Focusing on the role of genes in SAD could lead to promising new treatments for this and other mood disorders.
A new study has uncovered how certain genetic variations in the circadian gene PERIOD3 (PER3) may contribute to seasonal affective disorder (SAD) during winter months. This research, published in Nature Metabolism, investigated how these PER3 gene variants disrupt serotonin production, a critical neurotransmitter for mood regulation, particularly under winter-like light conditions.
SAD is a type of mood disorder that tends to show up during certain times of the year, usually in the colder months when there’s less daylight and the skin absorbs less vitamin D, an essential vitamin that supports mood regulations and energy. People with SAD often experience symptoms similar to depression, like feeling down, lacking energy, feeling a need to withdraw from social activities, and losing interest in things they normally enjoy. What makes SAD different from other depressive disorders, though, is that its symptoms are closely linked to changes in the seasons, particularly the reduction in sunlight, and they tend to fade away once the days get longer and sunnier.
For the current study, scientists introduced human-specific PER3 variants, known as P415A and H417R, into laboratory mice, creating a model to observe the effect of these genetic modifications under different light cycles. Male mice with these variants demonstrated behaviors similar to those seen in human seasonal affective disorder patients, including reduced interest in social interaction and less activity in tests designed to measure motivation and endurance. These mice became models for understanding the molecular underpinnings of SAD, showing significant promise in future studies of seasonal depression.
The experiment drew attention to how these genetic variants interfere with the body’s adrenal response to winter daylight. When functioning as it should, the hypothalamic-pituitary-adrenal (HPA) axis helps regulate the release of cortisol, a hormone that follows a daily rhythm to aid in stress response. However, the study found that in mice with the P415A and H417R variants, glucocorticoid signaling—driven by elevated levels of corticosterone, the rodent equivalent of cortisol—was overstimulated. This led to suppressed production of Tryptophan hydroxylase 2 (Tph2), a key enzyme for synthesizing serotonin. Low serotonin levels are closely associated with depression.
The study’s findings build upon prior research suggesting that individuals with genetic predispositions might be more susceptible to developing SAD at some point in their lives. Seasonal rhythms are well-established in human biology, impacting not only mood but various health conditions. SAD’s cyclical nature appears to be linked to these rhythms, specifically as they relate to monoamine neurotransmitter levels, like serotonin and dopamine, which are essential to regulating mood.
Previous research has found that light therapy, which is often used as a treatment for SAD, can help reset circadian rhythms, improving symptoms for many patients, and today, it’s possible to purchase mirrors with special lighting and other home devices relatively easily to help support this. These products can be found both online and in numerous stores. However, this study’s discovery of a genetic basis offers potential for developing targeted medications to adjust HPA axis regulation and serotonin production directly, as well, providing an alternative for those who do not respond fully to light therapy alone.
In exploring this connection further, researchers compared the SAD-like behaviors in genetically modified mice across both winter and normal photoperiods. When subjected to short daylight cycles, the mice displayed significant increases in immobility during behavioral tests, a sign of depressive behavior. Interestingly, when these mice returned to longer light cycles, their behavior improved. To further verify that there is a genetic component, the researchers administered Fluoxetine hydrochloride, a serotonin uptake inhibitor commonly known as Prozac, to the mice, which normalized serotonin levels and improved these behaviors.
The mouse model allowed the team to examine potential therapies targeting the HPA axis and serotonin synthesis pathways. If similar genetic interventions or medications could produce the same results in humans, it could lead to promising new treatments for SAD and other mood disorders.
Sources:
New study links circadian gene variants to winter depression
Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signalling
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