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The dark depths of winter can trigger a form of depression called seasonal affective disorder. Now, researchers think they have discovered how a particular light-sensitive gene mediates the effect of light—or its absence—on mood.
Period 1 (Per1) is one of the clock genes, which play key roles in the functioning of the body’s circadian rhythm. The study, published July 8 in PLOS Genetics, suggests that just a 15-minute pulse of bright light very early in the morning can alleviate depressive behaviors in mice by increasing expression of this gene in a region of the brain known to be involved in mood.
Study coauthor Urs Albrecht, a biochemist at the University of Fribourg in Switzerland, first became interested in the link between light exposure and mood when he was a medical student in Zurich and noticed that he would experience more depressive moods during the dark, foggy winters there.
Later, while working on the period genes, Per1, he read reports that people with seasonal affective disorder (SAD) who were treated with light therapy in the very early hours of the morning showed improvements in mood. “Practically, one knew that this could help, but nobody understood why that works,” Albrecht tells The Scientist.
Previous research in mice showed that light-sensitive neurons in the retina of the eye connect to many regions of the brain—including the suprachiasmatic nuclei, the brain’s central “clock,” and the lateral habenula, which helps regulate mood.
The Per1 clock gene is expressed in both the suprachiasmatic nuclei and the lateral habenula. Albrecht and colleagues wanted to see what happened to the activity of this and related genes in the lateral habenula in mice when they were exposed to light at different times of a 12-hour/12-hour light-dark cycle, and whether this was associated with changes in the mice’s behavior.
Practically, one knew that [light] could help, but nobody understood why that works.
—Urs Albrecht, University of Fribourg
Exposing the mice to a pulse of bright light early in the 12-hour dark period—at hour 14 of the 24-hour cycle—had no effect on behaviors associated with depressed mood, such as swimming less actively when placed in a container of water: the mice behaved the same as those not exposed to light. But exposing them toward the end of the 12-hour dark period—at hour 22 of the 24-hour cycle, similar to when light has beneficial effects in humans—decreased this behavioral despair activity.
Next, the team looked at the levels of Per1 gene activity when the mice were exposed to light at hour 22, two hours before the start of the light cycle. They found that the mice exposed to light at this time—near the end of the dark cycle—had increased Per1 activity in the lateral habenula, which correlated with improved mood in behavioral tests. When the animals were exposed to light at hour 14, two hours after the start of the dark cycle, it did not change expression of Per1.
The effect of light on Per1 toward the end of the dark cycle was observed despite the fact that mice are nocturnal. Albrecht says previous research has found that the light-mediated induction of Per1 gene expression only happens during the dark phase, regardless of whether animals are diurnal or nocturnal, but it’s not yet clear why this is the case.
The researchers also examined the downstream effects of increased activity of Per1 in the lateral habenula on two other regions of the brain, the ventral tegmental area (VTA) and nucleus accumbens, which work together with the lateral habenula to regulate mood in what’s called the mesolimbic dopaminergic system.
The lateral habenula is like a valve or balancer of the VTA and the nucleus accumbens, Albrecht says. “It inhibits or activates to keep the balance between the VTA and the nucleus accumbens to make a nice dosing of the dopamine,” known as the ‘feel good’ neurotransmitter.
As the expression of Per1 increased in the lateral habenula in response to light at the end of the dark cycle, there were also changes in activity of other genes—but not Per1—in the VTA and especially in the nucleus accumbens.
“If you put light to this lateral habenula, you basically influence the balancer and then by this mechanism you can influence these neurotransmitter levels in the other brain regions—in the VTA and the nucleus accumbens—and thereby you influence indirectly mood,” Albrecht says.
For Chelsea Vadnie, a neuroscientist at Ohio Wesleyan University who was not involved in the work, the effect of light on expression of Per1 in the lateral habenula was the most interesting finding of the study. “This increase in Period 1 in the lateral habenula seems to be important for the therapeutic-like effects of this light pulse late in the dark phase,” she says.
The study also looked at the effect of light exposure on mice in whom the Per1 gene had been switched off in the lateral habenula, and found that light pulses early or late in the dark cycle didn’t have any effect on mood.
David Welsh, who studies circadian clocks and mood disorders at the UC San Diego School of Medicine and was not involved in the study, says the paper is important because it addresses the mechanism of the therapeutic benefit of light. Compared to previous studies on this question, “this current paper takes a more translational, straightforward approach to the stimulus, which is to deliver a stimulus a couple of hours before dawn . . . and that’s very similar to what is done clinically with light therapy,” Welsh says.
While light therapy is commonly used for seasonal affective disorder, Welsh says there’s emerging evidence that it can also be effective for nonseasonal depression.
Vadnie speculates that the findings could open the door to new therapies that target Per1 in the lateral habenula, or genes whose expression is affected by that region, to simulate the effect of light.
The great thing about light is that it’s safe, easy to administer, and nearly free, and it has a significant effect on the brain, Albrecht says. “When you get light at a particular time, it can have positive influences.”
