Feeling down in the winter? The culprit might be in your genes! Researchers have discovered that a special mutation in the PERIOD3 (PER3) circadian clock gene can wreak havoc during short winter days. This mutation causes stress hormone cortisol levels to spike, suppressing the production of serotonin, the happiness molecule and leaving you stuck in the winter blues. But here’s the good news: scientists managed to restore joy in experimental mice by blocking cortisol’s effects. This groundbreaking study not only uncovers the hidden cause of seasonal depression but also paves the way for new strategies to banish winter gloom!
What is seasonal affective disorder (SAD)?
Do you feel like your mood turns as gloomy as the winter weather? Cold, windy mornings and early sunsets seem to drag your spirits down, making it hard to stay motivated. This “winter blues” isn’t just in your head—it’s so common that scientists have a name for it: Seasonal Affective Disorder (SAD). As it turns out, winter doesn’t just chill the air; it might be messing with your mood too! Though SAD was first defined over 40 years ago, its underlying mechanisms are still not fully understood.
Research finds: Gene mutations linked to winter blues
Recently, a team led by Professor Luoying Zhang from Huazhong University of Science and Technology published a paper in Nature Metabolism titled Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signaling. The study reveals that a specific variation in the human circadian gene PERIOD3 (PER3-P415A/H417R) can lead to increased secretion of the stress hormone cortisol under simulated winter daylight conditions, resulting in depression-like behaviors. This groundbreaking research not only sheds light on the biological basis of winter depression but also provides crucial insights into how seasonal changes impact our emotions.
The team had previously identified that individuals carrying the PER3-P415A/H417R mutation in a specific genetic lineage were more prone to developing winter depression. To investigate further, they created transgenic mouse models carrying either the normal human PER3 gene (PER3-WT) or the two mutated variants (PER3-P415A and H417R).
First, the researchers exposed these mice to simulated winter conditions—only 4 hours of light and 20 hours of darkness per day (4L20D)—and observed their behavior. Mice carrying the PER3-P415A and H417R mutations displayed pronounced depressive-like behaviors, such as prolonged immobility in the tail suspension test and the forced swim test. Under standard 12-hour light/12-hour dark conditions (12L12D), however, these behaviors disappeared. These findings strongly suggest that the P415A and H417R mutations are key contributors to winter depression.
Figure 1: PER3 mutants cause a phenotype similar to winter depression
Why do gene mutations cause depression?
Further investigation revealed that the mutated mice had significantly higher cortisol levels under winter-like conditions. To test whether elevated cortisol caused the depressive behaviors, researchers administered mifepristone, a drug that blocks cortisol's effects. The depressive behaviors in the mutant mice improved, and when their adrenal glands—the organ that produces cortisol—were removed, both the behavioral and cortisol differences between mutant and normal mice disappeared.
Figure 2: PER3 mutants act in the adrenal glands and increase adrenocorticotropic hormone (ACTH)-induced corticosterone synthesis
Interestingly, the researchers found that the mutant mice’s elevated cortisol levels were not driven by higher levels of adrenocorticotropic hormone (ACTH), which typically stimulates cortisol production. This suggested that the mutations directly enhanced the adrenal gland's cortisol production. Lab tests confirmed this: adrenal cells from mutant mice produced more cortisol when stimulated with ACTH compared to normal mice.
To confirm this link, the team engineered mice that expressed the PER3 mutations only in their adrenal glands. These mice also exhibited heightened cortisol levels and depression-like behaviors under winter-like conditions but behaved normally under standard light conditions. This demonstrated that the PER3 mutations directly enhance the adrenal glands' ability to produce cortisol, leading to symptoms of winter depression.
How does excessive cortisol affect mood?
The study found that cortisol signaling suppresses the production of tryptophan hydroxylase-2 (Tph2), an enzyme critical for synthesizing serotonin—a key “happiness” molecule—in the brain's dorsal raphe nucleus (DRN). Mutant mice had reduced Tph2 levels, but mifepristone treatment restored it, confirming the link between high cortisol and low Tph2.
Figure 3: Reduced expression of tryptophan hydroxylase-2 (Tph2) in PER3 mutant mice is caused by enhanced glucocorticoid signaling
Additionally, injecting a cortisol-like compound (dexamethasone) into normal mice decreased Tph2 levels and induced depression-like behaviors. Remarkably, boosting Tph2 levels in mutant mice alleviated their depressive symptoms.
Figure 4: Model of PER3 mutant-induced winter depression-like behavior
In Summary
This study establishes a direct connection between PER3 gene mutations and winter depression, highlighting the crucial role of cortisol in mood regulation. Winter blues aren’t just a mental health issue—they’re a biological phenomenon. By exploring the mechanisms behind stress hormones and serotonin, we’re one step closer to helping people overcome seasonal affective disorder and make every winter as warm and joyful as spring.