The clock shop: Coupled circadian oscillators

YEXNR-11285; No. of pages: 7; 4C: 2, 4, 5 Experimental Neurology xxx (2012) xxx–xxx

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Review

The clock shop: Coupled circadian oscillators Daniel Granados-Fuentes, Erik D. Herzog ⁎ Department of Biology, Washington University, St. Louis, MO 63130, USA

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Article history: Received 30 May 2012 Revised 4 September 2012 Accepted 16 October 2012 Available online xxxx Keywords: Pacemaker Period gene Vasoactive intestinal polypeptide Suprachiasmatic nucleus Neuropeptide

a b s t r a c t Daily rhythms in neural activity underlie circadian rhythms in sleep–wake and other daily behaviors. The cells within the mammalian suprachiasmatic nucleus (SCN) are intrinsically capable of 24-h timekeeping. These cells synchronize with each other and with local environmental cycles to drive coherent rhythms in daily behaviors. Recent studies have identified a small number of neuropeptides critical for this ability to synchronize and sustain coordinated daily rhythms. This review highlights the roles of specific intracellular and intercellular signals within the SCN that underlie circadian synchrony. © 2012 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A simple circadian system: input–pacemaker–output . . . . . . . . . . . . . . . . . Pacemaker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Input . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Many intrinsically circadian cells of the SCN collectively encode the precision, amplitude, Neuropeptides synchronize SCN cells to each other . . . . . . . . . . . . . . . . . Vasoactive intestinal polypeptide is required for synchrony . . . . . . . . Other neuropeptides can modulate synchrony . . . . . . . . . . . . . . GABA rapidly communicates timing information over long distances . . . . Multiple signals synchronize SCN cells to environmental cycles . . . . . . . . . . . . All roads lead through cAMP and Ca + 2 . . . . . . . . . . . . . . . . . . . . . . . Circadian sleep disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction What woke you up today? If you ask this question of people in developed countries today, over 80% will credit their alarm clock (Roenneberg et al., 2012). But when they permit themselves a morning without an external timer, they will wake naturally to the call of an internal, daily clock. This chapter is about the cellular organization of this daily clock. We review evidence that this daily clock is

⁎ Corresponding author. E-mail address: [email protected] (E.D. Herzog).

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comprised of thousands of intrinsically oscillatory cells that must synchronize with environmental cues and with each other. We summarize what is known about the signaling pathways involved in their communication with each other to generate a coherent daily rhythm in behavior. Life on Earth has evolved in the presence of a daily light–dark, warm–cool cycle. Nearly all organisms alive today anticipate and synchronize (entrain) with these potent cues (Dunlap, 1999). These daily rhythms persist in the absence of these cues, for example in a deep cave or during the dark winter months near the Poles (Cavallari et al., 2011). Under these constant conditions, most organisms will wake and sleep with a period close to 24 h. These circadian (from the Latin, circa meaning approximately and diem, a day) rhythms

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Please cite this article as: Granados-Fuentes, D., Herzog, E.D., The clock shop: Coupled circadian oscillators, Exp. Neurol. (2012), http:// dx.doi.org/10.1016/j.expneurol.2012.10.011

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include cycles of sleep–wakefulness, feeding–fasting, metabolism and hormone release (Honma et al., 2003; Sack et al., 2007). This same circadian clock regulates seasonal changes in many mammals including breeding, fat storage and hibernation (Geiser, 2004).

