Circadian Regulation of Endocrine Functions

13 Circadian Regulation of Endocrine Functions M P Butler, Columbia University, New York, NY, USA L J Kriegsfeld, University of California, Berkeley, CA, USA R Silver, Barnard College, Columbia University, New York, NY, USA ß 2009 Elsevier Inc. All rights reserved.

Chapter Outline 13.1 13.2 13.3 13.4 13.4.1 13.4.2 13.4.3 13.4.4 13.5 13.6 References

Introduction to Circadian Rhythms Molecular Basis of Circadian Timekeeping The Circadian System Circadian Regulation of the Endocrine System Circadian Regulation of HPA Axis Circadian Regulation of the Hypothalamic–Pituitary–Gonadal Axis Circadian Regulation of Melatonin and Seasonality Circadian Regulation of Prolactin Rhythms in Aging The Circadian System: From Bench to Bedside

Glossary circadian A cycle or oscillation with a period close to 24h, from circa = about and diem = day. This term is generally restricted to processes that are endogenously driven, cf. diurnal. clock gene A gene involved in the basic genetic loops underlying circadian rhythms. diurnal Used to describe rhythmic phenomena that are driven by the external light–dark cycle. Also used to refer to day-active animals. endogenous rhythm Self-sustained rhythm that persists in constant conditions. entrainment Synchronization of the circadian system to external cues. The light–dark cycle is the dominant entraining signal for most organisms, but other cues, such as food, can also entrain organisms. free-running The state of an oscillator running at its own endogenous period, without external perturbations. The free-running period of an animal is usually measured in constant darkness. nocturnal Night active. period The duration of a cycle, typically close to 24 h for circadian processes. phase The time at which a cyclic event occurs as measured against another time frame such

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as other rhythms or external conditions, for example, the time of activity onset. phase shift Advances or delays of the circadian phase, such as changing time zones.

13.1 Introduction to Circadian Rhythms Overview of clocks and timing. All organisms have daily rhythms in metabolism, physiology, and behavior. These rhythms are driven by an endogenous circadian timing mechanism and are synchronized to the local environment. Because they oscillate with a period of about 24h, these rhythms are termed circadian (circa¼about, diem¼day). Daily rhythms can be driven by external signals from the environment or they can emerge as a product of internally organized processes, and chronobiologists have developed terminology to distinguish the mechanisms underlying these processes. Diurnal rhythms are those driven by an external temporal signal (e.g., light and darkness), and these cease when environmental conditions are constant. In contrast, circadian rhythms are endogenous and persist in the absence of external temporal cues. This chapter focuses on the regulation of circadian endocrine rhythms by clocks throughout the body.

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A fundamental interest in the nature of circadian rhythms stems from their ubiquity, their broad impact, and the availability of novel tools to study them at organismal to subcellular levels. The importance of the circadian system in maintaining optimal health is revealed in the physiological and psychological consequences of temporal disturbances due to irregular work schedules or sleep disorders. Individuals with chronic circadian disruptions often present with pronounced clinical pathologies, including cognitive deficits associated with reductions in temporal lobe structures (Cho et al., 2000; Cho, 2001), a higher incidence of cancer (Reiter et al., 2007), diabetes and cardiovascular disease (Prasai et al., 2008), ulcers (Kolmodin-Hedman and Swensson, 1975; Segawa et al., 1987; Costa, 1996), psychological disorders (Skipper et al., 1990; Leonard et al., 1998; Munakata et al., 2001), and a host of other clinical issues. Experimental evidence indicates a relationship between circadian rhythm disorders and breast cancer. Circadian rhythms are disrupted in human patients with breast cancer (Chen et al., 2005). Mice with disruptions of their circadian system are more prone to developing lymphomas (Fu et al., 2002). Time of day is an important factor in therapeutic interventions as well. The timing of cancer chemotherapy has dramatic effects on its efficacy, toxicity, and patient prognosis (Levi et al., 2007). These findings point to a critical role for internal circadian timing in maintaining normal brain functioning and peripheral physiology. The principle that time of exposure to a hormone can have marked effects on the response of endocrine tissues has long been established in experimental work (Figure 1; Ungar and Halberg, 1962). Developments in molecular biology have led to the identification of genes that are gated or modulated by the circadian system and canonical circadian clock genes that are part of the cellular timing mechanism. These tools have enabled discovery of a role for clock genes in critical cellular processes in cancer progression, including the promotion of the cell cycle from G1 to S and from G2 to M (Fu et al., 2002; Matsuo et al., 2003; Filipski et al., 2005; Granda et al., 2005). In summary, the extraordinary interest in circadian chronobiology derives from a convergence of practical and medical needs with technological and theoretical developments. In the practical domain, shift work and long-distance travel have become so common that management of jet lag is a general concern. The range of medical phenomena that are

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Figure 1 Time of hormone administration determines the amplitude of the response. In phenomenological studies done throughout the world, Franz Halberg and his associates monitored physiological rhythms in numerous variables as part of his neuroendocrinologic armamentarium. In experimental work, he showed a circadian influence on the response of mouse adrenals to fixed doses of adrenocorticotropic hormone (ACTH) administered in vitro. Corticosterone was either extracted directly from adrenal glands, or extracted after incubation with several doses of ACTH. Reprinted from Ungar F and Halberg F (1962) Circadian rhythm in the in vitro response of mouse adrenal to adrenocorticotropic hormone. Science 137: 1058–1060, with permission from AAAS.

modulated by the circadian system has expanded to include alcoholism, cardiovascular crises, cancer and cell division, and aging. Technical breakthroughs now allow real-time measurement of clock function in vivo and in vitro making high-throughput screening of gene expression possible. The goal of this chapter is to delineate the basic phenomena important in the field of circadian rhythmicity insofar as they impact the understanding of hormones and behavioral endocrinology, and to highlight current developments and future directions in which the field is moving. Functions of rhythms. The two fundamental functions of the circadian system, the correct temporal staging of processes internal to the body and the entrainment of these processes to the environment,

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are necessary for optimal regulation of physiology and behavior. This temporal coordination is achieved by a circadian system comprised of a master circadian clock in the brain, located upstream of a regulatory system that modulates the timing and synchronization of clock cells elsewhere in the body. The output of some of these downstream systems, such as the hormones produced by the major glands of the body, in turn, feeds back to provide temporal information to the brain clock. Hormones and circadian rhythms. The importance of circadian regulation of endocrine processes was known well before the nature of the brain clock and circadian timing mechanisms were understood. It is informative that the pioneering work of Everett and Sawyer (1950) on the timing of ovulation was motivated by the question of whether there was any role for the central nervous system (CNS) in the regulation of hormone release. Everett and Sawyer knew that the luteinizing hormone (LH) surge in rats occurs at a particular time of day – termed the critical period – on the afternoon of proestrus. They demonstrated that when hypothalamic activity is blocked in proestrous females by transient barbiturate anesthesia, the LH surge is delayed for a full 24h rather than for the 2h of anesthetic sedation, pointing to participation of a circadian timing system in generating the LH surge. This was also the first work to demonstrate a role for the brain in timing the LH surge. Today, the tide has turned so far that it is considered newsworthy that the periphery actually has a role in timing ovulation. As reported in the commentary titled, ‘‘The ovary knows more than you think!. . .,’’ this gland participates in determining the timing of ovulation (Ball, 2007). Since the time of these initial studies, the phenomenology has remained the same – the circadian clock still gates the preovulatory surge in rats. While questions of how the circadian system regulates endocrine secretions remain, the nature of the unknowns and the kind of questions asked and answered has changed. This is due, in part, to the ability to more easily and accurately measure circadian variables over long time intervals. The grueling nature of collecting time series data has become less grueling. The strength of the evidence supporting a role for the circadian system in regulating fundamental biological processes throughout the body is now undeniable. The resulting knowledge has enabled the development of screening tools and will likely allow for more effective treatment and

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prevention of pathologies known to be tied to circadian irregularities.

