The genetic basis of circadian behavior - Wiley Online Library

Genes, Brain and Behavior (2006), 5 (Suppl. 2), 73–79

# 2006 The Author Journal compilation # 2006 Blackwell Munksgaard

Review

The genetic basis of circadian behavior H. Oster* Laboratory for Chronobiology and Signal Transduction, Max Planck Institute for Experimental Endocrinology, 30625 Hannover, Germany *Corresponding author: H. Oster, Laboratory for Chronobiology and Signal Transduction, Max Planck Institute for Experimental Endocrinology, 30625 Hannover, Germany. E-mail: henrik.oster@ mpihan.mpg.de

In most species, an endogenous timing system synchronizes physiology and behavior to the rhythmic succession of day and night. The mammalian circadian pacemaker residing in the suprachiasmatic nuclei (SCN) of the hypothalamus controls peripheral clocks throughout the brain and the body via humoral and neuronal transmission. On the cellular level, these clockworks consist of a set of interwoven transcriptional/translational feedback loops. Recent work emphasizes the tissue specificity of some components of these molecular clockworks and the differential regulation of their rhythmicity by the SCN. Keywords: Behavior, circadian, clock genes, physiology, SCN Received 20 January 2005, revised 17 May 2005, accepted for publication 14 June 2005

One of the most prominent characteristic features of life on earth is the constant repetition of night and day. The 24-h rhythm of light and darkness, coupled with warm and cold, exerts a fundamental influence on physiology and behavior of most species dwelling on this planet. Life has coped with this rhythm by evolving biological clocks tracking time and enabling the organism to anticipate and prepare for predictable environmental changes (Pittendrigh 1993). Biological clocks exist not only to deal with daily rhythms (termed circadian clocks, from the Latin circa dies, meaning about one day) but are also employed to measure shorter (ultradian) or longer (infradian) intervals of time (Wollnik 1989). We are currently beginning to unravel the molecular basis of some of these clocks measuring short and long time spans such as the circannual timekeeper controlling migration behavior in birds (Dawson et al. 2001). This review, however, will focus on the circadian system, the so far best characterized clockwork constituting a unique showcase of the molecular basis underlying the regulation of complex physiological and behavioral processes. doi: 10.1111/j.1601-183X.2006.00226.x

Most aspects of temporal homeostasis, the timed coordination of the physiological status, are under the control of the internal pacemaker (Perreau-Lenz et al. 2004). The signaling pathways employed to transmit timing information from the central clockwork of the hypothalamus to the various sites controlling metabolism and physiology and the mechanisms that keep these oscillations in phase are still poorly understood (Gachon et al. 2004). Even less is known about the molecules that mediate the circadian control of complex behavioral systems such as the sleep/wake cycle (Monk & Welsh 2003; Pace-Schott & Hobson 2002), anxiety (Jones & King 2001), learning and memory consolidation (Chaudhury & Colwell 2002), behavioral flexibility and attention (Aston-Jones et al. 2000), and social behavior (Insel & Young 2001; Reijmers et al. 2001; Schwartz & Reppert 1985). In addition to its ability of self-sustained oscillation, the endogenous clock also receives input from the environment to synchronize internal and external time. The most prominent timing signal or Zeitgeber (German for time cue) of the mammalian circadian system is light. Illuminance levels are measured by special photosensory cells in the retina (Berson 2003) that signal via glutamate and pituitary adenylate cyclase-activating peptide (PACAP) to light responsive cells of the central mammalian pacemaker, the suprachiasmatic nuclei (SCN), localized in the ventral part of the hypothalamus (Moore 1978; Rusak & Zucker 1979). Other synchronizing signals have also been identified and include temperature (Rensing & Ruoff 2002), enforced locomotor activity (Wickland & Turek 1991), sleep deprivation (Mistlberger 1992), injections of melatonin (Korf & Stehle 2002), leptin (Prosser & Bergeron 2003), gastrin-releasing peptide (GRP) (McArthur et al. 2000), steroids (Pinto & Golombek 1999) and opioids (Byku & Gannon 2000). Many of these so-called non-photic effectors are thought to operate as feedback mechanisms by which the body affects the central clock. They use signaling pathways to distinct parts of the SCN employing neuropeptide Y (NPY) and serotonin as major neurotransmitters (Mrosovsky 1996).

