When brain clocks lose track of time: cause or consequence of neuropsychiatric disorders

Abstract

Patients suffering from neuropsychiatric disorders often exhibit a loss of regulation of their biological rhythms which leads to altered sleep/wake cycle, body temperature rhythm and hormonal rhythms. Whereas these symptoms have long been considered to result from the pathology of the underlying disease, increasing evidence now indicates that the circadian system may be more directly involved in the etiology of psychiatric disorders. This emerging view originated with the discovery that the genes involved in the generation of biological rhythms are expressed in many brain structures where clocks function-and perhaps malfunction. It is also due to the interesting phenotypes of clock mutant mice. Here we summarize recent reports showing that alteration of circadian clocks within key brain regions associated with neuropsychiatric disorders may be an underlying cause of the development of mental illness. We discuss how these alterations take place at both systems and molecular levels.

Figure 1. Multi-levels organization of the circadian system in the human brain

A/ Clocks are found in many different cerebral structures, including those involved in the neuropsychiatric disorders. These are called peripheral clocks (orange), and contrast with the master circadian clock (yellow) located in the suprachiasmatic nucleus (SCN) of the hypothalamus. B/ As a master clock, the SCN generates and synchronizes many biological rhythms such as hormones, neuronal connections, body temperature, metabolites and paracrine signals. These circadian signals in turn entrain the molecular clockwork within peripheral clocks, so that their biological and physiological functions are optimal at the most appropriate times of day (plain, thick arrow). The SCN is, in contrast, resistant to most rhythmic signals it synchronizes (dashed, thin arrow). The molecular clockwork in humans relies on transcriptional feedback loops in which the transcriptions factors BMAL1, CLK and NPAS2 rhythmically activate the expression of their transcriptional repressors Per and Cry genes, as well as many other “clock-controlled genes”. Clock-controlled genes are the output of the clocks and contribute to their rhythmic physiology. External factors that desynchronize rhythmic signals within peripheral oscillators, as well as genetic mutation of clock genes, provoke improper clock function, which impacts on overall gene expression. Such a clock malfunction within brain oscillators accounts for some of the symptoms observed in patients suffering from neuropsychiatric disorders.