Researchers from McGill University may have discovered the “holy grail” of bipolar disorder research: understanding what causes shifts between manic and depressed states.

Sleep-wake rhythms in normal adults usually have a periodicity of 24 hours, while 48-hour sleep-wake cycles have been reported in patients with bipolar disorder. These sleep cycles typically coincide with mood states, with short-sleep days associated with mania and long-sleep days associated with depression.

In a study published in Science Advances, the McGill scientists reported that mood swings that regularly occur in patients with bipolar disorder are driven by two internal “clocks.” One is the sleep-wake clock, and the second is a clock that is driven by dopamine-producing neurons that typically influence alertness. The second dopamine-based clock is thought to stay dormant in healthy people, but those with bipolar disorder may shift between manic or depressed states depending on how these two clocks align over time.

In the study, the second clock was activated in mice to create behavioral rhythms similar to mood swings in bipolar disorder. When dopamine-producing neurons in the brain’s reward center were disrupted, the behavioral rhythms stopped, indicating that these dopamine neurons are a key factor in bipolar mood swings.

Specifically, mice were given water containing methamphetamine to develop locomotor rhythms with periods of 48 hours or more and behaviors associated with a manic state. This cycle was negated by disrupting or destroying dopamine-producing neurons in the ventral tegmental area (VTA) or that project to the nucleus accumbens (NAc). Activation of these same neurons led to locomotor period lengthening that was counteracted by antipsychotic treatment. The VTA and NAc are key parts of the brain’s motivation and reward system, and together they form a critical circuit known as the mesolimbic pathway.

“Our model offers the first universal mechanism for mood switching or cycling, which operates analogously to the sun and the moon driving spring tides at specific, recurring times,” said lead author Dr. Kai-Florian Storch, Associate Professor in McGill’s Department of Psychiatry.

While current treatments for bipolar disorder focus on stabilizing moods, they often don’t address the root causes of mood swings. “Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes,” said Dr. Storch.

The specific molecular workings of the dopamine clock remain unknown. The research team plans to continue investigating the dopamine clock’s physiological mechanisms and the genetic and environmental factors that may activate this clock in humans.