Researchers map the circadian neurogenetics involved in brain aging.


It is known that a 24-hour circadian rhythm controls nearly all brain and body processes, such as the sleep/wake cycle, metabolism, alertness and cognition. These daily activity patterns are regulated by certain genes that are found in almost all cells.  However, these genes have rarely been studied in the human brain.  Now, a study from researchers at the University of Pittsburgh has examined thousands of genes from 146 human brains to map the circadian rhythm of gene activity changes during aging. The team state that their findings also identify a novel biological clock which only begins ticking in the older brain.  The study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies show that twenty-four-hour rhythms in physiology and behaviour are generated through interaction between environmental cycles and endogenous self-sustained circadian oscillators. In mammals, circadian oscillators are present in the brain and most peripheral tissues.  The mammalian circadian system is organized in a hierarchical manner, with a central pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Synchronization of central and peripheral oscillators is achieved through direct neural connections between the SCN and target tissues, endocrine rhythms that are driven by the SCN, such as cortisol and melatonin, and behaviours such as food intake and sleep and associated changes in physiology.  With aging, significant changes in circadian rhythms occur, including a shift in phase toward a ‘morning’ chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive.  The current study investigates the effect of normal aging on molecular rhythms in the human prefrontal cortex, an area of the brain involved in learning, memory and other aspects of cognitive performance.

The current study examined brain samples of 146 people with no history of mental health or neurological problems whose families had donated their remains for medical research and for whom the time of death was known. The group categorized the brains depending on whether they had come from a person younger than 40 or older than 60, and used a newly developed statistical technique to analyze two tissue samples from the prefrontal cortex for rhythmic activity, or expression, of thousands of genes.  Results identified 235 core genes that make up the molecular clock in this part of the brain.

Data findings show that younger people had the daily rhythm in all the classic ‘clock’ genes.  However, the researchers state that there was a loss of rhythm in many of these genes in older people, which might explain some of the alterations that occur in sleep, cognition and mood in later life. The lab also identified a set of genes that gained rhythmicity in older individuals.

The team surmise that their findings could ultimately be useful in the development of treatments for cognitive and sleep problems that can occur with aging, as well as a possible treatment for ‘sundowning,’ a condition in which older individuals with dementia become agitated, confused and anxious in the evening.  They go on to add that since depression is associated with accelerated molecular aging, and with disruptions in daily routines, their results also may shed light on molecular changes occurring in adults with depression.  For the future, the researchers state that they will explore the function of the brain’s circadian-rhythm genes in lab and animal models, and also investigate whether they are altered in people who have psychiatric or neurological illnesses.

Source: University of Pittsburgh Schools of the Health Sciences

 

Direct interaction networks between genes for which at least one transcript had a statistically significant interaction between sleep condition and sample time or a main effect of sleep condition. Node color (see key) represents the most enriched association with a top 10 GO biological process.  Mistimed sleep disrupts circadian regulation of the human transcriptome.  Dijk et al 2013.

Direct interaction networks between genes for which at least one transcript had a statistically significant interaction between sleep condition and sample time or a main effect of sleep condition. Node color (see key) represents the most enriched association with a top 10 GO biological process. Mistimed sleep disrupts circadian regulation of the human transcriptome. Dijk et al 2013.

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