13.2 Molecular Basis of Circadian Timekeeping Overview. The main themes of chronobiological research have evolved over the last two decades, from macroscopic studies of rhythms and mathematical models addressing the number and relationships of clocks, to molecular mechanisms of biological clocks. The enigma of how isolated and interacting cells measure the passing of time and the other riddle of how a cell-free assemblage of proteins could do the same are under study (Figure 2). These findings lay the groundwork for many of today’s studies of rhythmicity and form the foundation for understanding rhythms in endocrine and neuroendocrine systems. We will describe the core genetic processes that underlie mammalian circadian rhythms following the convention of writing genes in italics and their protein products in capitals. Core clock genes and transcription/translation feedback loops. It is generally accepted that the cell-based circadian pacemaker is composed of a small number of gene families that together interact in interlocked transcription–translation feedback loops that complete one cycle in approximately 24h (Figure 2; Hastings et al., 2007). In the primary loop, two basic helix–loop–helix transcription factors, CLOCK and BMAL1, dimerize and drive transcription of the Period (Per1, Per2, and Per3) and the Cryptochrome (Cry1 and Cry2) genes by binding to the E-box motif (CACGTG) in the promoter regions of these genes. The resultant PER and CRY proteins form hetero- and homodimers in the cytoplasm of the cell and are then translocated back to the nucleus where they inhibit their own transcription via direct interactions with the CLOCK:BMAL1 protein complex (reviewed in Ko and Takahashi (2006)). In addition to rhythmic negative feedback via PER and CRY, there is a rhythm in CLOCK:BMAL1 transactivation based on cycling abundance of BMAL1. These rhythms are generated by a second loop. CLOCK:BMAL1 again acts as a positive regulator, driving transcription of two Rev-erb genes and four retinoic acid receptor-related orphan receptor (Ror) genes. The protein products compete to bind ROR response elements (ROREs) in the promoter region of Bmal1, with REV-ERBa inhibiting and

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Positive loop KaiA Clock KaiB

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Figure 2 (a) The fundamental core clock elements in mammals. At the genetic level, circadian rhythms are generated in single cells by interlocked positive and negative feedback loops. BMAL1 and CLOCK (or its homolog NPAS2 depending on the tissue) dimerize and transactivate several clock genes, including the Period and Cryptochrome families and Rev-erba. The negative regulators, Per and Cry, are translated and then translocated as a single complex to the nucleus where they inhibit CLOCK:BMAL1 transactivation. There is some evidence that REV-ERBa acts as a positive regulator of BMAL1 (Preitner et al., 2002) but it may not have a necessary role in clock function (Liu et al., 2008). (b) In cyanobacteria, phosphorylation alone can produce circadian oscillations in constant darkness, when the Kai proteins (KaiA, KaiB, and KaiC) are combined with ATP. Although Kai protein abundance oscillates in light–dark cycles, there is no oscillation in constant darkness. Under these conditions, KaiC oscillates between a phosphorylated and dephosphorylated state, possibly forming complexes with KaiA and KaiB during these transitions. KaiA stimulates, whereas KaiB inhibits, KaiC autophosphorylation (Tomita et al., 2005). It is not yet known whether similar mechanisms occur in mammalian cells.

RORa stimulating transcription, ultimately leading to rhythms in BMAL1 abundance (Guillaumond et al., 2005). Although the Bmal1 gene is necessary for circadian function – indeed it is the only single gene whose knockout produces arrhythmic behavior – the precise functions of the Rev-erb/Ror/Bmal1 loop and the oscillations of BMAL1 remain unclear. By monitoring molecular rhythms in mouse fibroblasts, Liu et al. (2008) show that Per2 rhythms remain normal even when Rev-erb is absent or when BMAL1 is expressed constitutively. The authors suggest that the Rev-erb/Bmal1 loop is not necessary for clock function per se, but is instead important for controlling clock output. Numerous other integrated feedback loops, often with elements that are themselves regulated by the core clock loop, mediate clock output to clockcontrolled genes. Two promoter elements in particular have emerged that are present in the promoters of many clock-controlled genes: the ROREs noted above and DBP/E4BP4-binding elements (D boxes; Ueda et al., 2005) The transcription factor DBP is positively regulated by the CLOCK:BMAL1 complex (Ripperger and Schibler, 2006) and acts at D boxes via a proline- and acid-rich (PAR) basic

leucine zipper (Lavery et al., 1999; Ueda et al., 2005). Although most work to date has focused on transcriptional regulation as the core mechanism leading to oscillations at the cellular level, several studies suggest an important role for posttranscriptional and post-translational events as well (Baggs and Green, 2003; Kramer et al., 2003; Reddy et al., 2006). Kinases, proteins, and the frontiers of clock research. In addition to transcriptional/translational control of cellular clock function, regulatory kinases play a pronounced role in regulation of circadian period. For example, the tau mutant hamster has a short 20-h free-running period, due to a mutation in a clock regulatory protein, casein kinase I epsilon (CKIe; Ralph and Menaker, 1988; Lowrey et al., 2000; Wang et al., 2007). In wild-type rodents, CKIe phosphorylates PER, leading eventually to its degradation. Late in the day, when PER outstrips CKIe, this protein dimerizes with CRY to translocate into the cell nucleus and inhibit CLOCK:BMAL1mediated transcription. In the case of the tau mutant hamster, CKIe is unable to phosphorylate PER, resulting in accelerated buildup of PER, premature entry of the PER:CRY complex into the cell nucleus,

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and a resultant shortening of the circadian period (Lowrey et al., 2000; Vielhaber et al., 2000). Breakthrough studies on oscillators of photosynthetic cyanobacteria challenge the generally accepted transcription–translation clock paradigm (Kondo, 2007). In cyanobacteria, virtually all genes undergo robust daily oscillations, and these depend on an operon encompassing three clock genes – kaiA, kaiB, and kaiC. Circadian oscillations in KaiC phosphorylation and dephosphorylation persist in the absence of transcription and translation, and this phosphorylation clock can be reconstituted in the test tube with just KaiA, KaiB, KaiC, and adenosine triphosphate (ATP; Figure 2). These studies prompt the consideration that molecular timing may be a consequence of protein interactions and present the principle that such interactions might underlie rhythmicity in other circadian clocks as well. It is also possible that clocks have evolved multiple times and that there exist multiple unique clock mechanisms.

