Anxiety, autism, schizophrenia and Tourette syndrome all have their own distinctive characteristics, but one factor linking these and most other mental disorders is circadian rhythm disruption, according to a team of neuroscience, pharmaceutical science and computer science researchers at the California University, Irvine.
In an article recently published in the journal Nature Translational psychiatryscientists suggest that CRD is a psychopathological factor shared by a wide range of mental illnesses, and that studying its molecular basis may hold the key to unlocking better therapies and treatments.
“Circadian rhythms play a fundamental role in all biological systems at all levels, from molecules to populations,” said senior author Pierre Baldi, UCI professor emeritus of computer science. “Our analysis found that circadian rhythm disruption is a factor that broadly overlaps with the entire spectrum of mental disorders.”
Lead author Amal Alackar, a neuroscientist and teaching professor in UCI’s Department of Pharmaceutical Sciences, noted the challenges of testing the team’s hypothesis at the molecular level, but said the researchers found sufficient evidence for the link through a thorough examination of the peer-reviewed literature for the most many prevalent mental health disorders.
“The telltale sign of a circadian rhythm disruption — trouble sleeping — was present in every disorder,” Alachar said. “Although our focus was on well-known conditions including autism, ADHD, and bipolar disorder, we argue that the psychopathological factor hypothesis of CRD may generalize to other mental health problems, such as obsessive-compulsive disorder, anorexia nervosa, bulimia nervousness, food addiction and Parkinson’s disease.”
Circadian rhythms regulate the physiological activity of our bodies and biological processes during each solar day. Synchronized with a 24-hour light/dark cycle, circadian rhythms influence when we should normally sleep and when we are awake. They also manage other functions such as the production and release of hormones, maintaining body temperature and consolidating memories. The efficient, continuous operation of this natural time-keeping system is necessary for the survival of all living organisms, according to the paper’s authors.
Circadian rhythms are inherently sensitive to light/dark cues, so they can be easily disrupted by nocturnal light exposure, and the level of disruption appears to be sex-dependent and changes with age. One example is a hormonal response to CRD experienced by pregnant women; both mother and fetus can experience clinical effects from CRD and chronic stress.
“An interesting question we investigated is the interaction of circadian rhythms and mental disorders with sex,” said Baldi, director of UCI’s Genomics and Bioinformatics Institute. “For example, Tourette’s syndrome is predominantly present in men, and Alzheimer’s disease is more common in women by a ratio of approximately two-thirds to one-third.”
Age is also an important factor, according to the scientists, as CRD can affect neurological development in early life in addition to leading to the onset of mental disorders associated with aging in the elderly.
Baldi said one important unresolved issue centers on the causal relationship between CRD and mental disorders: Is CRD a key factor in the origin and onset of these disorders or a self-reinforcing symptom of disease progression?
To answer this and other questions, the UCI-led team is proposing to study CRD at the molecular level using transcriptomic (gene expression) and metabolomic technologies in mouse models.
“This will be a high-throughput process, with researchers sampling healthy and diseased subjects every few hours during the circadian cycle,” Baldi said. “This approach can be applied with limitations in humans, since only serum samples can really be used, but it can be applied on a large scale in animal models, especially mice, by sampling tissue from different brain regions and various organs, in addition to serum. These are extensive, painstaking experiments that could benefit from having a consortium of laboratories.”
He added that if experiments are conducted in a systematic manner across age, gender and brain regions to examine circadian molecular rhythmicity before and during disease progression, it will help the mental health research community identify potential biomarkers, causal relationships and new therapeutic targets and pathways.
This project included scientists from UCI’s Department of Pharmaceutical Sciences, the Center for the Neurobiology of Learning and Memory, the Department of Computer Science, the Department of Neurobiology and Behavior, and the Institute for Genomics and Bioinformatics; as well as UCLA’s Oppenheimer Center for the Neurobiology of Stress and Resilience and the Goodman-Luskin Microbiome Center. The National Institutes of Health provided financial support.