Abstract
Ultradian (~4 hr) 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.
Highlights
Ultradian rhythms with periods ranging from one to several hours have been linked to various aspects of mammalian physiology
We examined running wheel activity in mice carrying a disruption in the Slc6a3 gene, which encodes the dopamine transporter (DAT)
The ∼12-hr rhythms observed in SCNx-Slc6a3−/− and Bmal1−/−, Slc6a3−/− animals may originate from an independent oscillator, one that is activated by DAT elimination, while the short period ultradian oscillator that operates in DAT intact, SCNx or Bmal1−/− animals is disengaged or otherwise obscured
Summary
Ultradian rhythms with periods ranging from one to several hours have been linked to various aspects of mammalian physiology. Ultradian locomotor oscillations persist in rodents housed in constant darkness even upon ablation of the suprachiasmatic nucleus (SCN), the site of the master circadian pacemaker (Ibuka et al, 1977; Rusak, 1977), or genetic disruption of the circadian clock (Vitaterna et al, 1994; Bunger et al, 2000) (Figure 1A,B) These ultradian activity cycles may not be driven by metabolic demand since the 2- to 3-hr rhythm in foraging activity observed in the common vole persists even in the absence of food (Gerkema and van der Leest, 1991). Studies in this species further indicate that one adaptive value of ultradian activity rhythms may lie in the facilitation of social synchrony, which is suggested to reduce predator risk in this species
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