A highly-tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal

  1. Ian D Blum
  2. Lei Zhu
  3. Luc Moquin
  4. Maia V Kokoeva
  5. Alain Gratton
  6. Bruno Giros
  7. Kai-Florian Storch  Is a corresponding author
  1. McGill University, Canada
  2. Douglas Mental Health University Institute, Canada

Abstract

Ultradian (~4 h) rhythms in locomotor activity that do not depend on the master circadian pacemaker in the suprachiasmatic nucleus have been observed across mammalian species, however, the underlying mechanisms driving these rhythms are unknown. We show that disruption of the dopamine transporter gene lengthens the period of ultradian locomotor rhythms in mice. Period lengthening also results from chemogenetic activation of midbrain dopamine neurons and psychostimulant treatment, while the antipsychotic haloperidol has the opposite effect. We further reveal that striatal dopamine levels fluctuate in synchrony with ultradian activity cycles and that dopaminergic tone strongly predicts ultradian period. Our data indicate that an arousal regulating, dopaminergic ultradian oscillator (DUO) operates in the mammalian brain, which normally cycles in harmony with the circadian clock, but can desynchronize when dopamine tone is elevated, thereby producing aberrant patterns of arousal which are strikingly similar to perturbed sleep-wake cycles comorbid with psychopathology.

Article and author information

Author details

  1. Ian D Blum

    Department of Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Lei Zhu

    Department of Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Luc Moquin

    Douglas Mental Health University Institute, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Maia V Kokoeva

    Department of Medicine, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Alain Gratton

    Department of Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Bruno Giros

    Department of Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Kai-Florian Storch

    Department of Psychiatry, McGill University, Montreal, Canada
    For correspondence
    florian.storch@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States

Ethics

Animal experimentation: All experimental procedures were performed in accordance with the Canadian Council on Animal Care guidelines and approved by the McGill University Animal Care Committee (animal use protocol #2010-5945).

Version history

  1. Received: October 10, 2014
  2. Accepted: December 28, 2014
  3. Accepted Manuscript published: December 29, 2014 (version 1)
  4. Version of Record published: February 12, 2015 (version 2)

Copyright

© 2014, Blum et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ian D Blum
  2. Lei Zhu
  3. Luc Moquin
  4. Maia V Kokoeva
  5. Alain Gratton
  6. Bruno Giros
  7. Kai-Florian Storch
(2014)
A highly-tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal
eLife 3:e05105.
https://doi.org/10.7554/eLife.05105

Share this article

https://doi.org/10.7554/eLife.05105

Further reading

  1. Dopamine drives an "ultradian" clock with a period of around four hours in mice.

    1. Cell Biology
    2. Neuroscience
    Zhenyong Wu, Grant F Kusick ... Shigeki Watanabe
    Research Article

    Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.