Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping

Daniel DeWoskin, Jihwan Myung, Mino D.C. Belle, Hugh D. Piggins, Toru Takumi, Daniel B. Forger

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

The suprachiasmatic nuclei (SCN), the central circadian pacemakers in mammals, comprise a multiscale neuronal system that times daily events. We use recent advances in graphics processing unit computing to generate a multiscale model for the SCN that resolves cellular electrical activity down to the timescale of individual action potentials and the intracellular molecular events that generate circadian rhythms. We use the model to study the role of the neurotransmitter GABA in synchronizing circadian rhythms among individual SCN neurons, a topic of much debate in the circadian community. The model predicts that GABA signaling has two components: phasic (fast) and tonic (slow). Phasic GABA postsynaptic currents are released after action potentials, and can both increase or decrease firing rate, depending on their timing in the interspike interval, a modeling hypothesis we experimentally validate; this allows flexibility in the timing of circadian output signals. Phasic GABA, however, does not significantly affect molecular timekeeping. The tonic GABA signal is released when cells become very excited and depolarized; it changes the excitability of neurons in the network, can shift molecular rhythms, and affects SCN synchrony. We measure which neurons are excited or inhibited by GABA across the day and find GABA-excited neurons are synchronized by-and GABA-inhibited neurons repelled from-this tonic GABA signal, which modulates the synchrony in the SCN provided by other signaling molecules. Our mathematical model also provides an important tool for circadian research, and a model computational system for the many multiscale projects currently studying brain function.

Original languageEnglish
Pages (from-to)E3911-E3919
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number29
DOIs
Publication statusPublished - Jul 21 2015
Externally publishedYes

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gamma-Aminobutyric Acid
Suprachiasmatic Nucleus
GABAergic Neurons
Circadian Rhythm
Neurons
Action Potentials
Synaptic Potentials
Neurotransmitter Agents
Mammals
Theoretical Models
Brain
Research

Keywords

  • Circadian
  • GABA
  • Mathematical modeling
  • Network
  • Synchronization

ASJC Scopus subject areas

  • General

Cite this

Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping. / DeWoskin, Daniel; Myung, Jihwan; Belle, Mino D.C.; Piggins, Hugh D.; Takumi, Toru; Forger, Daniel B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 29, 21.07.2015, p. E3911-E3919.

Research output: Contribution to journalArticle

DeWoskin, Daniel ; Myung, Jihwan ; Belle, Mino D.C. ; Piggins, Hugh D. ; Takumi, Toru ; Forger, Daniel B. / Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 29. pp. E3911-E3919.
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