
The findings provide new evidence for the relationship between dopamine and behavioral cycles in bipolar disorder. The identification of a dopamine oscillator in the brain that regulates infradian rhythms such as the 48-hour cycle paves the way for new treatment strategies focused on regulating this oscillatory system in patients.
Sleep-wake rhythms are naturally regulated by the 24-hour cycle of the solar day, controlled by our internal biological clocks. However, some people have sleep cycles that exceed this pattern, with periods longer than a day.
This phenomenon occurs in the so-called “non-24-hour sleep-wake rhythm disorder” (N24SWD), in which cycles can reach infradian periods, that is, cycles much longer than 24 hours.
In bipolar disorder (BD), an example of infradian rhythms is the 48-hour cycle. In these cases, sleep patterns alternate between days of short sleep, often associated with manic or hypomanic states, and days of prolonged sleep, associated with depression.
What is intriguing is that these sleep and mood cycles persist even when the person is in temporal isolation, without external stimuli to regulate time, suggesting that the origin of the cycle is endogenous, that is, controlled by internal mechanisms in the brain. Despite this, the biological mechanisms behind these cycles are still not fully understood.

Animal studies have shown that infradian rhythms can be experimentally induced using methamphetamine (Meth). Mice chronically treated with Meth via their drinking water develop a second locomotor rhythm (2ndC), distinct from the standard circadian rhythm.
This new rhythm, which can have periods longer than 24 hours, is independent of the traditional circadian biological clock, suggesting the existence of another oscillatory mechanism in the brain.
Methamphetamine is known to act on the dopamine transporter (DAT), a protein that regulates dopamine levels in the brain, reversing its function and increasing dopamine release.
Interestingly, even without the use of Meth, simple genetic disruption of the dopamine transporter can also generate this second locomotor rhythm in mice. This suggests that dopamine plays a central role in the development of these alternative rhythms.
Based on these findings, the hypothesis was raised that dopaminergic neurons, which express DAT, are crucial for the generation of these rhythms, possibly operating as a "dopamine oscillator".
The main objective of the study was to identify which areas of the brain and which neurons are involved in the generation of infradian rhythms and to verify how they are related to the behavioral cycles observed in bipolar disorder.
To this end, researchers from McGill University, Canada, used mice as an experimental model and analyzed the role of dopamine and dopaminergic neurons located in the ventral tegmental area (VTA).

The researchers induced infradian rhythms in mice by chronically exposing them to methamphetamine in their drinking water. They monitored the mice’s locomotor behavior and sleep over several weeks to identify changes in the rhythmic cycles.
In addition, genetic and pharmacological manipulations were used to investigate the role of dopamine neurons. Genetically modified mice, such as those with the dopamine transporter gene knocked out, were analyzed to see if the absence of DAT affected the formation of the rhythms.
Chemogenetics was used to selectively activate or deactivate dopamine neurons in the ventral tegmental area and assess the impacts on locomotor rhythm.
Finally, antipsychotic drug treatments were tested to determine whether these compounds could counteract the altered rhythms.

Selective disruption of TH (tyrosine hydroxylase) in the ventral tegmental area eliminates the ability to generate infradian rhythms. (A) Schematic illustrating methamphetamine-mediated elevation of extracellular DA in a dopaminergic neuronal terminal. DDC: l-dopa decarboxylase. (B) Strategy for selective elimination of dopamine production in dopaminergic neurons of the ventral tegmental area. (C and D) TH immunostaining in midbrain sections from saline-treated [(C), control] and AAV-GFP-Cre-injected [(D), THKO] mice.
The researchers also examined how infradian rhythms correlated with behaviors associated with manic or depressive states in the mice, assessing the pattern of activity on short versus long sleep days.
Methamphetamine-treated mice developed infradian rhythms with periods of 48 hours or longer. These cycles extended beyond locomotor behavior, also affecting sleep duration and behavioral patterns.
Days of increased activity, associated with manic states, coincided with short sleep, while days of decreased activity, associated with depressive states, coincided with prolonged sleep.
Genetically disrupting the dopamine transporter in mice prevented the emergence of infradian rhythms, even when they were treated with Meth. This demonstrated that DAT plays a central role in the generation of these rhythms.
Furthermore, selective activation of dopamine neurons in the ventral tegmental area prolonged the locomotor period in mice, reinforcing the hypothesis that these neurons are essential for the creation of the infradian rhythm.

Dopamine neurons projecting from the ventral tegmental area to the nucleus accumbens were found to be particularly important. When these connections were eliminated, the infradian rhythms disappeared completely.
In contrast, antipsychotic treatments counteracted the effects of dopamine neuron activation, indicating that these drugs could regulate the dopamine oscillator.
The results indicate that the infradian rhythms observed in bipolar disorder may be mediated by an internal dopamine-related mechanism. Dopamine neurons in the VTA appear to play a key role in this process, possibly acting as part of a “dopamine oscillator.”
An intriguing aspect is that the generation of these rhythms does not depend exclusively on vesicular dopamine release. Even when dopamine release was blocked, infradian rhythms still emerged.
This suggests that dopamine transporter (DAT) dynamics and other interactions in the dopamine system play critical roles in the mechanism.

Furthermore, the fact that infradian rhythms span 48 hours or more challenges the idea that the mechanism involved is solely circadian. Instead, the data support the existence of a “dopamine oscillator” that can regulate rest-arousal cycles over periods much longer than 24 hours.
This study provides new evidence on how infradian rhythms in bipolar disorder may be generated by endogenous dopamine-based mechanisms. The identification of the “dopamine oscillator” as a regulator of behavioral cycles offers valuable insights into understanding mood and sleep rhythms in bipolar disorder.
In addition, these findings pave the way for the development of new therapeutic approaches that aim to regulate this oscillator in patients with BD.
READ MORE:
Mesolimbic dopamine neurons drive infradian rhythms in sleep-wake and heightened activity state
PRATAP S. MARKAM, CLÉMENT BOURGUIGNON, LEI ZHU,
BRIDGET WARD, MARTIN DARVAS, PAUL V. SABATINI, MAIA V. KOKOEVA,
BRUNO GIROS, and KAI-FLORIAN STORCH
SCIENCE ADVANCES, 1 Jan 2025, Vol 11, Issue 1
DOI: 10.1126/sciadv.ado9965
Abstract:
Infradian mood and sleep-wake rhythms with periods of 48 hours and beyond have been observed in patients with bipolar disorder (BD), which even persist in the absence of exogenous timing cues, indicating an endogenous origin. Here, we show that mice exposed to methamphetamine in drinking water develop infradian locomotor rhythms with periods of 48 hours 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 projecting DA neurons. Furthermore, chemogenetic activation of VTADA neurons including those that project to the nucleus accumbens 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 neurons.
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