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Circadian Rhythm Dysfunction in Psychiatric Disorders What is the Molecular Clock? Components of the Molecular Clock The Molecular Clock Involves a Cycle of Feedback Inhibition Virtually all living creatures have an internal molecular clock that synchronizes biological processes such as sleep/wake cycles, metabolism, and body temperature. The molecular clock oscillates with a period of approximately 24-hours; thus, these biologically processes are described as circadian rhythms. Although the molecular clock is self-sustaining, it needs to be reset daily or else it will drift and be out of synch with environmental cues and resources. Such environmental stimuli include light/dark cycles generated by the movement of the Earth and food availability. There are various factors that can reset the clock, however, light is the most powerful synchronizer. Light entering through the eye is translated via the retinohypothalamic tract to the suprachiasmatic nucleus (SCN) within the hypothalamus. During periods of darkness, the SCN induces release of melatonin from the pineal gland. Interestingly, melatonin can then act on receptors in the SCN to reset the molecular clock (Fig. 1). At the molecular level, the circadian clock consists of various proteins called transcription factors that work together in a series of negative feedback loops. These transcription factors bind to DNA regions called promoters, which are DNA sequences found near a gene. The binding of a transcription factor to a promoter may turn the gene on or off, thereby controlling production of proteins. In some cases, a heterodimer complex, formed by two different proteins, can act together to regulate transcription. Specifically, the transcription factors that make up the molecular clock include: Heterodimers of CLOCK and BMAL1 bind to the E box promoter regions that regulate transcription of various proteins, including PER and CRY. As PER and CRY accumulate, they heterodimerize to form a complex. Expression of the nuclear receptor, REV-ERBα, is also regulated by binding of the BMAL/CLOCK complex to an upstream promoter called the ROR/REV-ERBα response element (RRE) (Fig 2A). PER, CRY, and REV-ERBα each provide negative feedback regulation of their own expression. PER and CRY form a complex that inhibits CLOCK/BMAL1-regulated transcription. When REV-ERBα binds the RRE, expression of BMAL1 is blocked (Fig 1B). With expression of PER, CRY, and REV-ERBα inhibited due to the lack of CLOCK/BMAL1, feedback inhibition is no longer an issue. Additionally, ROR binding to the RRE, stimulates expression of BMAL1. Once present, BMAL1 can heterodimerize with CLOCK to begin the cycle of expression and feedback inhibition again (Fig 2C). Both ROR and REV-ERBα are nuclear receptors poised to respond to cues from the environment, such as light and melatonin. Other elements of the molecular clock, acting as transcriptional regulators at other genes, can set into motion circadian behaviors such as sleep and metabolism. Given the sensitivity of the molecular clock to external and internal cues, it is not surprising that the molecular clock may become desynchronized due to many different factors. Social or lifestyle factors, such as shift work, can desynchronize the molecular clock. Mutations in the clock genes that comprise the molecular clock can lead to aberrant regulation of the molecular clock. Impaired neurotransmission, resulting in excessive or insufficient neurotransmitter concentrations can also lead to desynchronization of the molecular clock. Just as the molecular clock is influenced by neurotransmitters, many of the components of the molecular clock in turn regulate levels of neurotransmitters, including serotonin. A malfunctioning clock may therefore lead to impaired neurotransmission. Conversely, impaired neurotransmission may have consequences to the synchronization of the molecular clock. Whether a broken molecular clock is cause or effect, many psychiatric disorders, including depression, schizophrenia, and bipolar disorder are