The complex relationship between the light‐entrainable and methamphetamine‐sensitive circadian oscillators: evidence from behavioral studies of Period‐mutant mice

Jul 23, 2013The European journal of neuroscience

The complex interaction between light-driven and drug-sensitive body clocks shown by behavior in mice with Period gene mutations

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Abstract

The methamphetamine-sensitive circadian oscillator (MASCO) rhythm exhibits a short period of 21 hours in certain genetically modified mice.

Disruption of all three Period gene paralogs in mice prevents the expression of the short-period MASCO rhythm.
Methamphetamine treatment lengthens the periods of activity rhythms in wild-type and some mutant mice but not in Per2(-/-) mice.
Per2(-/-) mice exhibit two distinct activity rhythms when released to constant light, suggesting a lack of coupling between the SCN and MASCO.
In Per1(-/-) /Per2(-/-) mice, the MASCO rhythm alternates between short (22-h) and long (27-h) periods, indicating potential birhythmicity.
A working model of the relationship between MASCO and the SCN is proposed, aimed at guiding future studies.

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The methamphetamine-sensitive circadian oscillator (MASCO) is an enigmatic circadian clock whose output is observed during continuous consumption of low-dose methamphetamine. The MASCO rhythm persists when the light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) is lesioned, but the anatomical location of MASCO is unknown. We recently found that the period of the MASCO rhythm is unusually short (21 h) in mice with disruption of all three paralogs of the canonical clock gene, Period. In this study, we investigated the contribution of each Period paralog to timekeeping in MASCO. We measured wheel-running activity rhythms in intact and SCN-lesioned Per1-, 2- and 3-mutant mice administered methamphetamine, and found that none of the mice displayed a short (21-h) period, demonstrating that no single Period gene is responsible for the short-period MASCO rhythm of Per1(-/-) /Per2(-/-) /Per3(-/-) mice. We also found that the periods of activity rhythms in constant darkness were lengthened by methamphetamine treatment in intact wild-type, Per1(-/-) and Per3(-/-) mice but not Per2(-/-) mice, and Per2(-/-) mice had two distinct activity rhythms upon release to constant light. These data suggest that the SCN and MASCO are not coupled in Per2(-/-) mice. The MASCO rhythm in Per1(-/-) /Per2(-/-) mice in constant darkness alternated between a short (22-h) and a long (27-h) period. This pattern could result from two coupled oscillators that are not synchronised to each other, or from a single oscillator displaying birhythmicity. Finally, we propose a working model of the in vivo relationship between MASCO and the SCN that poses testable hypotheses for future studies.

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The complex relationship between the light‐entrainable and methamphetamine‐sensitive circadian oscillators: evidence from behavioral studies of Period‐mutant mice

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