Genes controlling circadian clock rhythms are profoundly altered in the brains of people with severe depression, a new study has found.
These clock genes regulate 24-hour circadian rhythms affecting hormonal, body temperature, sleep and behavioural patterns.
The research findings provide the first evidence of altered circadian gene rhythms in brain tissue of people with depression and suggest a physical basis for many of the symptoms that depressed patients report.
The study involved researchers from University of California Irvine Health, University of Michigan, University of California Davis, Cornell University, the Hudson Alpha Institute for Biotechnology and Stanford University.
"Our findings involved the analysis of a large amount of data involving 12,000 gene transcripts obtained from donated brain tissue from depressed and normal people," said Dr William Bunney, the study's senior author, and Distinguished Professor of Psychiatry & Human Behaviour at UC Irvine.
"We were amazed that our data revealed that clock gene rhythms varied in synchrony across six regions of normal human brain and that these rhythms were significantly disrupted in depressed patients.
"The findings provide clues for potential new classes of compounds to rapidly treat depression that may reset abnormal clock genes and normalise circadian rhythms," Bunney said.
Circadian clock genes play an important role in regulating many body rhythms over a 24-hour cycle. Although animal data provide evidence for the circadian expression of genes in brain, little has been known as to whether there is a similar rhythmicity in the human brain.
In the study, the researchers analysed genome-wide gene expression patterns in brain samples from 55 individuals with no history of psychiatric or neurological illness and compared them to the expression patterns in samples from 34 severely depressed patients.
The investigators isolated multiple RNA samples from six regions of each brain and arranged the gene expression data around a 24-hour cycle based on time of death.
Several hundred genes in each of six brain regions displayed rhythmic patterns of expression over the 24-hour cycle, including many genes essential to the body's circadian machinery.
"There really was a moment of discovery when we realised that many of the genes that we saw expressed in the normal individuals were well-known circadian rhythm genes - and when we saw that the people with depression were not synchronised to the usual solar day in terms of this gene activity," said Jun Li, an assistant professor in the Department of Human Genetics at the University of Michigan who led the analysis of the massive amount of data generated by the rest of the team.
The study was published in the journal Proceedings of the National Academy of Sciences.
