title: Fine-Tuning Circadian Rhythms: The Importance ofBmal1Expression in the Ventral Forebrain.
abstract: Although, the suprachiasmatic nucleus (SCN) of the hypothalamus acts as the central clock in mammals, the circadian expression of clock genes has been demonstrated not only in the SCN, but also in peripheral tissues and brain regions outside the SCN. However, the physiological roles of extra-SCN circadian clocks in the brain remain largely elusive. In response, we generatedNkx2.1-Bmal1-/-mice in whichBmal1, an essential clock component, was genetically deleted specifically in the ventral forebrain, including the preoptic area, nucleus of the diagonal band, and most of the hypothalamus except the SCN. In these mice, as expected, PER2::LUC oscillation was drastically attenuated in the explants of mediobasal hypothalamus, whereas it was maintained in those of the SCN. Although,Nkx2.1-Bmal1-/-mice were rhythmic and nocturnal, they showed altered patterns of locomotor activity during the night in a 12:12-h light:dark cycle and during subjective night in constant darkness. Control mice were more active during the first half than the second half of the dark phase or subjective night, whereasNkx2.1-Bmal1-/-mice showed the opposite pattern of locomotor activity. Temporal patterns of sleep-wakefulness and feeding also changed accordingly. Such results suggest that along with mechanisms in the SCN, localBmal1-dependent clocks in the ventral forebrain are critical for generating precise temporal patterns of circadian behaviors.
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mieda
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Hasegawa
authors.affiliation: Department of Cell and Developmental Biology, Wolfson Institute for Biomedical Research, University College London London, UK.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Kessaris
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
keywords: Nkx2.1; bmal1; circadian rhythm; food intake; hypothalamus; sleep-wakefulness regulation