al., 2002; Yamazaki et al., 1999). This was not a foregone conclusion since all other vertebrates need the presence of extraocular photoreceptors for entrainment (Meijer et al., 1999; Nelson and Zucker, 1981). Intriguingly, some “blind” patients with rod/cone degeneration, while unable to form images, can respond to light by entraining their circadian rhythms, suppressing their nighttime melatonin production, constricting their pupils and, in a few cases, reporting awareness of the light (Czeisler et al., 1995; Klerman et al., 2002; Zaidi et al., 2007). These residual light responses arise from a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment, melanopsin (Berson et al., 2002; Hattar et al., 2002). ipRGCs form the retino-hypothalamic tract and convey light information transduced by rods and cones in addition to their intrinsic light responses (Foster et al., 2007; Freedman et al., 1999; Guler et al., 2008). Thus, ipRGCs are the sole conduit for light information of all intensities to the SCN and for photic entrainment (Guler et al., 2008; Hatori et al., 2008). Light is not the only input signal important for entrainment of the clock, as other non-photic input signals have been also implicated to participate. For example, exercise, social signals, temperature cycles or sleep deprivation can reset the clock (Hastings et al., 1997; Herzog and Huckfeldt, 2003; Mistlberger and Skene, 2005; Mrosovsky, 1996).

A simple circadian system: input–pacemaker–output It has been useful to evaluate the circadian system conceptually as a pacemaker that regulates a variety of rhythmic outputs and entrains to a variety of environmental timing cues through input pathways. Anatomically, the master circadian pacemaker of mammals has been localized to the suprachiasmatic nucleus (SCN), a group of cells in the base of the anterior hypothalamus situated directly above the optic chiasm (Fig. 1). The bilateral rodent suprachiasmatic nuclei are composed of about 20,000 neurons packed into an area approximately 1 mm in diameter (Klein et al., 1991). Pacemaker Evidence that the SCN acts as a master circadian pacemaker comes primarily from lesion and transplantation studies. Destruction of the SCN results in a loss of daily rhythms in a wide variety of functions including sleep–wake, locomotor activity, feeding, drinking, body temperature and secretion of adrenal, pineal and pituitary hormones (Meyer-Bernstein et al., 1999; Moore and Eichler, 1972; Stephan and Zucker, 1972; Tahara et al., 2012). Rhythms in locomotion, feeding, drinking and body temperature can be restored by a SCN transplant, remarkably, with the period of the donor (Cho et al., 2005; Meyer-Bernstein et al., 1999; Ralph et al., 1990; Silver et al., 1996). In addition, the isolated SCN displays circadian rhythms in glucose metabolism, electrical firing, neuropeptide secretion, and gene expression (Earnest and Sladek, 1986; Green and Gillette, 1982; Meijer et al., 1997; Shibata and Moore, 1993; Yamazaki et al., 2000). Taken together, these results indicate that the coordinated daily rhythms of SCN cells drive circadian rhythms in the brain and, ultimately, the body.

Output The SCN can convey time-of-day information to the rest of the brain and body via neuronal and humoral pathways (Hatcher et al., 2008; Kalsbeek and Buijs, 2002; LeSauter and Silver, 1998). Efferents from the SCN project primarily to nuclei within the hypothalamus (see Chapter by Larry Morin). Many intrinsically circadian cells of the SCN collectively encode the precision, amplitude, waveform and robustness of daily rhythms In 1995, David Welsh and colleagues demonstrated that individual SCN neurons fire action potentials each day and fall silent each night for many days in vitro (Welsh et al., 1995). Remarkably, they found that when dispersed into a culture dish at relatively low density (~ 3000 cells/mm2), SCN neurons expressed different circadian periods from each other so that, for example, some neurons started their daily firing every 23 h while others initiated firing every 28 h.

Input In mammals, the eyes are required to entrain the SCN to light cycles (Berson et al., 2002; Hattar et al., 2002; Morin et al., 2003; Wee et

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Fig. 1. The cellular and molecular organization of the mammalian circadian system. Neurons within the suprachiasmatic nucleus (SCN) are competent circadian pacemakers (1). They depend on intracellular, transcription-translation negative-feedback (2) mechanisms to generate near 24-h oscillations. When they synchronize with each other through neuropeptide signaling (3), they drive daily rhythms including metabolism, gene expression, cAMP levels, membrane excitability, firing rate and neuropeptide secretion (4). The coordinated daily rhythms of the SCN are entrained to light cycles by direct input from intrinsically photosensitive retinal ganglion cells (ipRGCs) (5). Projections from the SCN to other hypothalamic structures (6) convey time-of-day information to regulate daily rhythms in the brain, body and behavior. SON, supraoptic nucleus; PVN, paraventricular hypothalamic nucleus.

