). We are grateful to Ms. T. Yasuda and K. Hosono for animal care.

References (40)

  • J.S Lin et al.

    Evidence for histaminergic arousal mechanisms in the hypothalamus of cat

    Neuropharmacology

    (1988)
  • J.M Monti

    Involvement of histamine in the control of the waking state

    Life Sci.

    (1993)
  • H Ohtsu et al.

    Mice lacking histidine decarboxylase exhibit abnormal mast cells

    FEBS Lett.

    (2001)
  • J.M Palacios et al.

    The distribution of histamine H1-receptors in the rat brain: an autoradiographic study

    Neuroscience

    (1981)
  • S Tanaka et al.

    Gastric acid secretion in l-histidine decarboxylase deficient mice

    Gastroenterology

    (2002)
  • T Watanabe et al.

    Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker

    Brain Res.

    (1984)
  • N Yamada et al.

    Change in period of free-running rhythms determined by two different tools in blinded rats

    Physiol. Behav.

    (1986)
  • K Yanai et al.

    Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors

    Neuroscience

    (1998)
  • H Abe et al.

    Behavioral rhythm splitting in the CS mouse is related to clock gene expression outside the suprachiasmatic nucleus

    Eur. J. Neurosci.

    (2001)
  • J Aschoff et al.

    Circadian rhythms of locomotor activity in the golden hamster (Mesocricetus auratus) measured with two different techniques

    J. Comp. Physiol. Psychol.

    (1973)
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