associated with disturbances to circadian rhythms. Pharmacological treatment of psychiatric disorders often entails restoring balance to dysfunctional neurotransmitter systems. However, optimal outcomes might be achieved by also addressing dysfunction in the molecular clock. CLOCK Circadian locomotor output cycles kaput BMAL1 Brain and muscle ARNT-like-1 PERIOD Period CRY Cryptochrome REV-ERBα Transcribed from the opposite strand of the thyroid receptor α (erb) gene ROR Retinoic acid-related orphan receptor A B Mutations in Clock Genes Linked to Mental Illness Many psychiatric disorders are associated with sleep disturbances. It is therefore not surprising that polymorphisms in the genes for BMAL,CLOCK, CRY, PER, and REV-ERBα have each been associated with various psychiatric disorders, including bipolar disorder, depression, schizophrenia, and seasonal affect disorder. C Clock genes associated with psychiatric disorders Clock Gene Suprachiasmatic nucleus (SCN) Mansour et al, 2006; Nievergelt et al, 2006. Bipolar Clock (or its homolog, NPAS) Benedetti et al, 2003; Soria et al 2010. E melatonin Pineal Gland Retinohypothalamic tract Bmal CLOCK CRY E E E box promoter region E PER E E Cry Retinohypothalamic Tract Per Figure 1. The suprachiasmatic nucleus is the master clock. Virtually all living creatures have an internal molecular clock that synchronizes biological processes such as sleep/wake cycles, metabolism, and body temperature. The molecular clock involves a set of f eedback loops that oscillate with a circadian rhythm of approximately 24-hours. Although the molecular clock is self -sustaining, it needs to be reset daily, using both internal and external cues, to prevent desynchronization. Synchronization of the molecular clock may be done by light/dark cycles, food intake, and by a variety of compounds, including melatonin and serotonin. Artioli P, Lorenzi C, Pirovano A et al. Eur Neuropsychopharmacol 2007;17(9):587-94. Benedetti F, Seretti A, Columbo C et al. Am J Genet B Neuropsychiatr Genet 2003;123B(1):23-6. Johansson C, Willeit M, Smedh C et al. Neuropsychopharmacol 2003;28(4):734-9. Kripke DF, Nievergelt CM, Joo E et al. J Circad Rhythms 2009;7:2. Mansour HA, Wood J, Logue T et al. Genes Brain Behav 2006;5(2):150-7. Meyer JH, Ginovart N, Boovariwala A et al. Arch Gen Psychiatry 2006;63:1209-16. Nievergelt CM, Kripke DF, Barrett TB et al. Am J Med Genet B Neuropsychiatr Genet 2006;141B(3):234-41. Orzel-Gryglewska J. Int J Occup Med Environ Health 2010;23(1):95-114. Partonen T, Treutlein J, Alpman A et al. Ann Med 2007;39(3):229-38. Severino G, Manchia M, Contu P et al. Bipolar Disord 2009;11(2):215-20. Soria V, Martínez-Amorós E, Escaramis G et al. Neuropsychopharmacol 2010;35(6):1279-89. Takao T, Tachikawa H, Kawanashi Y et al. Eur Neuropsychopharmacol 2007;17(4):273-6. Wulff K, Gatti S, Wettstein JG et al. Nat Rev Neurosci 2010;11(8):589-99. E REV-ERB α E E ROR RRE ROR/REV-ERBα response element RRE RRE Figure 2. Feedback Inhibition of Molecular Clock Genes A series of negative f eedback loops underlies the circadian rhythm of biological f unctions. A) A heterodimer complex of CLOCK and BMAL1 binds to the E box promoter region turning on expression of CRY and PER. The BMALl1/CLOCK complex also turns off further expression of BMAL1. B) A heterodimer complex of PER and CRY prevents BMAL1/CLOCK -regulated expression of PER and CRY proteins whereas the transcription f actor ROR turns on expression of BMAL1. C) The cycle repeats as BMAL1 and CLOCK proteins accumulate and again turn on transcription of PER and CRY. References Bipolar BMAL1 Suprachiasmatic nucleus (SCN) Disorder Rev-erbα Depression Soria et al 2010 Schizophrenia Takao et al, 2007 Seasonal Affect Disorder Johansson et al, 2003; Partonen et al, 2007. Depression Soria et al, 2010 Bipolar Nievergelt et al, 2006; Artioli et al, 2007; Mansour et al, 2006. Depression Artioli et al, 2007 Schizophrenia Mansour et al, 2006. Seasonal Affect Disorder Partonen et al, 2007. Bipolar Kripke et al 2009; Severino et al, 2009. Presented at the 2011 NEI Global Psychopharmacology Congress.