13.3 The Circadian System Overview of the hierarchical circadian system. A master circadian clock localized to the hypothalamic suprachiasmatic nucleus (SCN) coordinates an assembly of

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subordinate clocks that together comprise the circadian system. The SCN maintains an orderly phase relationship between cell-based clocks throughout the body. The SCN has access to environmental time via direct retinal projections and communicates such information to target sites in the brain and thence to the rest of the CNS and the periphery. The oscillatory behavior of these extra-SCN sites can communicate phase information back to the SCN, creating a closed loop feedback system. Finally, in addition to the core clock genes, tissue-specific clock-controlled genes are important outputs and provide for local coordination. The stability of this hierarchical arrangement is necessary for normal body functioning and disease prevention. The brain clock. The search for a light-synchronized brain clock took an important turn in 1972 when Moore and Lenn uncovered a novel retinohypothalamic tract (RHT) projecting to the SCN (Figure 3; Moore and Lenn, 1972). Lesions of this hypothalamic area abolish circadian rhythmicity (Moore and Eichler, 1972; Stephan and Zucker, 1972). SCNlesioned animals show the full range of normal behaviors, but temporal organization is lost and never recovers, irrespective of how early in development the lesions are performed (Mosko and Moore, 1979). Today, multiple lines of evidence support the

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Figure 3 (a) Two percent of retinal ganglion cells contain the photopigment melanopsin and are photosensitive (termed intrinsically photosensitive retinal ganglion cells: ipRGCs). The ipRGCs also receive photic information from rods and cones, and they project via the retinohypothalamic tract (RHT) to the SCN. Elimination of ipRGCs abolishes circadian responses to light (entrainment and phase shifting) but does not impact vision (Guler et al., 2008). The remaining RGCs bypass the SCN and project to visual centers. (b) The core region of the SCN receives a dense retinal input. Both core and shell send efferents to target sites in the brain. The SCN communicates timing information to the body by means of both neural and diffusible signals. (c) The schematic shows locomotor and endocrine activity in constant conditions in an animal before and after an SCN lesion (SCN-x) and then following a transplant of a fetal SCN graft. Each consecutive day is plotted on lines from the top, and the black bars indicate the periods of activity. The animal becomes arrhythmic following the lesion. In support of an SCN diffusible output signal, transplantation of fetal SCN tissue sealed in a semipermeable membrane into the lesioned host restores locomotor rhythmicity. In contrast, the endocrinogram shows that the graft does not restore endocrine rhythms, indicating that neural outputs are required for these responses.

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conclusion that the SCN is the master pacemaker. The most convincing evidence comes from studies in which transplanted SCN tissue restores behavioral rhythms in arrhythmic SCN-lesioned animals with the period of the donor tissue (Lehman et al., 1987; Ralph et al., 1990). Further support comes from studies showing that circadian rhythms in neural firing rate and clock-gene expression persist for many cycles in vitro, proving that the rhythms can be sustained without input from extra-SCN brain sites (Green and Gillette, 1982; Groos and Hendriks, 1982; Shibata et al., 1982; Yamazaki et al., 2000). The cells of the SCN are heterogeneous in neurotransmitter and peptide content, in their dendritic and axonal morphologies, and in their afferent and efferent connections. Nevertheless, this complexity was not addressed for many years, as the simple heuristic of a circadian system comprised of three components, namely input, clock mechanism, and output, satisfactorily explained key concepts of circadian timekeeping (Pittendrigh, 1960; Eskin, 1979). Analysis of the SCN, however, points to the importance of emergent properties of its many interacting elements. Individual dissociated neurons of the SCN can exhibit autonomous rhythms with a wide range of free-running periods (Welsh et al., 1995), and it is not yet clear how a cohesive rhythm emerges from these underlying cellular oscillators. Furthermore, cellular properties differ between subregions of the SCN (reviewed in Antle and Silver (2005)). In the ventral core, a light pulse induces the expression of clock genes, including Per1 and Per2, but these genes do not oscillate detectably. In the dorsal shell on the other hand, Per1 and Per2 oscillate with a circadian rhythm, but are not directly induced by light. These results beg the question of how light-induced and oscillating cells of the SCN interact to communicate their phasic and rhythmic information to the rest of the brain/body. Understanding the network organization of the SCN has become increasingly relevant in the context of studies showing that its function as a clock is dependent on its circuitry, evident in the spatial and temporal patterns of clock-gene expression (Hamada et al., 2001; Herzog, 2007; Yan et al., 2007). While multiple mechanisms have been proposed for coupling among SCN neurons, to date, relatively little is known of the precise nature of its anatomical circuitry. Entrainment of the circadian system. Circadian rhythms are entrained (or synchronized) to local environmental time primarily via light information conveyed by the RHT (Moore and Klein, 1974; Klein

and Moore, 1979). This nonvisual pathway is necessary and sufficient for photic entrainment. If the primary visual pathway is transected at the level of the optic tract beyond the optic chiasm (i.e., caudal to the SCN), then the mammal is visually blind, but the circadian system continues to respond to photic cues and the animal remains entrained (Klein and Moore, 1979; Johnson et al., 1988). An early conundrum was the observation that mice lacking both rod and cone photoreceptors (rd/ rd mouse) exhibit entrainment even though they are visually blind and despite the absence of any extraretinal entrainment mechanism. The resolution came with the identification of an intrinsically photosensitive retinal ganglion cell (ipRGC) containing the photopigment melanopsin (Berson, 2003). These cells (2% of the total RGC population) project directly to the SCN. A mutation resulting in the loss of melanopsin, however, does not compromise circadian entrainment; entrainment is only abolished when all photopigments are absent (Hattar et al., 2003). The ipRGCs, independent of melanopsin, remain a critical link. All photic input to the SCN, which can be derived from photopigments in rods, cones, or ipRGCs, is channeled through the ipRGCs (Guler et al., 2008). Impressively, animals that lack ipRGCs, but that have an otherwise normal retina, retain pattern vision but are deficient in circadian photoentrainment (Guler et al., 2008). These results indicate that light signals for irradiance detection and circadian entrainment are dissociated from pattern vision at the ganglion cell layer of the retina (Figure 3). Given the extensive efferent connections of these cells, it will be interesting to explore the functions of projections to areas that are rich in neuroendocrine cells such as the lateral and ventral preoptic area, diagonal band of Broca, the subparaventricular zone (SPVZ), anterior hypothalamus, and the supraoptic nucleus (Hattar et al., 2006). Diffusible SCN output. SCN tissue from a fetal donor, when implanted into the third ventricle of an adult SCN-lesioned host, restores circadian patterns in activity-related behaviors such as locomotor, drinking, and gnawing rhythms (Lehman et al., 1987; Ralph et al., 1990; Silver et al., 1990). While some neural connections are established between the donor tissue and the host brain, the transplant also produces diffusible factors. That a diffusible signal is sufficient to restore locomotor rhythmicity in SCN-lesioned hosts was demonstrated definitively by encapsulating donor SCN tissue in a membrane that prevented neural

