Summary: New research suggests that mood swings caused by bipolar disorder are regulated by two clocks: a 24-hour circadian rhythm and a dopaminergic clock that influences alertness. When these clocks align at specific intervals, they can trigger alternations between mania and depression.
The researchers demonstrated this phenomenon in mice by activating the dopaminergic clock, creating emotional rhythms similar to bipolar cycles. These findings open the door to developing therapies that work by fine-tuning dopamine-linked timing systems in the brain. By targeting these internal “clocks,” scientists may be able to restore balance in neural activity, creating a more stable emotional state for individuals prone to mood disturbances.
Such treatments could help prevent extreme mood shifts before they occur, reducing both their frequency and intensity. Over time, this approach may offer a more precise and sustainable way to manage mood disorders compared to conventional methods, improving quality of life for those affected.
Important facts:
- Dual Clocks Drive Bipolar Mood Swings Bipolar mood changes are influenced by two internal timers—the circadian rhythm and a dopamine-based clock—that work together to shape emotional highs and lows.
- Role of dopamine: Dopamine-driven rhythms regulate mood cycles, unlike circadian rhythms.
- Treatment goal: Silencing the dopamine clock could offer a new approach to bipolar treatment.
Source: McGill University
According to new research, brain rhythms that work in conjunction with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression.
The McGill-led study, published in Science Advances, marks a step forward in understanding what changes between the two states, which lead author Kai Florian Storch says is considered the “Holy Grail” of bipolar disorder research.
“Our model offers the first universal mechanism for mood change or cycling, working in tandem with the sun and moon, which cause spring tides at specific, recurring times,” said Storch, an associate professor in McGill’s Department of Psychology and a researcher at the Douglas Research Centre.
The results point to a dual-timing system at work in bipolar disorder, where mood swings are influenced by both the body’s 24-hour circadian rhythm and a second, dopamine-driven clock that normally regulates alertness and motivation. When these two systems fall out of sync, they may create the conditions for shifts between manic and depressive states, offering a fresh perspective on the biological underpinnings of mood instability.
Understanding this interplay opens new avenues for treatment. By targeting the dopamine-based clock alongside circadian regulation, future therapies could help stabilize mood patterns, reducing the frequency and severity of episodes. This approach could lead to more precise, biologically informed interventions that address the root timing mechanisms behind bipolar mood cycles.
A manic or depressive state can depend on how these two clocks, which operate at different speeds, align at a particular moment.
The authors specifically argue that this second dopamine-based clock likely remains inactive in healthy people.
To study this, scientists activated a second clock in mice to create behavioral rhythms similar to the mood swings of bipolar disorder. By selectively disrupting dopamine-producing neurons in the brain’s reward center, researchers were able to halt the rhythmic patterns linked to mood regulation. This shutdown of the brain’s internal timing signals highlights how deeply dopamine is intertwined with the mechanisms that drive mood changes in bipolar disorder. It also reinforces the idea that mood instability is not solely tied to the body’s circadian rhythm but is also shaped by a separate dopamine-based clock.
These insights point toward new therapeutic possibilities. If treatments can be developed to stabilize or recalibrate this dopamine-driven timing system, it may be possible to prevent or lessen the severity of mood episodes. Such an approach could complement existing therapies that target circadian rhythms, offering a more comprehensive strategy for managing bipolar disorder and improving long-term emotional stability.
Hope for a new treatment: silencing the clock
Researchers said current treatments for bipolar disorder focus on stabilizing mood, but often fail to address the underlying causes of mood swings.
Storch explained that identifying a dopamine-based wake rhythm generator offers a completely new avenue for treatment. This internal timing mechanism, separate from the body’s circadian clock, appears to play a pivotal role in triggering mood episodes. By understanding how this dopamine-driven system operates, researchers can begin to design interventions that directly address one of the root causes of mood instability in bipolar disorder.
He emphasized that future therapies could focus on correcting or silencing this overactive clock to help stabilize emotional patterns. Such an approach has the potential to reduce both the frequency and intensity of mood events, offering patients a more targeted and effective way to manage their condition and improve long-term quality of life.
What remains unknown is the precise molecular workings of the dopaminergic clock, as well as the genetic and environmental factors that might trigger it in humans. The research team’s next step will be to focus on these molecular mechanisms and study these potential triggers.
Funding: This research was funded by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the National Institutes of Health, and the Graham Boch Foundation.
Abstract
Mesolimbic dopamine neurons control infradyne rhythms in states of sleep-wakefulness and increased activity.
Infradiurnal rhythms of mood and sleep with a duration of 48 hours or more have been observed in patients with bipolar disorder (BD), which persist even in the absence of exogenous temporal cues, indicating an endogenous origin.
Here, we show that rats exposed to methamphetamine in drinking water develop infradyne locomotor rhythms with a duration of 48 hours or more that extend to sleep periods and behaviors associated with a manic state, supporting a cycling model of bipolar disorder.
Cycling ability is abrogated by genetically disrupting dopamine (DA) production in DA neurons of the ventral tegmental area (VTA) or by ablating DA neurons projecting to the nucleus accumbens.
Furthermore, chemogenetic activation of VTA DA neurons, including those projecting to the nucleus accumbens, led to prolonged locomotor activity in circadian clock-deficient mice, which was reversed by antipsychotic treatment.
Taken together, the findings indicate that bipolar disorder (BD) mood cycling is driven by an infradian rhythm—one with a period longer than 24 hours—that depends on the activity of mesolimbic dopamine (DA) neurons. This suggests that these neurons, which are central to the brain’s reward and motivation pathways, play a pivotal role in setting the longer-term timing patterns that underlie mood shifts in BD.
