Rhythms in gene expression in the brain are highly disrupted in people with schizophrenia, according to a new University of Pittsburgh-led study.
The findings, published today by researchers from the Pitt’s School of Medicine in the journal Nature Communications, also suggest that researchers studying schizophrenia-linked genes in the brain could have missed important clues that would help understand the disease.
“Our study shows for the first time that there are significant disruptions in the daily timing of when some genes are turned on or off, which has implications for how we understand the disease at a molecular level,” said senior author Colleen McClung, Ph.D., professor of psychiatry at Pitt’s School of Medicine.
Many bodily functions run on a 24-hour cycle, called a circadian rhythm, which extends to how genes are expressed within cells.
Some genes turn on or off at certain times of the day or night.
In this study, McClung and colleagues analyzed gene expression data from the dorsolateral prefrontal cortex – a brain region responsible for cognition and memory – from 46 people with schizophrenia and 46 sex- and age-matched healthy subjects.
The data was obtained from the CommonMind Consortium, a public-private partnership that has curated a rich brain tissue and data bank for studying neuropsychiatric disorders.
By knowing the time of death, the researchers were able to use a statistical method to determine changes in the rhythmicity of different genes, which revealed some interesting patterns.
McClung explained the findings by drawing an analogy of gene expression to electrical appliances in a house.
“In a normal house – like a healthy brain – let’s say the lights are turned on at night, but the refrigerator needs to be on all the time.
What we saw was that in a schizophrenia-affected brain, the lights are on all day and the refrigerator shuts off at night.”
This is problematic, explains McClung, because it can affect how cells function.
In their samples, the genes that gained rhythmicity were involved in how mitochondria – the cell’s powerhouse – functions, and those that lost rhythmicity were linked to inflammation.
The results also have implications for other researchers studying the genetics of schizophrenia, according to Marianne Seney, Ph.D., assistant professor of psychiatry at Pitt’s School of Medicine and the study’s first author.
By not considering circadian rhythms, they could be missing out on important findings.
When Seney and McClung compared gene expression in brains from people who died during the day, the control and schizophrenia subjects were not different, but in those who died at night, there were major differences, since genes that had gained a rhythm had hit their low point during the night.
Seney alludes to the analogy of the house. “If we only looked to see if the refrigerator was on during the day we would see no difference, but at night, there would be one.”
Disturbances of sleep and abnormal sleep-wake cycles are common features of psychiatric disorders.1 In schizophrenia, polysomnographic studies comparing healthy individuals with participants who are drug-naive or drug-treated, when either acutely psychotic or clinically stable, have found delayed sleep onset, impaired sleep continuity and increased time awake.2–5
There are also sleep architectural changes already evident in individuals not on medication at psychosis onset, characterised by shorter rapid eye movement sleep and less slow-wave sleep.6Slow-wave sleep deficits have been shown to correlate with lower frontal lobe metabolism and ventriculomegaly suggesting a neurodevelopmental trait.7,8
Sleep is only part of the 24 h circadian cycle.
The generation and regulation of sleep that arises from multiple brain regions, neurotransmitter systems and modulatory hormones is driven by a complex interaction of wake and sleep mechanisms involving:
(a) a wake-dependant homeostatic buildup of sleep pressure that increases with prolonged wakefulness and dissipates during sleep; and
(b) a 24 h body clock or circadian system (‘circa diem’ – about a day) that aligns sleep to the dark phase and activity to the light phase of the 24 h day through precisely controlled, cyclic expression of a number of genes, so-called clock genes.
It has recently been shown that genetic variability in a number of these genes is associated not only with phenotypic differences in morning v. evening preference, rhythm-related sleep disorders, sleep homeostasis and cognitive performance following sleep loss9 but also with midbrain dopamine regulation and reward processing10 known to be disrupted in schizophrenia.11
These findings suggest that sleep-wake disruption in schizophrenia may have a genetic basis and that the presence of specific sleep-wake patterns may serve as a useful endophenotypic dimension to assess familial pre-disposition.12
To date there have been few studies of circadian rhythms over extended periods of time in people with schizophrenia and these are mainly case reports or small group reports; none has controlled for the possibility that a lack of structured routine, common in schizophrenia, may be a cause of circadian misalignment in sleep-wake activity.
The main aim of this study was to provide a comprehensive description of sleep-wake phenotypes in individuals with stable, non-acute schizophrenia who have sleep complaints, and to determine the contribution of probable circadian rhythm dysfunction to self-reported sleep disturbances.
We measured day-to-day motor activity and light exposure with unobtrusive ‘watches’ (wrist actigraphy) over 6 weeks, and we established melatonin profiles from weekly urine collections, thereby using melatonin’s property as a physiological phase marker of the circadian clock.
To control for the non-specific effect that the lack of a daytime routine may have on sleep-wake cycles, we compared the circadian rhythms of participants with schizophrenia with those of unemployed, healthy individuals.
More information:Nature Communications (2019). DOI: 10.1038/s41467-019-11335-1
Journal information: Nature Communications
Provided by University of Pittsburgh
