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

研究成果: 雜誌貢獻文章

61 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)E3911-E3919
期刊Proceedings of the National Academy of Sciences of the United States of America
112
發行號29
DOIs
出版狀態已發佈 - 七月 21 2015
對外發佈Yes

指紋

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

ASJC Scopus subject areas

  • General

引用此文

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.

於: Proceedings of the National Academy of Sciences of the United States of America, 卷 112, 編號 29, 21.07.2015, p. E3911-E3919.

研究成果: 雜誌貢獻文章

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. 於: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; 卷 112, 編號 29. 頁 E3911-E3919.
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AB - 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.

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