Decision letter: Absent phasing of respiratory and locomotor rhythms in running mice

Following general anaesthesia (GA), patients frequently experience sleep disruption and fatigue, which has been hypothesized to result at least in part by GA affecting the circadian clock. Here, we provide the first comprehensive time-dependent analysis of the effects of the commonly administered inhalational anaesthetic, isoflurane, on the murine circadian clock, by analysing its effects on (a) behavioural locomotor rhythms and (b) PER2::LUC expression in the suprachiasmatic nuclei (SCN) of the mouse brain. Behavioural phase shifts elicited by exposure of mice (n = 80) to six hours of GA (2% isoflurane) were determined by recording wheel-running rhythms in constant conditions (DD). Phase shifts in PER2::LUC expression were determined by recording bioluminescence in organotypic SCN slices (n = 38) prior to and following GA exposure (2% isoflurane). Full phase response curves for the effects of GA on behaviour and PER2::LUC rhythms were constructed, which show that the effects of GA are highly time-dependent. Shifts in SCN PER2 expression were much larger than those of behaviour (c. 0.7 h behaviour vs. 7.5 h PER2::LUC). We discuss the implications of this work for understanding how GA affects the clock, and how it may inform the development of chronotherapeutic strategies to reduce GA-induced phase-shifting in patients.

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Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione

Molecules ◽

10.3390/molecules26092514 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2514

Author(s):

Santiago Andrés Plano ◽

Fernando Martín Baidanoff ◽

Laura Lucía Trebucq ◽

Sebastián Ángel Suarez ◽

Fabio Doctorovich ◽

...

Keyword(s):

Soluble Guanylate Cyclase ◽

Phase Locking ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Circadian Phase ◽

Subjective Night ◽

Circadian Time ◽

Electron Reduction ◽

Locomotor Rhythms ◽

The One

The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli’s salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator.

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Circadian Locomotor Rhythms in Birds Correlate with and May Be Explained by Rhythms in Serotonin, N-Acetyltransferase, and Melatonin

Proceedings in Life Sciences - Processing of Environmental Information in Vertebrates ◽

10.1007/978-1-4612-3740-2_5 ◽

1988 ◽

pp. 85-100

Author(s):

Sue Binkley

Keyword(s):

Locomotor Rhythms

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A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal

eLife ◽

10.7554/elife.05105 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 59

Author(s):

Ian D Blum ◽

Lei Zhu ◽

Luc Moquin ◽

Maia V Kokoeva ◽

Alain Gratton ◽

...

Keyword(s):

Mammalian Species ◽

Dopamine Neurons ◽

Mammalian Brain ◽

Behavioral Arousal ◽

Dopaminergic Tone ◽

Activity Cycles ◽

Midbrain Dopamine ◽

Locomotor Rhythms ◽

Underlying Mechanisms ◽

Period Lengthening

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.

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Electrophysiological and Anatomical Characterization of PDF-Positive Clock Neurons in the Intact Adult Drosophila Brain

Journal of Neurophysiology ◽

10.1152/jn.00117.2006 ◽

2006 ◽

Vol 95 (6) ◽

pp. 3955-3960 ◽

Cited By ~ 38

Author(s):

Demian Park ◽

Leslie C. Griffith

Keyword(s):

Biological Rhythms ◽

Cell Group ◽

Resting Membrane Potential ◽

Electrophysiological Properties ◽

Drosophila Brain ◽

A Cell ◽

Locomotor Rhythms ◽

Firing Properties ◽

First Time

Daily biological rhythms in both prokaryotes and eukaryotes are controlled by circadian clocks. In Drosophila, there is a good basic understanding of both the molecular and anatomical components of the clock. In this study we directly measure, for the first time, electrophysiological properties and anatomy of individual filled large lateral PDF-positive clock neurons, a cell group believed to be involved in synchronization of the clock in constant conditions. We find that the large PDF-positive neurons are morphologically homogeneous and that their resting membrane potential is modulated both by the clock and by light inputs. Expression of a leak channel, dORK-ΔC, which has been shown to disrupt circadian locomotor rhythms, hyperpolarizes these neurons, and blocks firing. These data imply that the firing properties of large PDF neurons are both regulated by and critical for clock function.

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