Circadian Regulation of Endocrine Functions

outgrowth while allowing the diffusion of signals between graft and host (Silver et al., 1996). One candidate diffusible signal is prokineticin-2 (PK2; Cheng et al., 2002). This secreted protein is expressed rhythmically in the SCN and its receptor is present in the SCN and in all major areas receiving SCN projections (Cheng et al., 2002, 2005). PK2 administration during the night (when levels are normally low) inhibits wheel-running behavior of mice. Mice deficient in either PK2 or its cognate receptor exhibit disrupted circadian coordination of the activity cycle, though entrainment by light is not affected (Li et al., 2006; Prosser et al., 2007). A second candidate diffusible signal is transforming growth factor-a (TGF-a) acting through epidermal growth factor receptor signaling (Kramer et al., 2001). As with PK2, TGF-a is expressed rhythmically in the SCN and its administration inhibits wheel-running behavior. The receptor for TGF-a is also expressed in the SPVZ, the major target of the SCN. Impressively, TGF-a has been implicated in modulating activity levels in worms, flies, and humans, making it an attractive candidate for regulation of circadian oscillations (Puttonen et al., 2007; Van Buskirk and Sternberg, 2007; Olofsson and de Bono, 2008). Furthermore, it is likely that other diffusible mediators remain to be discovered. Whether these signals are normally released in a diffusible manner and/or released synaptically, at what target loci they act, and the effects at these target sites will be fruitful topics for analysis. Neural control of neurosecretory factors. Early studies using knife cuts and SCN transplants suggested that, unlike behavioral rhythms, endocrine rhythms require neural output for their expression (Nunez and Stephan, 1977; Hakim et al., 1991; Silver et al., 1996; Meyer-Bernstein et al., 1999). Further evidence for a neural SCN output signal regulating hormone secretion is seen in studies of hamsters. When housed in constant light, the locomotor activity of hamsters splits into two separate activity bouts within a 24-h interval (as though they have 12-h days). Split females display two daily preovulatory LH surges, 12h apart and each approximately half the concentration of a single surge in a nonsplit female (Swann and Turek, 1985). While both halves of the bilaterally symmetrical SCN are active in synchrony under normal conditions, in split hamsters, rhythms of SCN activity (measured by FOS expression) on each side of the brain are 12h out of phase (de la Iglesia et al., 2000). Remarkably, FOS expression in gonadotropin-releasing hormone (GnRH) neurons is only observed ipsilaterally to the FOS-

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expressing side of the SCN (de la Iglesia et al., 2003). These findings support the conclusion that the precise timing of the LH surge is derived from a neural signal originating in the SCN and communicated to ipsilateral GnRH neurons, as a diffusible output signal would reach both sides of the brain. Further analysis of the split hamster indicates that within each nucleus, the SCN splits into two parts, oscillating in antiphase (Tavakoli-Nezhad and Schwartz, 2005; Yan et al., 2005). Importantly, some hypothalamic sites are activated bilaterally in the split animal, while others are activated unilaterally, again supporting the notion of multiple SCN output pathways. Neural output from the SCN has been extensively investigated in mice, rats, and hamsters using tracttracing techniques (Stephan et al., 1981; Watts and Swanson, 1987; Kalsbeek et al., 1993; Morin et al., 1994; Leak and Moore, 2001; Kriegsfeld et al., 2004; Abrahamson and Moore, 2006). Projections arise from both the core and the shell of the SCN. Many of these monosynaptic projections target brain regions containing neuroendocrine cells producing hypothalamic-releasing hormones. Direct projections have been traced from the SCN to the medial preoptic area (mPOA), supraoptic nucleus, anteroventral periventricular nucleus (AVPV), the paraventricular nucleus (PVN), dorsomedial nucleus of the hypothalamus (DMH), lateral septum, and the arcuate nucleus. The SCN also projects to the pineal gland through a multisynaptic pathway (Klein et al., 1983; Klein, 1985). There is abundant evidence for direct neural SCN control of neuroendocrine cell populations (van der Beek et al., 1993, 1997; Vrang et al., 1995; Kalsbeek et al., 1996, 2000a; Buijs et al., 1998, 2003; Horvath et al., 1998; Gerhold et al., 2001; Kalsbeek and Buijs, 2002; Kriegsfeld et al., 2002b; 2003; Egli et al., 2004). Because these cell populations can regulate neurochemicals that are secreted into the cerebrospinal fluid, pituitary portal system, and general circulation, SCN-derived signals can control widespread systems in the brain and body (Figure 4; Skinner and Malpaux, 1999; Reiter and Tan, 2002; Skinner and Caraty, 2002; Tricoire et al., 2003). Extra-SCN brain oscillators. While circadian rhythmicity is, for the most part, lost following SCN ablation, there are certain circumstances under which behavioral rhythms do not require an intact SCN. While this may be taken for evidence that the master clock in the SCN lacks a dominant role (Guilding and Piggins, 2007), it is more reasonable to take the view that these special conditions reveal the hierarchical organization and feedback control mechanisms

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Figure 4 The circadian system is hierarchically organized. The master clock of the SCN provides timing cues to the rest of the body clocks, including those in endocrine organs. These peripheral clocks in turn participate in coordinating local endocrine function and feed back at many sites (not shown). Each hormone rhythm cycles with its own characteristic wave form and phase, shown here for a typical diurnal mammal. On the right panel, the shaded area indicates night. Despite the overt testosterone rhythm, the evidence for clock function in the testis is equivocal (see Section 13.4.2).

of the circadian system. We consider two examples that point to a role for extra-SCN clocks: oscillators entrainable by food and by methamphetamine administration. When animals are offered food during a restricted time period during the day, they entrain to the feeding schedule, and exhibit anticipatory locomotor activity several hours before access to the meal (reviewed in Mistlberger (2006)). The endogenous nature of this rhythm is revealed during subsequent total food deprivation, when animals continue to display free-running anticipatory behavior, pointing to a food-entrained oscillator (FEO). There is considerable interest in understanding whether this FEO is localized in a specific site or constitutes a network, and this has been a topic of much heated debate (Gooley and Saper, 2007; Landry and Mistlberger, 2007; Landry et al., 2007). In the present context, the phenomenon of food entrained oscillations is interesting because nutrients from food can constitute a timed signal that can influence rhythmicity of downstream oscillators in both the brain and in endocrine organs (discussed below). In turn, changes in

the timing of hormone secretion may influence other timed physiological and behavioral responses. The methamphetamine-sensitive circadian oscillator (MASCO) is perhaps even more mysterious than the FEO. Administration of methamphetamine in the drinking water restores rhythmicity in SCN-lesioned rats and mice, as well as in Clock mutant mice and arrhythmic Cry1/Cry2 double knockout mice (Honma et al., 1987, 2008; Masubuchi et al., 2001; Tataroglu et al., 2006). While drinking itself may be phasic, chronic methamphetamine treatment also reveals the MASCO in SCN-intact animals. Methamphetamine causes locomotor activity to desynchronize from the light–dark cycle. SCN Per1 expression and the plasma melatonin rhythm remain entrained normally to the light–dark cycle, but clock gene rhythms in the caudate putamen and parietal cortex and locomotor activity free-run (Masubuchi et al., 2000). Such results are consistent with the notion that brain regions bearing receptors for methamphetamine lie downstream of the SCN, and may act in relaying SCN outputs to control locomotor activity. Methamphetamine may couple and resynchronize

