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.
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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).
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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A highly-tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal
eLife 3:e05105.
https://doi.org/10.7554/eLife.05105
Further reading
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Dopamine drives an "ultradian" clock with a period of around four hours in mice.
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- Neuroscience
Complex structural and functional changes occurring in typical and atypical development necessitate multidimensional approaches to better understand the risk of developing psychopathology. Here, we simultaneously examined structural and functional brain network patterns in relation to dimensions of psychopathology in the Adolescent Brain Cognitive Development dataset. Several components were identified, recapitulating the psychopathology hierarchy, with the general psychopathology (p) factor explaining most covariance with multimodal imaging features, while the internalizing, externalizing, and neurodevelopmental dimensions were each associated with distinct morphological and functional connectivity signatures. Connectivity signatures associated with the p factor and neurodevelopmental dimensions followed the sensory-to-transmodal axis of cortical organization, which is related to the emergence of complex cognition and risk for psychopathology. Results were consistent in two separate data subsamples and robust to variations in analytical parameters. Although model parameters yielded statistically significant brain-behavior associations in unseen data, generalizability of the model was rather limited for all three latent components (r change from within- to out-of-sample statistics: LC1within=0.36, LC1out=0.03; LC2within=0.34, LC2out=0.05; LC3within=0.35, LC3out=0.07). Our findings help in better understanding biological mechanisms underpinning dimensions of psychopathology, and could provide brain-based vulnerability markers.
