A highly-tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal
- McGill University, Canada
- 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
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).
Reviewing Editor
- Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States
Publication history
- Received: October 10, 2014
- Accepted: December 28, 2014
- Accepted Manuscript published: December 29, 2014 (version 1)
- 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.
Metrics
-
- 9,099
- Page views
-
- 1,053
- Downloads
-
- 95
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
A highly-tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal
eLife 3:e05105.
https://doi.org/10.7554/eLife.05105
Further reading
-
Dopamine drives an "ultradian" clock with a period of around four hours in mice.
-
- Neuroscience
Fluctuations in brain and behavioral state are supported by broadly projecting neuromodulatory systems. In this study, we use mesoscale two-photon calcium imaging to examine spontaneous activity of cholinergic and noradrenergic axons in awake mice in order to determine the interaction between arousal/movement state transitions and neuromodulatory activity across the dorsal cortex at distances separated by up to 4 mm. We confirm that GCaMP6s activity within axonal projections of both basal forebrain cholinergic and locus coeruleus noradrenergic neurons track arousal, indexed as pupil diameter, and changes in behavioral engagement, as reflected by bouts of whisker movement and/or locomotion. The broad coordination in activity between even distant axonal segments indicates that both of these systems can communicate, in part, through a global signal, especially in relation to changes in behavioral state. In addition to this broadly coordinated activity, we also find evidence that a subpopulation of both cholinergic and noradrenergic axons may exhibit heterogeneity in activity that appears to be independent of our measures of behavioral state. By monitoring the activity of cholinergic interneurons in the cortex, we found that a subpopulation of these cells also exhibit state-dependent (arousal/movement) activity. These results demonstrate that cholinergic and noradrenergic systems provide a prominent and broadly synchronized signal related to behavioral state, and therefore may contribute to state-dependent cortical activity and excitability.
