Missing sleep for a single night can leave you irritable, but months of disrupted sleep may contribute to lasting mood problems such as depression. Researchers at the Howard Hughes Medical Institute (HHMI) now report a possible molecular link between the circadian clock that governs sleep-wake timing and mood regulation.
A team led by HHMI investigator Louis Ptáček and Ying-Hui Fu of the University of California, San Francisco, identified variants in the circadian clock gene PERIOD3 (PER3) that appear to connect daily timing and seasonal mood changes. Their study, published February 22, 2016 in Proceedings of the National Academy of Sciences (PNAS), provides experimental evidence that PER3 influences how organisms adapt to changing day length and how that adaptation can affect behavior associated with depression.
“Sleep deprivation affects many aspects of health, including mental health,” says Ptáček. Shift workers and others with disrupted circadian rhythms are known to be at higher risk for a range of illnesses, including mood disorders. Until now, however, a clear molecular mechanism linking circadian disruption to mood disorders has been elusive.
The researchers began by studying a family in which several members displayed familial advanced sleep phase (FASP). People with FASP are extreme morning types who naturally wake very early—often before 5:30 AM and sometimes as early as 2:00 AM—while still obtaining a normal total sleep time. Although FASP itself is not considered a disease, it can be socially disruptive: individuals often feel sleepy by early evening and struggle to align their schedules with typical social or work hours. Notably, all three family members examined showed seasonal affective disorder (SAD), a recurrent depression that typically emerges during the short daylight months of winter.
Genetic analysis revealed that these family members carried rare PER3 variants. To test whether PER3 could influence mood-like behavior and circadian responses to day length, the team created mouse models carrying human-like PER3 variants. Because mice are nocturnal—sleeping mainly during the day and active at night—researchers measure their daily activity cycles using running wheels.
Under a 12-hour light/12-hour dark schedule, the genetically altered mice showed normal timing of activity compared with control animals. However, when researchers simulated short winter days by limiting light exposure to only four hours per day, the PER3-variant mice shifted their activity onset and offset by about four hours relative to unmodified mice. This result indicates that the defective PER3 allele alters the animals’ circadian response to short photoperiods.
The team then assessed depression-like behaviors in the mice. While it is not possible to diagnose a rodent with clinical depression, several behavioral assays reveal changes that parallel human depressive symptoms. In the tail suspension test—an established measure in which mice are suspended briefly and researchers record how long they struggle—the PER3-variant mice gave up sooner than controls, suggesting increased despair-like behavior. The modified animals also displayed disrupted sleep patterns under short day lengths, mirroring the seasonal emergence of mood disturbance in humans.
To better mimic the human condition, the group also studied mice that completely lack PER3. These knockout mice displayed consistent depression-like behaviors when exposed to short photoperiods. For example, in a test of reward-related behavior, Per3-deficient mice consumed significantly less sweetened water than normal mice—an animal correlate of anhedonia, the loss of pleasure in normally rewarding activities. “It seems that the mice are not taking pleasure in something that is pleasurable,” Ptáček notes.
At the molecular level, the rare human PER3 variants destabilized PER3 protein and failed to stabilize other key clock proteins (PER1 and PER2), which are essential for precise circadian timing. These biochemical changes offer a plausible mechanism by which PER3 variants could alter circadian dynamics and downstream mood-related pathways.
“Many have suspected a biological connection between sleep and depression, but direct evidence has been limited,” Ptáček says. “Our data indicate that PER3 can serve as a nexus between circadian timing and mood regulation, particularly in the context of changing day length.” While the findings do not point to an immediate therapy for mood disorders, they provide a clearer biological target for future research aimed at seasonal affective disorder and related conditions. Improved understanding of the PER3 pathway could guide more rational approaches to developing treatments that modulate circadian and mood circuits.
Source: Jim Keeley – HHMI
Image Source: Adapted from HHMI materials.
Original Research: Abstract for “A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait” by Luoying Zhang, Arisa Hirano, Pei-Ken Hsu, Christopher R. Jones, Noriaki Sakai, Masashi Okuro, Thomas McMahon, Maya Yamazaki, Ying Xu, Noriko Saigoh, Kazumasa Saigoh, Shu-Ting Lin, Krista Kaasik, Seiji Nishino, Louis J. Ptáček, and Ying-Hui Fu in PNAS. Published online February 22, 2016. DOI: 10.1073/pnas.1600039113
Abstract
A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait
Associations between sleep and mood are well known in humans, but direct molecular links have been limited. Researchers identified rare PER3 variants (PER3-P415A/H417R) in individuals with familial advanced sleep phase who also scored higher on depression and seasonality assessments. Mice expressing the human PER3 variants exhibited altered circadian periods under constant light and showed delayed sleep-wake phase shifts under short-day conditions. Molecular studies revealed that the variants destabilized PER3 and failed to stabilize PER1/2 proteins, which are central to circadian timing. While transgenic mice carrying the human variants displayed mild depression-like behaviors, Per3 knockout mice showed robust depression-like responses particularly under short photoperiods, supporting a role for PER3 in mood regulation. These findings suggest PER3 may help coordinate circadian timing and mood responses to seasonal changes.