The anatomy of the mammalian circadian timing system The central clockwork of the SCN controls circadian adaptation of the physiological state via direct humoral and neuronal

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regulation of the metabolic, the endocrine, the immune and the nervous system (Perreau-Lenz et al. 2004; Reppert & Weaver 2002) and indirectly via its influence on the animal’s activity, coupled to body temperature (Schibler et al. 2003). Some peptides secreted from the SCN – such as Prokineticin 2 (PK2; Cheng et al. 2002) or transforming growth factor a (TGFa; Kramer et al. 2001) – have been shown to suppress wheel running activity. The expression pattern of the corresponding receptors, however, suggests a primary action on adjacent nuclei of the hypothalamus that conduct relay signals from the SCN. Glucocorticoids (Balsalobre et al. 2000), retinoic acid (McNamara et al. 2001) and noradrenaline (Terazono et al. 2003) have the potential to reset specific body clocks, but so far no general mechanism has been described for peripheral pacemaker regulation in vivo (Hirota & Fukada 2004; Schibler et al. 2003). It is not entirely clear whether these peripheral clocks are self-sustaining pacemakers or merely hourglass-like timekeepers that need to be regularly reset by SCN signals to continue working (Yamazaki et al. 2000; Yoo et al. 2004). A unique organization of coupling between the single neurons in the SCN may ensure the rhythm persistence within this nucleus and distinguish it from the rest of the body (Ohta et al. 2005). In the periphery, in the absence of exogenous synchronizing signals from the SCN the phases of single cell oscillators would gradually drift apart resulting in a dampened oscillation observed on the whole tissue level (Welsh et al. 2004). While an animal’s locomotor activity rhythms are controlled at least partially via diffusible molecules (Ralph et al. 1990; Silver et al. 1996), some rhythms such as the release of corticosteroids from the adrenal gland have been shown to require neuronal input (Dijkstra et al. 1996; MeyerBernstein et al. 1999) emphasizing the importance of intact SCN projections to other centers of the CNS (Watts & Swanson 1987; Watts et al. 1987) and indirectly to various organs of the body (Fig. 1) (Buijs et al. 2003; de la Iglesia et al. 2003; Terazono et al. 2003; Warren et al. 1994). Electrophysiological studies have shown that neurons display circadian firing rhythms in many brain regions outside the hypothalamus (Aston-Jones et al. 2001; GranadosFuentes et al. 2004; Koolhaas et al. 1980; Ono et al. 1986; Semm & Vollrath 1980; Watts et al. 1987). The SCN projects to three different neuronal targets: endocrine and autonomic neurons of the paraventricular nucleus of the hypothalamus (PVN) and other hypothalamic structures such as the dorsomedial nucleus of the hypothalamus (DMH) and the subparaventricular zone (Leak & Moore 2001) that relay timing signals to other parts of the brain. The PVN secretes hormones that regulate the activity of the pituitary and controls peripheral targets via autonomic innervation (Buijs & Kalsbeek 2001). The DMH regulates the circadian firing pattern of the locus coeruleus (LC) (Aston-Jones et al. 2001) that sends noradrenergic projections to many brain

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IML ACTH

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Figure 1: Circadian regulation of the arousal system. As shown here in the rodent brain, pacemaker neurons of the SCN rhythmically innervate a web of nuclei in and outside the hypothalamus which relay timing information to the brain and the periphery (exemplified here by the adrenal gland). The bimodal regulatory action of endocrine (dotted lines) and neuronal signals (solid lines) ensures a co-ordinated control of the organism’s attention state. Noradrenergic and serotonergic projections from nuclei of the brainstem activate neurons in various areas of the brain (including the cerebellum and the cortex), thereby promoting vigilance and arousal. In addition, these systems have descending projections by which they can enhance or modulate muscle tonus and activity in the periphery via endocrine pathways (e.g. the hypothalamus–pituitary–adrenal (HPA) axis and melatonin synthesis by the pineal gland) and the autonomic nervous system (ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DMH, dorsomedial nucleus of the hypothalamus; IML, intermediolateral column of the spinal cord; LC, locus coeruleus; PVN, paraventricular nucleus of the hypothalamus; SCG, superior cervical ganglion).

