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.

The neurons that drive infradian sleep-wake and mania-like behavioral rhythms

“…Our finding that the period of 2ndC reaches far into infradian range challenges the currently held view that the oscillator which Meth engages is circadian in nature, a notion also reflected in the wide-spread use of ‘MASCO’ (methamphetamine-sensitive circadian oscillator) as descriptor for this process 7,13 . Considering our previous findings that 2ndC emergence does not require Meth but instead can also result from DAT disruption 12 along with our data presented here (Figure 1), we now propose to use ‘ dopaminergic oscillator ’ or DO to identify the oscillator that drives infradian rest-arousal cycles and relies on DA production.…”

“…In the past, Meth-induced 2ndCs were generally viewed as additional circadian rhythms as they typically exhibited periods not far from 24 hr. However, most of these studies used Meth at concentrations up to 50mg/L drinking water, which may account for the rather limited period range that was observed 13 . Here we examined running wheel activity of mice exposed to increasing levels of Meth, up to 100mg/L, which is twice the concentration normally used (Figure 1A).…”

“…Mice were subsequently maintained in individual housing for at least 2 weeks prior to CNO treatment and/or locomotor activity recording. Viruses: AAV5-hSyn-GFP-Cre (University of North Carolina (UNC) Vector Core, titer 3.5x10 12 genomes copies per ml, diluted 1:1 with saline); AAV5-Flex-taCasp3-TEVp (9) (UNC Vector Core, titer 4.6x10 12 gc/ml); AAV8-hSyn-DIO-hM3D(Gq)-mCherry (14) (MTP, CERVO Brain Research Center, Laval, titer 7.9x10 12 gc/ml); AAV8-hSYN1-DIO-GFP-2A-TetTox (University of Michigan Vector Core, titer 8.22x10 13 gc/ml). The AAV-hSYN1-DIO-GFP-2A-TetTox plasmid was generated by PCR amplifying the GFP-2A-TetTox cassette (from addgene plasmid #166603, gifted by Martin Myers Jr) and introducing AscI and BsiWI enzyme sites to the 5’ and 3’ ends, respectively.…”

“…48 hr rhythms in rest-arousal could be considered a peculiar finding due to the scarcity of its accounts in the animal and human literature 13,37 . However, a recent BD case study showed that pausing treatment of the widely used antipsychotic aripiprazole resulted in the emergence of 48hr cycles in sleep-wake with sleep cycles again normalizing to daily (24 hr) rhythms after drug reinstatement 38 .…”

Circadian rhythms in colonic function

“…Inversion of feeding times in mice results in an inversion of peripheral clocks in the gut, but not the SCN ( Hoogerwerf et al, 2007 ). Indeed, peripheral and local oscillators outside the SCN that can control general activity rhythms are implied by experiments showing that non-photic cues such as timed food access (the food-entrainable oscillator; FEO) and methamphetamine administration (methamphetamine sensitive circadian oscillator; MASCO) can restore rhythmicity after SCN disruption, but little is known of their anatomical substrates ( Mistlberger, 1994 ; Menaker et al, 2013 ; Pendergast and Yamazaki, 2018 ; Mistlberger, 2020 ; Taufique et al, 2022 ).…”