Please cite this article as: Granados-Fuentes, D., Herzog, E.D., The clock shop: Coupled circadian oscillators, Exp. Neurol. (2012), http:// dx.doi.org/10.1016/j.expneurol.2012.10.011

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These period differences between cells appeared to persist even when all action potentials were blocked with tetrodotoxin. They concluded that single SCN neurons are likely to be competent circadian pacemakers. Subsequently, this has been assumed to be the case in all of the molecular analyses of the mechanisms that generate circadian rhythms (see Chapter by Joseph Takahashi). Over a decade later, Alexis Webb and colleagues isolated single SCN neurons (by killing all but one cell) in the Petri dish and found that individual SCN neurons can indeed express circadian rhythms in firing rate and in gene expression (Webb et al., 2009). She went on to show that this was a property of multiple cell types in the SCN. Notably, when isolated from their network, SCN neurons express unstable circadian rhythms with lower amplitude and more variable cycle-to-cycle periods. This has led to the conclusion that cell–cell interactions within the SCN make the circadian pacemaker more robust (Hogenesch and Herzog, 2011; Hogenesch and Ueda, 2011). Thus, the machinery needed to generate circadian rhythms appears to be intracellular and intrinsic to many cells in the SCN. Watching the SCN tick in vitro and in vivo is now possible in real-time. Using reporters of gene or protein expression, intracellular Ca +2 levels or phosphorylated CREB activity, researchers have noted that while the cells in the SCN march to the same beat, they vary in the waveform and phasing of their daily rhythms (Cheng et al., 2009; Kuhlman et al., 2000; Welsh et al., 2005; Yamaguchi et al., 2001, 2003; Yoo et al., 2004). Although it is not yet clear whether all cells at all times are capable of circadian rhythmicity (Silver and Schwartz, 2005), the heterogeneity in the relative phasing of cells appears to underlie adaptation to the long days of summer and short days of winter (Ciarleglio et al., 2011; Inagaki et al., 2007; Jagota et al., 2000; Schaap et al., 2003; Schwartz et al., 2011; VanderLeest et al., 2007). In this way, the population of SCN oscillators encodes photoperiod. Neuropeptides synchronize SCN cells to each other To produce a coherent daily output, the cells of the SCN must entrain to each other. Early work showed that nonlinear integration unifies the intrinsic properties of cells to produce circadian rhythms in behavior (Butler and Silver, 2009; Low-Zeddies and Takahashi, 2005; Mohawk and Takahashi, 2011; Welsh et al., 2010). More than 20 transcription factors, kinases, phosphatases and their regulators have been shown to determine circadian cycle length (Maywood et al., 2011a; Reppert and Weaver, 2002; Shimomura et al., 2001; Ueda et al., 2005)(and see Chapter by Joseph Takahashi), yet only a few signaling molecules have been identified as critical for synchrony among SCN cells (Fig. 2). Vasoactive intestinal polypeptide is required for synchrony Vasoactive intestinal polypeptide (VIP) is produced by neurons in the ventral part of the SCN and is released in a circadian pattern (Cagampang et al., 1998; Shinohara et al., 1999). Through its receptor (VPAC2R, encoded by the Vipr2 gene), VIP signaling has at least two distinct roles in the SCN: to maintain the amplitude of circadian rhythms in individual neurons, and to maintain synchrony between intrinsically rhythmic neurons. The loss of VIP or VPAC2R results in a phenotype much like isolating SCN neurons from each other: Individual cells show unstable, low amplitude circadian cycling and fail to synchronize with each other. Similarly, mice lacking VIP or VPAC2R show weak-to-no circadian cycling (Aton et al., 2005; Cutler et al., 2003; Harmar et al., 2002; Vosko et al., 2007). Daily application of a VIP agonist (e.g. Ro 25–1553) can restore synchrony and amplitude to these cellular oscillations. Importantly, circadian rhythms can be reinstated in VIP-deficient mice by providing, for example, daily, restricted access to a running wheel (Maywood et al., 2011b; Power et

