Genetics and functional significance of the understudied methamphetamine sensitive circadian oscillator (MASCO)

Abstract

The last 50 years have witnessed extraordinary discoveries in the field of circadian rhythms. However, there are still several mysteries that remain. One of these chronobiological mysteries is the circadian rhythm that is revealed by administration of stimulant drugs to rodents. Herein we describe the discovery of this circadian rhythm and its underlying oscillator, which is frequently called the methamphetamine-sensitive circadian oscillator, or MASCO. This oscillator is distinct from canonical circadian oscillators because it controls robust activity rhythms independently of the suprachiasmatic nucleus and circadian genes are not essential for its timekeeping. We discuss these fundamental properties of MASCO and integrate studies of strain, sex, and circadian gene mutations on MASCO. The anatomical loci of MASCO are not known, so it has not been possible thus far to discover its novel molecular timekeeping mechanism or its functional significance. However, studies in mutant mice suggest that genetic approaches can be used to identify the neural network involved in the rhythm generation of MASCO. We also discuss parallels between human and rodent studies that support our working hypothesis that a function of MASCO may be to regulate sleep-wake cycles.