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

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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.

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Ian D Blum

Department of Psychiatry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Lei Zhu

Department of Psychiatry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Luc Moquin

Douglas Mental Health University Institute, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Maia V Kokoeva

Department of Medicine, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Alain Gratton

Department of Psychiatry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Bruno Giros

Department of Psychiatry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
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.

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).

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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.