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al., 2010). These results indicate that VIP is the primary, but not unique, circadian synchronizer. Other neuropeptides can modulate synchrony Recent screens have identified more than 100 peptides secreted by SCN cells including novel neuropeptide precursors, cytokines, chemotrophins, growth factors and transmembrane proteins that signal when cleaved (Hatcher et al., 2008; Kramer et al., 2005). These signals appear to be hierarchically organized with VIP having the largest phase shifting effects on the largest number of SCN cells. The SCN likely integrates these diverse signals. For example, the roles of arginine vasopressin (AVP) acting through V1a and V1b receptors and gastrin releasing peptide (GRP) acting through BB2 receptors have recently been explored. Although loss of AVP or GRP appears to have little effect on wild-type SCN rhythmicity, addition of either to SCN lacking VIP can restore synchrony and blocking either can further weaken synchrony in VIP-deficient SCN. (Brown et al., 2005; Maywood et al., 2011b). Taken together, these results indicate that other neuropeptides can contribute to synchrony and are, perhaps, recruited to participate under specific environmental conditions. GABA rapidly communicates timing information over long distances Interestingly, these neuropeptides are released by distinct populations of cells whereas the neurotransmitter α-aminobutyric acid (GABA) is released and received by most, if not all, SCN neurons (Atkins et al., 2010; Belenky et al., 2007; Castel and Morris, 2000; Itri and Colwell, 2003; Moore and Speh, 1993; Speh and Moore, 1993). When applied daily to SCN cultures, GABA has also been reported to synchronize SCN firing rate rhythms (Liu and Reppert, 2000) although, like AVP or GRP, blockade of GABA signaling does not reduce circadian synchrony (Aton et al., 2006). GABA signaling from the ventral SCN acutely excites neurons in the dorsal SCN and from the dorsal SCN acutely inhibits neurons in the ventral SCN (Albus et al., 2005). Decreasing GABAergic tone by genetically deleting the Na(V)1.1 sodium channel leads to impaired communication between the ventral and dorsal SCN and, intriguingly, a longer circadian period (Han et al., 2012). Furthermore, pharmacological blockade of GABAA receptors or reducing GABA release with Na(V)1.1 deletion decreases the ability of the SCN to adjust to shifts in the light cycle, presumably by impairing communication between ventral and dorsal SCN (Albus et al., 2005; Han et al., 2012). Thus, GABA appears to play an important role in long-range, rapid synaptic communication in the SCN to facilitate entrainment to environmental cycles. It remains to be determined if or how changes during development and aging or in response to changing environmental conditions modulate these signals. It is clear that adjustments in neuropeptide and neurotransmitter signaling in the SCN could tune the amplitude, phase or waveform of daily rhythms controlled by the SCN. Importantly, when synchrony among SCN cells fails (e.g. in VIP-deficient mice), a litany of problems follows including a loss of hormonal and metabolic rhythms, learning impairment and cardiac disease (Bechtold et al., 2008; Chaudhury et al., 2008; Loh et al., 2008; Schroeder et al., 2011). Multiple signals synchronize SCN cells to environmental cycles How do we synchronize with local time and what makes adjusting to travel across time zone or shift work so difficult? It is clear that we depend on the SCN to both entrain to daily cues and to coordinate with the brain and body to produce internal synchrony and wellbeing. Here, we briefly review mechanisms by which the SCN entrains to light (Fig. 3).

