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

Area of Science:

• Neuroscience
• Chronobiology
• Psychiatry

Background:

• Patients with bipolar disorder (BD) exhibit infradian rhythms (periods >48 hours) in mood and sleep-wake cycles, suggesting an endogenous origin.
• These rhythms persist even without external time cues, highlighting a potential internal biological basis for mood cycling.

Purpose of the Study:

• To investigate the role of dopamine (DA) signaling in generating infradian rhythms relevant to bipolar disorder (BD) cycling.
• To establish a mouse model that mimics infradian behavioral cycling observed in BD.

Main Methods:

• Methamphetamine administration in drinking water to induce infradian locomotor rhythms in mice.
• Genetic manipulation of dopamine (DA) production in ventral tegmental area (VTA) DA neurons and ablation of nucleus accumbens-projecting DA neurons.
• Chemogenetic activation of VTA DA neurons and treatment with antipsychotics in circadian clock-deficient mice.

Main Results:

• Methamphetamine-exposed mice developed infradian locomotor rhythms (>48 hours), mirroring sleep patterns and manic-like behaviors seen in BD.
• Disrupting DA production in VTA DA neurons or ablating nucleus accumbens-projecting DA neurons abolished these infradian rhythms.
• Activating VTA DA neurons lengthened locomotor periods in clock-deficient mice, an effect reversed by antipsychotic treatment.

Conclusions:

• Bipolar disorder (BD) cycling is dependent on infradian rhythm generation.
• Mesolimbic dopamine (DA) neurons are critical for this infradian rhythm generation, providing a potential mechanism for BD pathophysiology.