areas and the spinal cord (Aston-Jones 2004), some of which may house their own circadian clockworks. A recent series of publications from the group of Steven McKnight has described one of these brain oscillators and characterized its specific contribution to the organism’s circadian timing system. It was found that the forebrain contains a neuronal PAS protein 2 (Npas2 )-dependent circadian clock (Reick et al. 2001). Npas2-deficient mice show changed locomotor activity patterns under normal lighting conditions as well as an altered adaptability to a rapid shift in the external light schedule (a simulated jet lag) and daytime feeding paradigms (Dudley et al. 2003). This pioneering work highlights the functional importance of extrahypothalamic oscillators and complements lesion studies emphasizing the necessity of correct neuronal wiring of the SCN within the CNS (e.g. Challet et al. 1996; Fischette et al. 1981; Goodless-Sanchez et al. 1991; Harrington & Rusak 1988; Lissak et al. 1975; Schwartz et al. 1986) for the functionality of the circadian system. Genes, Brain and Behavior (2006), 5 (Suppl. 2), 73–79

Genetic basis of circadian behavior

The molecular clockwork Circadian clocks have been shown to function in a cellautonomous fashion (Welsh et al. 1995), and our current view is that most if not all cells of the body contain their own circadian clockwork (Balsalobre et al. 2000). Genetic tools were first applied to circadian biology by the seminal work of Konopka and Benzer studying rhythm mutants in Drosophila (Konopka & Benzer 1971). Yet, it was not until 1994 that the first mammalian clock gene – circadian locomotor output cycles kaput or Clock – was discovered in a mutagenesis screen in mice (Vitaterna et al. 1994). From the late 90’s onward, an increasing number of other clock genes have been identified and characterized in the animal model including the Clock partner Bmal1 (or Mop3; Bunger et al. 2000), Per1, Per2 and Per3 (Bae et al. 2001; Cermakian et al. 2001; Shearman et al. 2000; Zheng et al. 1999; Zheng et al. 2001), Cry1 and Cry2 (van der Horst et al. 1999; Vitaterna et al. 1999), Casein kinase1e (CK1e) (Lowrey et al. 2000; Ralph & Menaker 1988), Rev-Erba (Nr1d1) (Preitner et al. 2002) and RORa (Sato et al. 2004). Other genes like the mammalian homolog of Drosophila timeless, mTim (Barnes et al. 2003) and the basic helix-loop-helix (bhlh)-PAS (Period-Arnt-Single minded) proteins Dec1 and Dec2 (Honma et al. 2002) constitute bona fide candidates but still await thorough testing in an appropriate animal model. The molecular clockwork is based on interconnected positive and negative transcriptional/translational feedback loops (TTLs; Fig. 2). The transcriptional activators CLOCK and BMAL1 form heterodimers that activate the expression of genes containing E-Box cis-regulatory enhancers (including the Pers, Crys, Rev-Erba and RORa) during the morning (Gekakis et al. 1998; Hogenesch et al. 1998). PER and CRY proteins are translated and accumulate in the cytoplasm. There they form heteromeric complexes together with CK1e (and maybe d) that eventually translocate into the nucleus where they interfere with CLOCK/BMAL1-driven transcription (Griffin et al. 1999; Jin et al. 1999; Kume et al. 1999). In addition, PER and CRY proteins form complexes which prevent those proteins from being phosphorylated by CK1 marking them for ubiquitination and degradation (Yagita et al. 2000). This equilibrium between translation, further posttranslational modification, translocation, and degradation postpones the highest inhibitory potential of PER/CRY complexes to the night phase when E-box-driven transcription declines. The suppressed transcription and subsequent decrease of PER/CRY protein levels first in the cytoplasm and later in the nucleus re-activates CLOCK/BMAL1-driven expression in the early morning and thereby re-initiates the next circadian cycle. Specificities for complex formation seem to exist between different PER and CRY paralogs in vivo (Oster et al. 2002b; Oster et al. 2003). Together with the opposite regulation of Per1 and Per2 expression under different lighting conditions