Please cite this article as: Granados-Fuentes, D., Herzog, E.D., The clock shop: Coupled circadian oscillators, Exp. Neurol. (2012), http:// dx.doi.org/10.1016/j.expneurol.2012.10.011

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GABA Fig. 2. A model of how SCN neurons synchronize their circadian cycles with each other. By releasing and responding to extracellular factors, SCN cells shift the intracellular rhythm-generating mechanism until all cells oscillate with the same circadian period. Vasoactive intestinal polypeptide (VIP) is the dominant synchronizer acting through the VPAC2 receptor (1). In vitro, VIP is released maximally around the middle of the subjective day from other SCN neurons (2). This coordinated stimulation of G-coupled protein receptors activates Gαs and adenylate cyclase (AC) (3) to increase intracellular cAMP levels. Parallel signaling through phospholipase C (PLC) (4) and production of IP3 activates the release of intracellular Ca+2 stores. Calcium and cAMP signaling likely converge to enhance transcriptional activation by phospho-CREB (5) on the promoters of key clock genes including the Period1, Period2 and Period3 genes. By appropriately timing the induction of these immediate early genes, cells can adjust the rhythms in their neighbors. The role in this synchrony of GABA, produced and received by nearly all SCN cells, and the more than 100 other secreted factors in the SCN remains unclear.

Photic entrainment likely depends on light-induced release of PACAP (Hannibal et al., 1997; Harrington et al., 1999) and glutamate (Akiyama et al., 1999; Asai et al., 2001; Ding et al., 1994; Meijer et al., 1988) from the terminals of the ipRGCs onto SCN neurons. This leads to a necessary increase in intracellular Ca +2 and activation of the mitogen activating protein kinase (MAPK) pathway (Golombek et al., 2004; Pizzio et al., 2003). In addition to this monosynaptic pathway from retina to SCN, light information must follow indirect paths to shifting SCN cells. Normal light-induced shifts of behavior also requires SCN cells to respond to nitric oxide, VIP, GRP and other neuropeptides released by SCN cells and to neuropeptide Y released by cells of the intergeniculate leaflet of the thalamus (Albers et al., 1995; Kallingal and Mintz, 2006; McArthur et al., 2000; Piggins et al., 1995; Reed et al., 2001; Watanabe et al., 2000). These diverse convergent (multiple cells influencing one cell) and divergent (one cell influencing many) pathways could be designed to filter and to encode aspects of the light cycle that change with time of day or time of year. This is supported, for example, by the recent discovery that VIP-deficient mice fail to show the behavioral and SCN adaptations following exposure to short days (Lucassen et al., 2012). All roads lead through cAMP and Ca +2 These extracellular signals must impinge on the intracellular circadian gene network to synchronize rhythms across the population of cells. The second messengers identified to date appear to all converge

on intracellular cAMP and calcium (Fig. 3). For example, VIP acts through its G-protein coupled receptor to modulate cAMP and calcium levels (Irwin and Allen, 2010) to upregulate expression of clock genes and, ultimately, adjust the circadian phase of each cell. We envision two mechanisms that cooperate to coordinate the rhythms of the SCN and behavior: circadian synchronization among cells within the SCN and induction of cell–cell signaling by environmental timing cues. For example, VIP release in the SCN is both circadian (Francl et al., 2010; Shinohara et al., 1995) and increased by light (Shinohara et al., 1993, 1995). Appropriately timed release of these signals appears to lead to entrainment. For example, daily exposure to VIP entrains SCN rhythms in vitro (An et al., 2011). VIP release during the day into the early evening leads to shifts of cellular circadian rhythms through parallel increases in the activities of both adenylate cyclase (AC) and phospholipase C (PLC) and subsequent increases in cAMP and Ca +2 (An et al., 2011). On a daily basis, this leads to a stable phase relationship between the molecular and physiological rhythms of the SCN and the light cycle. The precise phase relationship of each cell to its neighbors and to the environment is likely defined by its intrinsic properties and the signals it receives. For example, cells in the ventral SCN are the first to respond and fastest to shift following light-induced release of glutamate from the RHT at night (when increasing cAMP alone does not shift) (Prosser and Gillette 1989; Tischkau et al., 2000). This is strikingly reminiscent of the integrative, state-dependent switching effects of neurotransmitters and neuropeptides in other neural networks like the

