Mesolimbic dopamine neurons drive infradian rhythms in sleep-wake and heightened activity state

Infradian mood and sleep-wake rhythms with periods of 48 hr and beyond have been observed in bipolar disorder (BD) subjects that even persist in the absence of exogenous timing cues, indicating an endogenous origin. Here we show that mice exposed to methamphetamine (Meth) in drinking water develop infradian locomotor rhythms with periods of 48 hr and beyond which extend to sleep length and manic state-associated behaviors in support of a model for cycling in BD. The cycling capacity is abrogated upon genetic disruption of dopamine (DA) production in DA neurons of the ventral tegmental area (VTA) or ablation of nucleus accumbens (NAc) projecting DA neurons. Furthermore, chemogenetic activation of VTADA neurons including those that project to the NAc led to locomotor period lengthening in circadian clock-deficient mice, which was counteracted by antipsychotic treatment. Together, our findings argue that BD cycling relies on infradian rhythm generation that depends on mesolimbic DA.

Methods
Unprocessed locomotor activity data recorded from passive infrared sensors. MATLAB scripts to decode this data into a timetable and plot an actogram from this timetable.