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.