Please cite this article as: Granados-Fuentes, D., Herzog, E.D., The clock shop: Coupled circadian oscillators, Exp. Neurol. (2012), http:// dx.doi.org/10.1016/j.expneurol.2012.10.011

D. Granados-Fuentes, E.D. Herzog / Experimental Neurology xxx (2012) xxx–xxx

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Fig. 3. A model of how SCN neurons synchronize to environmental cycles. For the master circadian pacemaker to be of use to an organism, it must entrain to local time. The SCN responds to pituitary adenylate cyclase activating peptide (PACAP) and glutamate released from ipRGCs (1). Glutamate release activates AMPA receptors on retinorecipient cells. Stimulation of these glutamate or PACAP receptors increases Ca+2 (2) influx or cAMP (3) respectively that in turn activates protein kinases inducing, ultimately, gene transcription (4). Other non-photic pathways also participate in synchronization including the nucleus basalis magnocellularies (NBM) in the basal forebrain (acting through M1 acetylcholine receptors to activate guanylyl cyclase and PKG) and the medial raphe nucleus (acting through serotonergic receptors 5HT7 to activate AC). The combined interactions of circadian release by SCN cells onto SCN cells and the evoked release onto SCN cells from extra-SCN centers allows the SCN to self-synchronize and adjust its timing to environmental conditions.

central pattern generators underlying other oscillatory behaviors like locomotion, respiration and chewing (Marder and Goaillard, 2006). Significantly, some clock genes, e.g. Period1 and Period2, are immediate early genes, whose promoters also contain functional CREs (cAMP/Ca +2-response elements). In the SCN, in vivo and in vitro, appropriate activation of cAMP/Ca +2 signaling by extracellular stimuli induces Period gene expression, and thereby facilitates clock resetting at night (phase entrainment) (Jenkins et al., 2007; O'Neill et al., 2008; Obrietan et al., 1998).

fragmented sleep. No human genetic variations have been linked to a loss of circadian rhythms yet, but aging, irregular work schedules and a variety of neurodegenerative diseases have been associated with a loss of daily rhythms and increasingly fragmented sleep (Kudo et al., 2011; Nakamura et al., 2011; Oliver et al., 2012). Finally, disruption of circadian outputs such as hormonal rhythms could impact one's ability to sleep soundly (De Leersnyder et al., 2001). Thus, factors which alter the entrainment of the SCN to the environment, synchrony among SCN cells, and the output signals from the SCN are likely to play critical roles in getting a good night's sleep.

Circadian sleep disorders The coordinated molecular and cellular interactions of the SCN generate a coherent daily timer that plays a fundamental role in regulating sleep. Disturbances to the circadian system (e.g. genetic or environmental) can lead to sleep disorders. This is formally distinct from the mechanisms that respond to cumulative hours of wakefulness (sleep homeostasis). As highlighted by the large number of sleep clinics and the dearth of circadian clinics, remarkably little is known about circadian disruptions causing sleep disorders. In principle, those changes which alter the period of the circadian clock can advance or delay the timing of sleep onset. The polymorphisms in the Period2 or Casein kinase1ε genes associated with Familial Advanced Phase Sleep Syndrome are examples of genetic perturbations in the rhythm generating mechanism that alter sleep timing (Xu et al., 2005, 2007). Loss of circadian timekeeping could lead to

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Please cite this article as: Granados-Fuentes, D., Herzog, E.D., The clock shop: Coupled circadian oscillators, Exp. Neurol. (2012), http:// dx.doi.org/10.1016/j.expneurol.2012.10.011