Summary: A new study reports that disrupting the natural circadian rhythm in mice causes depression and anxiety.
Disruptions of daily rhythms of the body’s master internal clock cause depression- and anxiety-like behaviors in mice, reports a new study in Biological Psychiatry. The findings provide insight into the role of the brain’s internal time keeping system in the development of mood disorders, such as bipolar disorder and major depressive disorder, which have been associated with disturbed daily (circadian) rhythms.
“Our data show that perturbing circadian rhythms in otherwise totally undisturbed animals is enough to cause behaviors similar to human depression,” commented first author Dr. Dominic Landgraf of the University of California, San Diego.
Inherent circadian clocks help us function throughout the day, by telling us when to sleep, wake and eat, as well as by synchronizing our bodily processes. “It is perhaps not surprising that disruptions of our natural synchronization can have heavy impacts on our physical and mental health,” Dr. Landgraf added.
However, until now researchers did not know if disturbed circadian rhythms were a cause or consequence of mood disorders. In the new study, a team led by David K. Welsh has shown for the first time a causal relationship between functioning circadian clocks and mood regulation.
The researchers developed a new genetic mouse model by suppressing Bmal1, one of the master genes that drives circadian rhythms, in the suprachiasmatic nucleus (SCN), which serves as the brain’s central clock regulator. Diminished Bmal1 expression reduced the strength of the clock signals produced by the SCN by about 80%. Targeting this particular brain region allowed the researchers to focus on the specific effects of the SCN circadian rhythms, and to avoid alterations in other brain regions that have confounded previous studies.
In behavioral tests, mice with reduced circadian rhythms, relative to control mice, were less motivated to escape an uncomfortable situation, which is commonly interpreted as despair or hopelessness in the animal. The mice also showed increased aversion to brightly lit areas, considered to be an indicator of anxiety-like behavior.
In addition to the altered behavior, mice with reduced circadian rhythms gained more weight than normal mice, even though they consumed the same amount of food. This finding suggests that disrupted SCN circadian rhythms could lead to metabolic abnormalities observed in many depressed patients.
Importantly, the findings show that even though the SCN does not directly regulate mood, alterations to circadian rhythms in the SCN are sufficient to cause depression- and anxiety-like behaviors in mice.
“We have long known that disruptions in circadian rhythms may contribute to depression, particularly in people at risk for major depression or bipolar disorder,” said Dr. John Krystal, Editor of Biological Psychiatry. “This new study provides additional evidence implicating the Bmal1 gene in the relationship between these circadian rhythms and mood.”
According to Dr. Landgraf, the results are an important step toward developing new depression treatments that directly target the circadian clock in humans.
Source: Rhiannon Bugno – Elsevier
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice” by Dominic Landgraf, Jaimie E. Long, Christophe D. Proulx, Rita Barandas, Roberto Malinow, and David K. Welsh in Biological Psychiatry. Published online November 12 2016 doi:10.1016/j.biopsych.2016.03.1050
Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice
Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established.
We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain’s master circadian pacemaker, the suprachiasmatic nucleus (SCN).
In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress.
Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression.
“Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice” by Dominic Landgraf, Jaimie E. Long, Christophe D. Proulx, Rita Barandas, Roberto Malinow, and David K. Welsh in Biological Psychiatry. Published online November 12 2016 doi:10.1016/j.biopsych.2016.03.1050