January 8, 2025
Why is bipolar disorder cyclic? New research in mice argues that the cycling between mania and depression in bipolar disorders is driven by an arousal rhythm generator that resides in the brain’s reward centres.
A recent study led by Dr. Kai-Florian Storch has been published in the journal Science Advances.
Focusing on the role of dopamine in mood-switching in bipolar disorder, the study is co-authored by Pratap S. Markam, Clément Bourguignon, Lei Zhu, Bridget Ward, Martin Darvas, Paul V. Sabatini, Maia V. Kokoeva, Bruno Giros & Kai- Florian Storch, and identifies a rhythm generator that may be responsible for mood switching in bipolar disorder.
Understanding what drives the mood switch from mania to depression and vice versa is considered the “holy grail” in bipolar disorder research. Interestingly, these switches can occur with great regularity, e.g. every few weeks or months. One extreme manifestation in this regard is 48hr cycling, where patients switch from mania to depression every other day, which can continue for weeks, months, or even years without much interruption.
In our study we are making the case that we have produced an animal model for 48hr cycling and using this model have identified the specific nerve cells that are driving this cycling.
Our findings support a model of mood switching that is governed by the action of two rhythm generators, the circadian clock, also known as our biological clock, and an arousal rhythm generator that resides in dopamine-producing neurons. Based on the temporal alignment of these two clocks, which tick at different speeds, a bipolar cycling patient is either manic or depressed.
According to our model, the concerted action of these two rhythm generators can account for any type of mood cycling, thereby providing -for the first time- a universal mechanistic understanding for mood switching that is simply based on the in- and out-of-phase traveling of two clocks, much like the sun and the moon together drive tides at specific, recurring times.
Notably, this second, dopamine clock is likely non-operational in healthy people but becomes activated in bipolar patients.
Overall, our research supports the view that rhythms play a critical role in bipolar disorder and 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.
Pratap S. Markam, Clément Bourguignon, Lei Zhu, Bridget Ward, Martin Darvas, Paul V. Sabatini, Maia V. Kokoeva, Bruno Giros, & Kai-Florian Storch.
Mesolimbic dopamine neurons drive infradian rhythms in sleep-wake and heightened activity state. Science Advances (2025)