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oscillators in methamphetamine targets whose synchrony is lost after SCN lesions. An alternative hypothesis is that methamphetamine-induced locomotor activity and associated changes in body temperature provide feedback to brain and peripheral oscillators, altering their activity and synchronicity. The existence of coherent locomotor rhythms in SCN-lesioned, methamphetamine-treated animals, along with dissociation of various circadian rhythms from each other, strongly suggests that discrete target sites in the brain responsible for staging the timing of various responses are sensitive to different input signals. The precise contribution and site(s) of action of various hormonal signals is largely an unexplored area of inquiry. Most circadian studies measure rhythmicity by locomotor activity alone. Studies of the MASCO indicate the significance of investigating a host of rhythmic outputs to gain insight into the complexity of the circadian hierarchy and the multitude of variables that can affect each system independently. This said, the availability of methods for examining rhythms in various tissues is rapidly changing this landscape. Extra-CNS, peripheral oscillators. The study of circadian gene expression in the late 1990s revealed the unexpected result that clock genes are expressed rhythmically in many peripheral tissues. After serum shock of fibroblasts or after explant of peripheral tissues, clock-gene expression is rhythmic for several cycles before damping out (Balsalobre et al., 1998; Yamazaki et al., 2000). In vitro damping of the cellular rhythms reflects desynchronization of selfsustained and cell-autonomous oscillators (Nagoshi et al., 2004; Welsh et al., 2004). In vivo, similar desynchronization among organs is observed in the absence of the SCN (Yoo et al., 2004). The coordination of peripheral oscillations depends primarily on the SCN, but may be modulated by other mechanisms. The SCN projects via multisynaptic pathways to peripheral endocrine organs, including the pineal gland, adrenals, thyroid, and pancreas (Moore, 1996; Buijs et al., 1999; Kalsbeek et al., 2000a; Bartness et al., 2001; Buijs and Kalsbeek, 2001). The SCN can also transmit timing cues indirectly via SCN-dependent behaviors, such as eating, that can alter physiological signals. The presence of oscillators throughout the body confers flexibility in entraining to cues (Figure 4). For example, when the feeding schedule and the light–dark schedule are dissociated, rhythms in SCN gene expression remain entrained to the light–dark

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schedule, but rhythms in the liver entrain to the feeding schedule (Damiola et al., 2000; Stokkan et al., 2001). By examining SCN-lesioned mice parabiotically paired with animals bearing an intact SCN (sharing 1–4% of their blood supply), it was revealed that non-neural signals are adequate to maintain circadian rhythms of clock-gene expression of Per1, Per2, or Bmal1 in liver and kidney (but not in heart, spleen, or skeletal muscle; Guo et al., 2005). This implicates a blood-borne cue, perhaps endocrine or metabolic, that can provide phase information to some, but not all, peripheral oscillators. Alternatively, the intact animal may communicate timing information to the SCN-lesioned mouse via activity and/or body temperature fluctuations. One interesting implication of this work is that an SCN-derived cue may synchronize each individual liver hepatocyte every single day in order to sustain phase coherence in peripheral tissues. A similar principle may apply to the process of synchronizing individual cells of glandular organs. Although the core clock genes are the same across tissues, the genes exhibiting rhythmic expression (clock-controlled genes) are tissue specific. Microarray studies have identified many cycling transcripts in several tissues, including SCN, liver, heart, skeletal muscle, adrenals, and fibroblasts (Figure 5; Grundschober et al., 2001; Akhtar et al., 2002; Duffield et al., 2002; Panda et al., 2002; Storch et al., 2002; Ueda et al., 2002; Oster et al., 2006a; McCarthy et al., 2007). In most tissues, 5–10% of transcripts probed display significant circadian cycling. What is most surprising, however, is the small degree of overlap among tissues. Thus, there is only 5% overlap between the rhythmic genes in the SCN and in the liver (Panda et al., 2002), or between the heart and liver (Storch et al., 2002). This finding immediately suggests that cycling transcripts are associated with specific tissue functions. In the case of endocrine organs, the cycling transcriptome may play an important role in enabling temporally organized hormone secretion and coordinating sensitivity to other physiological cues, including signals from the brain that themselves may or may not be rhythmic. These experiments also raise the question of how circadian oscillators, expressed ubiquitously throughout the body, are able to regulate the expression of diverse genes in a tissue-dependent manner, what genes are regulated in the endocrine tissues of the body, and how these might be sexually differentiated. We shall examine rhythmicity in several endocrine organs and also in the liver, where the most substantial evidence is available.

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SCN Rhythmic behavior, metabolic, or endocrine cues Peripheral cell

We have previously described circadian patterns of secretion in a number of hormones in both diurnal and nocturnal species (Kriegsfeld et al., 2002a). Here, we focus on high-amplitude rhythms whose circadian basis and functions are well understood, and where a great number of new developments have emerged during the past few years, especially the role of peripheral clocks and tissue-specific cycling transcriptomes. 13.4.1

Rhythmic transcriptome

RORE

E-box

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CRE

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Target gene

CREB Other Glucocorticoids

Figure 5 Rhythmic gene expression occurs in many central and peripheral cells. The phase of these rhythms can be set by many cues, either by the SCN or by signals such as circulating metabolic or endocrine cues. Within a cell, a given gene may be clock controlled or regulated by other cues. This is illustrated at the bottom of the figure by a target gene with several possible upstream promoters, including an E-box, a retinoic acid–receptor-related orphan receptor response element (RORE), a cAMP response element (CRE), and a glucocorticoid response element (GRE).

13.4 Circadian Regulation of the Endocrine System Overview. The precise pattern of variation in plasma hormone levels results from interactions among the ultradian and circadian timing systems, regularly recurring periodic cues (such as eating) and nonrhythmic factors such as homeostatic mechanisms (e.g., sleep). This broad circadian control is achieved through monosynaptic neural connections of the SCN with neurosecretory cells producing hypothalamic-releasing hormones, multisynaptic pathways to many other brain regions, to the autonomic nervous system, and to brain sites that modulate behaviors such as activity and eating that themselves ultimately provide timing information to the body (Kriegsfeld and Silver, 2006). Thus, SCN-derived signals are widespread in the brain and body.

