The methamphetamine-sensitive circadian oscillator does not employ canonical clock genes

Abstract

The ''master clock'' in the suprachiasmatic nucleus (SCN) of the hypothalamus controls most behavioral, physiological, and molecular circadian rhythms in mammals. However, there are other, still unidentified, circadian oscillators that are able to carry out some SCN functions. Here we show that one of these, the methamphetaminesensitive circadian oscillator (MASCO), which generates behavioral rhythms in the absence of the SCN, is based on an entirely different molecular mechanism. We tested mice lacking, or with mutations of, genes that form the canonical circadian machinery. In all cases, animals that were arrhythmic as a consequence of genetic defect expressed circadian locomotor rhythms when treated with methamphetamine. These results strongly support the hypothesis that the mechanism generating MASCO does not involve the molecular feedback loops that underlie canonical circadian rhythmicity. The properties of MASCO may provide insight into the evolution of circadian mechanisms. Importantly, MASCO may play a role in addiction to psychostimulants.mouse ͉ suprachiasmatic nucleus ͉ psychostimulant T he dominant circadian pacemaker in the mammalian brain is contained within the suprachiasmatic nucleus (SCN) of the hypothalamus (1, 2). However, if the SCN is ablated by lesion or suppressed by constant bright light, resulting in arrhythmic locomotor behavior, circadian rhythmicity can be reconstituted with methamphetamine (3, 4). Arrhythmic, SCN-lesioned rats (SCNX) (3) and mice (4) given ad libitum access to drinking water containing a low dose of methamphetamine produce clear, robust locomotor rhythms with circadian periods that are considerably longer than those of intact animals drinking pure water. Such methamphetamine-induced rhythms continue under constant conditions as long as the drug is present in the drinking water and often for several cycles after its removal (4). These experiments, together with the appropriate controls (3, 4), demonstrate that these rhythms are not the result of a non-oscillating ''hourglass'' but rather constitute clear evidence of the existence of an effective circadian pacemaker outside the SCN. We have called this pacemaker the methamphetamine-sensitive circadian oscillator (MASCO) and are studying its properties.As yet very little is known about MASCO despite overwhelming evidence of its existence. Its location is unknown, although it would be surprising if it were not somewhere in the brain, perhaps associated with dopaminergic and/or serotonergic pathways. Parsimony would suggest that it might be generated by the same molecular feedback loops that produce circadian rhythmicity in the SCN itself and in many peripheral cells, tissues, and organs. However there is reason to believe that this may not be the case. Mice carrying the Clock⌬19 gene mutation and others in which the 2 cryptochromes have been knocked out have arrhythmic phenotypes in constant conditions but become rhythmic when given methamphetamine (5, 6). These data suggest that the molecular events that underlie MASCO...

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

“…Additionally, an independent methamphetamine-sensitive circadian oscillator (MASCO) may interact with the SCN to alter behavioral rhythms of mice. Independent of the SCN and of circadian clock function, chronic methamphetamine administration induces activity rhythms with a period close to 24 h (Mohawk et al, 2009;Tataroglu et al, 2006). A recent study from Blum and colleagues indicates that the MASCO is a manifestation of a newly discovered dopaminergic oscillator (Blum et al, 2014).…”

Perioddetermination in the food-entrainable and methamphetamine-sensitive circadian oscillator(s)

“…20). Recent studies investigating the FEO and MASCO in circadian mutant mice have raised the possibility that these oscillators do not require canonical circadian genes to maintain their rhythmicities (5)(6)(7)(8)(9)(10)(11). In this study, we initially sought to investigate the putative noncanonical nature of the MASCO and FEO, and, surprisingly, found that the canonical Period genes participate in period determination in the MASCO and FEO.…”

“…12,13). Because only two paralogs of the Period gene, Per1 and Per2, are necessary to generate circadian rhythms in the SCN, previous studies concluded that the FEO and MASCO are "noncanonical" clocks in part because they are functional in Per1 −/− / Per2 −/− mice (5,6). Although the third Period paralog, Per3, is not usually considered a functional component of circadian clocks, we recently demonstrated that Per3 participates in period determination in certain peripheral circadian oscillators (14,15).…”

The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks

“…This suggests that known clock components either are part of the MASCO or link the MASCO to the regular circadian oscillator (RCO). In favor of the second possibility are the findings that all clock gene mutants having methamphetamine in their drinking water can display rhythmic behavior with a period length of between 25 and 37 h, even when the SCN is surgically removed (156). Therefore, one can hypothesize that some clock components are MASCO: methamphetaminesensitive circadian oscillator involved in coupling the long-period MASCO to the shorter-period RCO to bring the two into resonance.…”