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

Infradian mood and sleep-wake rhythms with periods of 48 hours and beyond have been observed in patients with bipolar disorder (BD), which even persist in the absence of exogenous timing cues, indicating an endogenous origin. Here, we show that mice exposed to methamphetamine in drinking water develop infradian locomotor rhythms with periods of 48 hours 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 projecting DA neurons. Furthermore, chemogenetic activation of VTA DA neurons including those that project to the nucleus accumbens 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 neurons.