Circadian Regulation of HPA Axis

Rhythms of the HPA axis. Rhythms in glucocorticoid secretion and serum concentration have long been recognized; indeed, elimination of corticosterone rhythms after SCN lesions was among the first data implicating the SCN as a brain clock (Moore and Eichler, 1972). Humans, nonhuman primates, and rodents all display circadian changes in glucocorticoid secretion that continue in constant conditions (Weitzman et al., 1971; Moore and Eichler, 1972; Gallagher et al., 1973; Dubey et al., 1983; Van Cauter and Refetoff, 1985; Czeisler and Klerman, 1999). Increases in pulse amplitude rather than pulse frequency drive the daily increase in corticoid secretion (Gudmundsson and Carnes, 1997). The phase of the rhythm differs between nocturnal and diurnal species, however, with corticoid secretion beginning to rise before waking in both and then peaking during the day in diurnal and during the night in nocturnal species (Wong et al., 1983; Albers et al., 1985; Ottenweller et al., 1987). The adrenal gland itself also manifests rhythms in clock-gene expression and these underlie rhythmic responsiveness to pituitary adrenocorticotropic hormone (ACTH), and to physical and physiological stressors (Ungar and Halberg, 1962; Dunn et al., 1972; Buijs et al., 1997; Bittman et al., 2003; Kalsbeek et al., 2003; Oishi et al., 2003; Guo et al., 2006; Oster et al., 2006b; Fahrenkrug et al., 2008). Regulation of the HPA axis by the SCN. Rhythms in circulating glucocorticoids are eliminated by SCN lesions and, unlike activity rhythms, are not restored by SCN transplants (Moore and Eichler, 1972; Meyer-Bernstein et al., 1999). Similarly, rhythms in clock-gene expression in the adrenal depend on the SCN (Guo et al., 2006). Two SCN efferent pathways are implicated in the regulation of the adrenal axis (Figure 6). First, monosynaptic projections to the corticotropin-releasing hormone (CRH) neurons in the PVN are thought to directly regulate ACTH release (Vrang et al., 1995; Kalsbeek et al., 1996; Buijs et al., 1998). In addition, the SCN may directly control adrenal rhythms via multisynaptic autonomic

Circadian Regulation of Endocrine Functions

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PVN CRH cells IML

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Figure 6 The SCN projects to the adrenal gland via synapses in the autonomic portion of the paraventricular nucleus (PVN) and the intermediolateral column (IML). In addition, SCN neurons make contacts with CRH-expressing cells of the PVN, which in turn promote the release of ACTH from the pituitary. The combination of signals synchronizes the cycling transcriptome of the adrenal which includes genes associated with adrenal function. The local cycling of gene expression in the adrenal may also contribute to the gating of the response to ACTH.

innervation of the adrenal cortex (Buijs et al., 1999). This second pathway may be critical to establishing proper adrenal function, for hypophysectomy does not alter adrenal clock-gene expression rhythms, indicating that ACTH does not by itself induce rhythms in the adrenal (Fahrenkrug et al., 2008). Regulation of the HPA axis by peripheral oscillators. Transcription profiles of the mouse adrenal reveal a large number of cycling genes (5% transcripts on an Affymetrix MG430v2.0 chip), among which are those involved in such adrenal functions as steroid biosynthesis and catecholamine metabolism (Oster et al., 2006a). The majority of the cycling transcriptome peaks at the sleep to wake transition; notably, 10 of 14 rhythmic genes associated with steroid biosynthesis were synchronous, peaking in early subjective night in parallel with the increasing plasma corticoid levels at this time (Oster et al., 2006a). The gating of adrenal ACTH sensitivity depends on this local cycling, as rhythms in sensitivity are eliminated in cultured adrenal slices from arrhythmic Per2/Cry1 knockout mice (Oster et al., 2006b). Synchronization of the adrenal oscillators by other cues may allow for rhythmic function in the absence of the SCN. SCN lesions do not prevent the corticosterone peak associated with restricted feeding (Krieger et al., 1977). In an elegant study, Oster et al. (2006b) tested the role of a functioning adrenal clock by crossimplanting adrenals between wild-type and Per2/Cry1 double mutant mice which lack rhythmic ACTH, corticosterone, and adrenal clock-gene expression.

The rhythm of ACTH responsiveness observed in vivo is also observed in vitro in wild-type but not Per2/Cry1 mutant adrenals, implicating the local clock in regulating the ACTH gating. In addition, corticoid excretion rhythms of wild-type mice with wild-type adrenal implants are nearly double the amplitude of those that had mutant adrenal implants. These data show that a functioning peripheral clock is necessary for appropriate endocrine function of a peripheral organ. HPA axis – feedback: The brain. The SCN does not express glucocorticoid receptors (Rosenfeld et al., 1988; Balsalobre et al., 2000). Glucocorticoids, nevertheless, may have indirect effects: glucocorticoid treatment in humans disrupts sleep and in the SCN reduces arginine vasopressin (AVP) expression (Liu et al., 2006). In rats, glucocorticoids upregulate glial fibrillary acidic protein in the SCN, possibly through effects on serotonergic neurons (Maurel et al., 2000). The specific neural targets by which corticoids influence SCN function remain to be determined. HPA axis – Feedforward: The brain. Glucocorticoid rhythms communicate phase information to the brain. In rat, PER2 is rhythmic in several extraSCN brain areas, including the oval nucleus of the bed nucleus of the stria terminalis (BNST-OV), and the central (CEA) and basolateral nuclei (BLA) of the amygdala (Amir et al., 2004; Lamont et al., 2005). The PER2 rhythm in the BLA is not affected by adrenalectomy. In contrast, rhythms in the BNST-OV and CEA depend on peripheral glucocorticoid cues for entrainment, for the rhythm in PER2 is abolished by

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adrenalectomy in these two structures. These rhythms are restored by corticosterone in the drinking water – producing a rhythm in circulating corticosterone – but not by implanted constant release corticosterone pellets (Segall et al., 2006). HPA axis – feedforward: The liver. Glucocorticoids are thought to communicate timing information to many peripheral organs, among which the liver has been best studied. Interest in the interplay between circadian clocks and metabolism has grown in recent years with the observation that clock disruptions can lead to obesity and metabolic syndrome (a suite of metabolic disruptions, including hyperphagia, hyperglycemia, hyperlipidemia, and hypoinsulinemia; Rudic et al., 2004; Turek et al., 2005). The liver is critical to metabolic control, and has a cycling transcriptome and proteome (Akhtar et al., 2002; Panda et al., 2002; Storch et al., 2002; Oishi et al., 2003; Reddy et al., 2006). Hepatic oscillators are central to hepatic rhythms, as local inactivation of the liver clock abolishes rhythmicity in 90% of its cycling transcriptome (Kornmann et al., 2007). The adrenal gland plays an important role in setting the phase of these hepatic rhythms. Using gene chip microarrays, Oishi et al. (2005) describe 169 genes that differ in expression level between night and day in the livers of normal mice, and in 100 of these, the day–night difference is eliminated by adrenalectomy. Reddy et al. (2007) further show that rhythms in 366 transcripts are abolished by SCN lesions, of which, 57% can be reinstated by dexamethasone (DEX) treatment. Only two-thirds of the genes whose rhythms were induced by DEX had a glucocorticoid response element (GRE) in their promoters (Reddy et al., 2007). Rhythms in some of the remaining genes may have been induced by clock genes, themselves with DEX-induced rhythms. Finally, other rhythmic genes must act as intermediaries between the clock- or DEX-responsive genes and remaining genes of the cycling transcriptome that lack both glucocorticoid and clock-responsive promoter elements. 13.4.2 Circadian Regulation of the Hypothalamic–Pituitary–Gonadal Axis Overview and new regulators. As noted in the introduction to this chapter, the importance of the brain in regulating the hypothalamic–pituitary–gonadal (HPG) axis was first established in the 1950s. It was in this era that the existence of neurosecretory hormones was first described in the classical studies of Harris (1955) where he showed that the

