Ask any new parent, shift worker, or college kid studying for finals and they will tell you the same thing: A cheerful mood often depends on how much shut-eye they got. While many scientists may agree with this popular theory, they hadn't worked out the molecular processes underlying a mood-sleep connection, until now. New research identifying a gene that straddles both our mood and our internal clock may explain how these two are linked.

Specifically, variants of the PERIOD3 gene may help to modulate not just our circadian rhythms, but also our state of mind, says a science team led by Dr. Louis Ptáček of Howard Hughes Medical Institute (HHMI) and Dr. Ying-Hui Fu of UC San Francisco.

Circadian Rhythms 101

In the brain, the hypothalamus acts as a communication link between our nervous system and our hormonal (endocrine) system, the HHMI website explains. In fact, the hypothalamus, which is about the size of a shelled walnut, regulates our most essential animal aspects, including our hunger, our thirst, and our body temperature. Within the hypothalamus is a collection of neurons known as the suprachiasmatic nucleus (SCN).

This tiny structure — it’s about the size of a grain of rice — is commonly referred to as our biological clock since it controls the circadian rhythms that govern when we sleep and wake. This complex process is actually a synchronized dance of thousands of neurons, which influence, in turn, the many local "clocks" contained within our organs and tissues along with the "wrist watches" in each of our cells.

In fact, each cell responds to the SCN with tidal waves of a protein called PERIOD, according to the authors of the current study. Levels of this protein rise during daylight hours, reaching a peak around evening, and then fall during the night. Endlessly, this cycle repeats itself over 24 hours a day. The protein is regulated by the PERIOD gene, which has variants that can shorten, lengthen, or even abolish these circadian cycles. One example of this: people with familial advanced sleep phase (FASP) have a naturally altered biological clock, waking before 5:30 AM each day.

Learning that three family members with FASP also happen to have a mood disorder, Ptáček, Fu, and their colleagues decided to investigate variants of a core clock gene to see whether it impacts state of mind and not just sleep patterns.

Testing the Theory

After sequencing the family members with both FASP and seasonal affective disorder, the research team discovered all of them carried faulty versions of the same PERIOD3 gene. Next, the researchers genetically modified a group of mice to carry two copies of the defective PER3 gene. Then the team designed a series of experiments comparing these modified mice to a second group of unaltered mice.

First, the researchers exposed the two groups of mice to 12 hours of light per day. Here, they found the genetically altered mice were active at the same times as the control mice. Next, the researchers provided the rodents with only four hours of light each day (to mimic the short winter days). This time, the modified mice started and stopped running in their wheels four hours later than the unaltered mice, suggesting that the faulty version of PER3 shifts the animals' circadian rhythms.

Next, the researchers examined the rodents’ moods — hard to gauge in a mouse. Past studies have shown a “depressed” mouse, when dangled by its tail, will stop struggling sooner than a normal mouse. Replicating this tail-dangling trick with their own mice, Ptáček and Fu observed the genetically modified mice giving up more quickly than their unaltered friends. In fact, just like depressed people, the mice with faulty PER3 showed abnormal sleep patterns as well.

While mouse genetics are not identical to our own human genetics, the researchers say their findings cannot be considered conclusive, only suggestive of how this same gene might impact our health. Looking to the future, Ptáček and Fu believe their study may help scientists create new treatments to help people who suffer from mood disorders, including the winter blues.

Source: Zhang L, Hirano A, Hsu P-K, et al. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. PNAS. 2016.

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