期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 29, 页码 E3911-E3919出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420753112
关键词
GABA; circadian; mathematical modeling; synchronization; network
资金
- Human Frontiers of Science Program [RPG 24/2012]
- Air Force Office of Scientific Research Grant [FA 9550-14-1-0092]
- RIKEN Incentive Research Project [G1E-54500]
- Ministry of Education, Culture, Sports, Science and Technology in Japan
- CREST from the Japan Science and Technology Agency
- Biotechnology and Biological Sciences Research Council UK Project [BB/L007665]
- Wellcome Trust Project [WT092319MA]
- National Science Foundation Grant [ACI-1053575]
- Grants-in-Aid for Scientific Research [25242077] Funding Source: KAKEN
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据