hypothalamic-hypophysial portal vasculature carries neurosecretions from hypothalamic nerve fibers to the anterior pituitary, unlike the direct neural control of the posterior pituitary. The first hypothalamicreleasing hormone was isolated in 1969 and resulted in a Nobel prize in 1977 for its seekers Guillemin and Schally. Following that work, other hypothalamicreleasing hormones were isolated and synthesized and one had the impression for the past decades that the most important elements of the neural basis of the HPG system were known. Thus, it came as a surprise to recently find major new neuroendocrine elements in the brain, and the tale of this discovery is an interesting (but perhaps not unusual) example of the jagged course of discovery in research. The cardioexcitatory neuropeptide containing the C-terminal Phe-Met-Arg-Phe-NH2 (FMRFamide) was first identified in the ganglia of the clam, Macrocallista nimbosa over 30years ago (Price and Greenberg, 1977). Following this discovery, antibodies to FMRFamide peptides were applied as a tool for labeling structurally similar peptides across taxa, although the identity of labeled peptides remained unknown. More recently, a host of vertebrate peptides sharing the RF motif (Arg-Phe-NH2: RFamide) have emerged as prominent regulators of neuroendocrine activity. Two RFamide peptides, kisspeptin and gonadotropininhibitory hormone (GnIH), have been shown to have marked direct, but opposing actions, on the reproductive axis. Kisspeptin provides positive drive to the GnRH system, whereas GnIH acts to suppress GnRH output. Given the location of these peptides in the rodent brain, both are in a position to relay circadian information to the reproductive axis (Figure 7). Gonadotropin-inhibitory hormone. GnIH was first identified in quail brain by probing the proteome using competitive enzyme-linked immunosorbant assays (ELISAs) with antibodies directed against the RF motif. Using this approach, a novel RFamide peptide was identified that rapidly and dose dependently inhibits gonadotropin release from cultured quail pituitaries (Tsutsui et al., 2000). Based on these initial findings, they named this peptide GnIH. In avian species, GnIH cell bodies are found in the PVN with extensive fibers projecting to both the pituitary and the GnRH system (Bentley et al., 2003; Ukena et al., 2003). In rodents, GnIH cells are confined to the DMH, with widespread projections to hypothalamic and limbic structures (Kriegsfeld et al., 2006). As in birds, GnIH cells project to GnRH perikarya and to the median eminence. Injections of

Circadian Regulation of Endocrine Functions

GnRH

+ +

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Figure 7 Model of circadian control of two key RFamide mediators of the reproductive axis. Kisspeptin and GnIH neurons project directly to the GnRH system to positively and negatively regulate GnRH secretion, respectively. GnIH cells also communicate directly with the anterior pituitary portal system to regulate gonadotropin secretion. The SCN controls the daily and seasonal activity of the kisspeptin, GnRH, and GnIH neurons, the last two of which receive direct projections from the SCN. There are prominent projections from the SCN to AVPV, but whether these projections specifically make synapses on kisspeptin cells is not yet known (Gibson et al., 2008).

GnIH lead to rapid suppression of LH release in rats, mice, and Syrian hamsters. Importantly, GnIH cells express estrogen receptors (ERs) and may subserve the steroid negative feedback on the reproductive axis (Kriegsfeld et al., 2006). The SCN sends pronounced projections to the DMH (Leak and Moore, 2001; Kriegsfeld et al., 2004), and in Syrian hamsters, over 60% of GnIH cells are contacted by SCN terminals (Gibson et al., 2008) In addition, the SCN may act to suppress GnIH cell activity at the time of the LH surge, thereby allowing the coordinated release of the GnRH axis from estrogenic negative feedback at this time (Gibson et al., 2008). As described below, the GnIH system is also implicated in seasonal changes in reproductive function. Kisspeptin. The Kiss-1 gene was originally discovered in a screen for tumor metastasis suppressors, and its protein named metastin for this property when it was identified in 2001 as the endogenous ligand for the orphan G-protein-coupled receptor, GPR54 (Kriegsfeld, 2006; Kauffman et al., 2007). A link between a mutation in GPR54 and hypogonadism suggested that this RFamide, now kisspeptin, plays a role in regulating reproductive function (de Roux et al., 2003). The effects of kisspeptin are mediated through its actions on the GnRH system; administration of kisspeptin

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leads to immediate early gene expression (i.e., FOS) in GnRH cells (Irwig et al., 2004; Matsui et al., 2004). In addition, kisspeptin-induced gonadotropin secretion is blocked across species by the GnRH receptor antagonist, acyline (Gottsch et al., 2004; Irwig et al., 2004; Shahab et al., 2005). Finally, a majority of GnRH cells co-express GPR54 mRNA across species (Irwig et al., 2004; Han et al., 2005; Messager et al., 2005). Kisspeptin cell bodies identified are concentrated in the AVPV and arcuate nuclei, with scattered cells in the PVN and anterodorsal preoptic nuclei. As with the GnIH system in rodents, kisspeptin cells co-localize sex-steroid receptors, making them a direct target for sex steroid actions (Smith, 2008). Recently, a potential role for the kisspeptin system in triggering ovulation has been suggested. The AVPV is a critical brain region mediating the positive feedback effects of estrogen, crucial to the initiation of the preovulatory LH surge and ovulation (Wintermantel et al., 2006). In the AVPV, Kiss-1 mRNA expression is at a maximum at the time of the LH surge and these neurons show peak activity, as measured by FOS expression, on the afternoon of proestrus (Smith et al., 2006). Because the SCN projects extensively to the AVPV (Leak and Moore, 2001; Kriegsfeld et al., 2004), the circadian system may stimulate the LH surge via projections to the kisspeptin cells in the AVPV. Rhythms of the HPG axis. Circadian rhythms are evident at all levels of the HPG axis. The importance of the SCN is underscored by the observation that disruptions of circadian rhythms, either by surgical lesions or by mutations in the underlying clock genes, interfere with or abolish female reproductive rhythms and maintenance of pregnancy (Gray et al., 1978; Miller et al., 2004). A circadian rhythm in gonadotropin secretion appears around the time of puberty due to increases in nighttime secretion of LH and follicle-stimulating hormone (FSH) (Dunkel et al., 1992; Apter et al., 1993). This rhythm disappears in adulthood due to increased daytime secretion of gonadotropins (Krieger et al., 1972; Veldhuis et al., 1986). Circadian rhythms are evident in the regulation of the preovulatory LH surge in rodents. The high estradiol (E) concentrations during proestrus are permissive in this regard and constant E treatment in ovariectomized (OVX) females reveals a circadian rhythm in daily LH surges at the same time each day (Legan et al., 1975). In adult males, there is a robust circadian rhythm in circulating T, with a trough in late evening and a

