Circadian Genes Help Predict Mood Changes In Bipolar Mice

Genes controlling the circadian rhythm could be closely linked to mood change-like behaviors associated with bipolar disorder, scientists say.

AsianScientist (Apr. 12, 2016) – Researchers in Japan have succeeded in predicting states of mood-change-like behavior in mouse models of bipolar disorder by studying gene expression patterns in their brains.

Interestingly, so-called circadian genes—the expressions of which increase and decrease over a 24-hour cycle—are over-represented in the prediction gene sets. This demonstrates an intrinsic link between circadian genes in the brain and mood change-like behavior. This research was published in Cell Reports.

People with bipolar disorder, also known as manic-depressive disorder, experience extreme fluctuations in mood and behavior which may occur in cycles lasting for days, months, or years. Such changes were first described more than half a century ago, but their molecular basis in the brain is still unclear.

Scientists have been trying to get a deeper understanding of the molecular basis of mood changes occurring with an infradian (longer than a day) rhythm. They have, however, been hampered by the lack of an animal model with similar behavioral patterns. Thus, Dr. Tsuyoshi Miyakawa and colleagues from the Institute for Comprehensive Medical Science, Fujita Health University, and ATR Computational Neuroscience Laboratories set out to screen over 180 mutant mouse strains for one that exhibits spontaneous behavioral changes related to the infradian oscillation of mood.

They found that mice with heterozygous knockout of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (αCaMKII) exhibit behavioral deficits and other brain features consistent with bipolar disorder. A recent human study also indicated a genetic association of the αCaMKII gene with bipolar disorder, and decreased expression of αCaMKII has been observed in postmortem brains of patients with the disorder.

Notably, the mutant mice also showed periodic changes in movement within their home cages with an approximate cycle length of 10-20 days. The changes in movement are associated with fluctuations of anxiety- and depression-like behaviors, substantially similar to those found in patients with bipolar disorder. As such, in the current study, the researchers used infradian cyclic movements in the mutant mice as a proxy for mood-associated changes.

At first, the researchers monitored the movements of 37 αCaMKII mutant mice by calculating the distance traveled in their cage for over two months. Subsequently, researchers dissected the hippocampus, a region thought to be involved in the regulation of mood, from the brain.

Gene expression patterns in the hippocampus samples were examined to measure the expression levels of over 30,000 genes (or transcripts) per sample. Based on the gene expression data, they constructed models for retrospectively predicting abnormal movements of individual mice.

The researchers found that gene expression patterns in the hippocampus accurately predicted whether the mice were in a state of high or low locomotor activity.

“This is the first demonstration, to our knowledge, of successful quantitative predictions of the individual behavioral state from gene expression patterns in the brain of a mammal,” said Miyakawa.

“Gene expression patterns in the hippocampus may retain information about past locomotor activity.”

The research team then carried out a prediction analysis of the gene expression data in order to identify the genes that are most useful to determine the state of cyclic changes in movement.

“To our surprise, the list of ‘prediction genes’ included a significantly higher number of circadian genes, genes that are known to fluctuate according to circadian rhythms. Circadian genes turned out to be also infradian genes, whose expressions go up and down with mood-change-like behaviors in these mice,” Miyakawa explained.

The team also found that levels of cAMP and pCREB, possible upstream regulators of some circadian genes, were correlated with activity levels.

“The current results provide the evidence for a novel concept that some circadian genes and their regulatory machinery in the brain may be involved in the generation of infradian rhythm behavior,” Miyakawa said.

“It is also of interest whether certain molecular signatures in the samples, such as blood and cerebrospinal fluid, obtained from living animals can predict past and future locomotor activity. If the successful predictions are confirmed in the mouse model, this strategy may have potential for developing new methods for diagnosis, as well as treatment, of patients with bipolar disorder.”

The article can be found at: Hagihara et al. (2016) Circadian Gene Circuitry Predicts Hyperactive Behavior in a Mood Disorder Mouse Model.


Source: Fujita Health University.
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