P

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Bmal1 Figure 2: Multiple transcriptional/translational feedback loops stabilize the cellular core oscillator of the circadian clock in the SCN. E-box containing clock and first-order clock-controlled genes (CCGs) are rhythmically activated by CLOCK/BMAL1. The translated proteins form positive and negative feedbacks on their own synthesis via regulation of Bmal1 transcription and direct inhibition of the CLOCK/BMAL1 enhancer complex. Complexation, posttranslational modification and subcellular localization of clock proteins ensure the delayed timing of this feedback essential for the oscillation of the molecular clockwork (for details see the text; RORE, retinoic acid-related orphan receptor response element).

(Steinlechner et al. 2002), this may adjust the duration of CLOCK/BMAL1 suppression to the photoperiod and may therefore constitute a mechanism of adaptation of the clockwork to winter and summer (Daan et al. 2001; Oster et al. 2002a). Rev-Erba and RORa form additional feedbacks that stabilize the clock rhythm via transcriptional regulation of Bmal1. These supporting TTLs seem to be less critical for normal rhythm generation but add to the precision of the clockwork and its insensitivity to external and internal noise (Preitner et al. 2002; Sato et al. 2004). In addition, CLOCK and BMAL1 directly (via E-boxes) or indirectly control the rhythmic transcription of a set of clockcontrolled genes (CCGs). These CCGs are tissue-specific and in the SCN include Vasopressin (Avp; Jin et al. 1999) and

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Prokineticin2 (Pk2) (Cheng et al. 2002) encoding neuropeptides that mediate clock rhythms to other areas in the brain.

Peripheral clocks Genomic approaches using microarray technology have revealed that in most tissues, about 8–10% of all expressed genes are oscillating in a circadian fashion (Akhtar et al. 2002; Panda et al. 2002; Storch et al. 2002; Ueda et al. 2002). In the liver, many transcripts encoding rate-limiting enzymes of essential metabolic pathways such as glycolysis, fatty acid metabolism and gluconeogenesis are under circadian regulation (Storch et al. 2002) offering a mechanism for the control of organ physiology by the circadian clock (Rutter et al. 2002). Not all of these CCGs are directly controlled by CLOCK/ BMAL1 or their tissue-specific paralogs (like NPAS2 in the forebrain and in the vasculature; McNamara et al. 2001). Second-order CCGs may be indirectly regulated via CLOCK/ BMAL1-controlled mediators such as D-element-binding protein (DBP) that has been shown to control the rhythmic expression of some metabolic enzymes in the liver (Lavery et al. 1999). DBP acts together with the basic leucine zipper transcription factor E4BP4, whose rhythm is opposite to that of DBP, via inverse effects on D-element cis-regulatory enhancers of responsive genes (Mitsui et al. 2001). The cell autonomy of the circadian clockwork is the basis of tissue and even cell-specific modulation and interpretation of endocrine or neuronal timing signals from the SCN. This specificity enables the organism to spatially and temporally fine tune its body functions in an efficient and economic manner. The SCN as the central pacemaker synchronizes the internal rhythm to the environment. It acts like the conductor of an orchestra that gives the pace he reads from the score (e.g. the sun). The music, however, is played by the instruments, the peripheral oscillators controlling the physiological and the behavioral state of the organism.

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Acknowledgments The author thanks Ms. Diya Abraham and Drs Gregor Eichele and Erik Maronde for their critical comments on the manuscript. This work was supported by the Max Planck Society and the EC BrainTime grant (QLG3-CT-2002-01829).

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