A poor night's sleep is enough to put anyone in a bad mood, and although scientists have long suspected a link between mood and sleep, the molecular basis of this connection remained a mystery. Now, new research has found several rare genetic mutations on the same gene that definitively connect the two.

Sleep goes hand-in-hand with mood. People suffering from depression and mania, for example, frequently have altered sleeping patterns, as do those with seasonal affective disorder (SAD). And although no one knows exactly how these changes come about, in SAD sufferers they are influenced by changes in light exposure, the brain’s time-keeping cue. But is mood affecting sleep, is sleep affecting mood, or is there a third factor influencing both? Although a number of tantalizing leads have linked the circadian clock to mood, there is “no definitive factor that proves causality or indicates the direction of the relationship,” says Michael McCarthy, a neurobiologist at the San Diego Veterans’ Affairs Medical Center and the University of California (UC), San Diego.

To see whether they could establish a link between the circadian clock, sleep, and mood, scientists in the new study looked at the genetics of a family that suffers from abnormal sleep patterns and mood disorders, including SAD and something called advanced sleep phase, a condition in which people wake earlier and sleep earlier than normal. The scientists screened the family for mutations in key genes involved in the circadian clock, and identified two rare variants of the PERIOD3 (PER3) gene in members suffering from SAD and advanced sleep phase. “We found a genetic change in people who have both seasonal affective disorder and the morning lark trait” says lead researcher Ying-Hui Fu, a neuroscientist at UC San Francisco. When the team tested for these mutations in DNA samples from the general population, they found that they were extremely rare, appearing in less than 1% of samples.

Fu and her team then created mice that carried the novel genetic variants. These transgenic mice showed an unusual sleep-wake cycle and struggled less when handled by the researchers, a typical sign of depression. They also had lower levels of PER2, a protein involved in circadian rhythms, than unmutated mice, providing a possible molecular explanation for the unusual sleep patterns in the family. Fu says this supports the link between the PER3 mutations and both sleep and mood. “PER3’s role in mood regulation has never been demonstrated directly before,” she says. “Our results indicate that PER3 might function in helping us adjust to seasonal changes,” by modifying the body’s internal clock.

To investigate further, the team studied mice lacking a functional PER3 gene. They found that these mice showed symptoms of SAD, exhibiting more severe depression when the duration of simulated daylight in the laboratory was reduced. Because SAD affects between 2% and 9% of people worldwide, the novel variants can’t explain it fully. But understanding the function of PER3 could yield insights into the molecular basis of a wide range of sleep and mood disorders, Fu says.

Together, these experiments show that the PERIOD3 gene likely plays a key role in regulating the sleep-wake cycle, influencing mood and regulating the relationship between depression and seasonal changes in light availability, the team reports today in the Proceedings of the National Academy of Sciences. "The identification of a mutation in PER3 with such a strong effect on mood is remarkable,” McCarthy says. “It suggests an important role for the circadian clock in determining mood.”

The next step will be to investigate how well these results generalize to other people suffering from mood and sleep disorders. “It will be interesting to see if other rare variants in PER3 are found, or if SAD is consistently observed in other carriers,” McCarthy says. That could eventually lead to new drugs that selectively target the gene, which McCarthy says, “could be a strategy for treating mood or sleep disorders.”