title: GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time.
abstract: The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABAA-mediated synaptic input. We show that increasing day-length changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABAA signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation-inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN.
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan; Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan;
authors.forename: Jihwan
authors.identifier: http://orcid.org/0000-0002-2529-8013
authors.initials: J
authors.lastname: Myung
authors.affiliation: Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Onna, Okinawa 904-0495, Japan;
authors.forename: Sungho
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Mathematics, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Daniel
authors.initials: D
authors.lastname: DeWoskin
authors.affiliation: Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Onna, Okinawa 904-0495, Japan;
authors.forename: Erik
authors.initials: E
authors.lastname: De Schutter
authors.affiliation: Department of Mathematics, University of Michigan, Ann Arbor, MI 48109; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Forger
authors.affiliation: RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan; Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Chiyoda-ku, Tokyo 102-0076, Japan toru.takumi@riken.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism; D057906:Circadian Clocks / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D042541:Intracellular Space / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D012621:Seasons; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D002712:Chlorides; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid
keywords: GABA; SCN; chloride; day-length encoding; repulsive coupling