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Circadian Regulation of Endocrine Functions

peak in the early morning (Spratt et al., 1988). T rhythms persist in constant conditions (Dubey et al., 1983). The disparity between a lack of adult male gonadotropin rhythms and a robust rhythm in T suggests some regulation of the T rhythm downstream from LH release. In adult women, ovarian hormone concentrations vary across the menstrual cycle, but their circadian rhythmicity is less clear. Nonhuman primates show diurnal variation in estrogen and progesterone (P) during the luteal, but not during the follicular, stage of the menstrual cycle (Spies et al., 1974). In humans, results are mixed, with some studies finding no diurnal variation in P or E, and others finding rhythms during some phases of the menstrual cycle (Aedo et al., 1981; Carandente et al., 1989; Rossmanith et al., 1990). Regulation of the HPG axis by the SCN. The circadian system determines the duration of the female reproductive cycle in rodents. Syrian hamsters have an estrous cycle that is 4 times the endogenous circadian cycle (t) or imposed day length (T). Thus, the interval between successive ovulations is 96h in a 24-h day (T ¼ 24). When hamsters are held in constant darkness (to reveal the endogenous period), or entrained to non-24-h days (e.g., 11-h light: 11-h dark, T ¼ 22), then the interval between successive ovulations is reliably 4t or 4T (Fitzgerald and Zucker, 1976; Carmichael et al., 1981). Similarly, the preovulatory LH surge occurs at a specific time of day on proestrus (Colombo et al., 1974). Surgical lesions of the SCN abolish both the LH surge and estrous cycling (Gray et al., 1978). The SCN projects directly to GnRH neurons via vasoactive intestinal polypeptide-(VIP-)ergic neurons (van der Beek et al., 1993, 1997; Horvath et al., 1998). In females, more of the GnRH cells receive VIP input and each cell receives more contacts than in males (Horvath et al., 1998). VIP contacts also increase following puberty (Kriegsfeld et al., 2002b). GnRH neurons in the female rat contain VIP2 receptors, providing further evidence for direct modulation of GnRH neurons (Smith et al., 2000). VIP may also alter signaling to GnRH neurons. Gerhold and Wise (2006) showed that astrocyte envelopment of GnRH neurons varies with time of day. These astrocytes express VIP receptors, and suppression of the SCN VIP rhythm with antisense nucleotides prevents the rhythm in astrocyte coverage. Such glial–neuronal signaling is an important aspect of the regulation of neuroendocrine secretion (GarciaSegura and McCarthy, 2004). The direct connections from the SCN underlie the unilateral activation of

neurosecretory cells in split hamsters (de la Iglesia et al., 2003; Gibson et al., 2008). Although the anatomical evidence for VIP projections to GnRH neurons is strong, the mechanisms governing VIP regulation of the GnRH surge are unclear. Most, but not all, experiments support an activational role for VIP. GnRH neurons receiving innervation from VIP cells in the SCN are preferentially activated (i.e., express Fos) during the LH surge (van der Beek et al., 1994). Blocking VIP signaling in the SCN by either VIP antisense or a VIP antibody also leads to an attenuation of the LH surge (Harney et al., 1996; van der Beek et al., 1999). In brain slices taken from OVX E-primed mice, acute VIP treatment increases firing rates in GnRH neurons from mice sacrificed around the time of LH surge onset, has a smaller effect around the time of surge peak, but generally has little effect on neurons before the surge (Christian and Moenter, 2008). In contrast, infusion of VIP into the third ventricle inhibits LH surges triggered by P injection in OVX E-primed rats (Weick and Stobie, 1995). Another important clock-controlled SCN peptide, AVP, peaks prior to and may activate the LH surge (Kalsbeek et al., 1995). Unlike VIP, there is no evidence of direct SCN to GnRH connections by AVPergic neurons, and GnRH cells very rarely express the 1a subtype of AVP receptor (V1a) (Kalamatianos et al., 2004). Nevertheless, the functional evidence for an AVP role is substantial. AVP administration into the mPOA induces an LH surge in SCN-lesioned, OVX rats treated with E (Palm et al., 1999), and in co-cultures of preoptic area (POA) and SCN tissue, the rhythm of GnRH release is in phase with the rhythm of AVP release, but not VIP (Funabashi et al., 2000). In Clock mutant mice that lack an LH surge, intracerebroventricular AVP infusion induces a surge in 50% of animals, and this surge is blocked by co-infusion with a specific V1a antagonist (Miller et al., 2006). Although AVP may not contact GnRH cells specifically, projections to the AVPV may be critical. The AVPV lacks GnRH neurons but expresses both ER subtypes (ERa and ERb) and V1a (Shughrue et al., 1997; Kalamatianos et al., 2004), and lesions of this area block the LH surge (Wiegand and Terasawa, 1982). Regulation of the HPG axis by extra-SCN oscillators – hypothalamus. Circadian oscillators in GnRH neurons or rhythmic changes in the properties of these neurons may participate in regulating GnRH secretion. In hypothalamic slice cultures in the absence of the SCN, circadian rhythms in neural firing rate of

Circadian Regulation of Endocrine Functions

GnRH neurons persist for several days in vitro when the slices are prepared from OVX E-treated mice but not from those of OVX untreated mice (Christian et al., 2005). Clock-gene and GnRH mRNA expression are rhythmic in GnRH-secreting GT1–7 cell lines (Gillespie et al., 2003). Moreover, transfection of the dominant negative mutant Clock-D19 gene into GT1–7 cells decreases GnRH-pulse frequency, indicating that the circadian clock genes can participate in regulating pulsatility (Chappell et al., 2003). The evidence for a functional clock in GnRH cells in vivo is less clear, however. GnRH mRNA is rhythmic in both OVX and intact female rats, but the GnRH neurons in vivo do not themselves seem to exhibit rhythms in clock-gene expression (Kriegsfeld and Silver, 2006; Schirman-Hildesheim et al., 2006). Regulation of the HPG axis by extra-SCN oscillators – ovarian rhythms. Recent data suggest that the ovary itself manifests circadian rhythms. Both Per1 and Per2 message and protein are rhythmically expressed in follicles, corpora lutea, and the interstitium; furthermore, distinct rhythms of cytoplasmic and nuclear localization are observed (Fahrenkrug et al., 2006). These circadian oscillations may be synchronized directly by rhythmic release of LH and FSH, both of which induce Per1 and Per2 rhythms in cultured granulosa cells (He et al., 2007). Research in birds suggests a connection between ovarian rhythms and ovulation. Clock genes are rhythmic in preovulatory follicles in Japanese quail, but not in smaller follicles (Nakao et al., 2007). This follicular clock in turn may control other physiological processes: the steroidogenic acute regulatory protein (StAR), a component of the P synthesis pathway, is expressed rhythmically, again in preovulatory but not smaller follicles. The StAR promoter region includes several E-box elements: Clock and Bmal1 induce promoter activity, and mutation of the E-boxes abolishes this response (Nakao et al., 2007). These data support the notion that clock-driven events in the gonad are necessary for critical local processes and the timing of hormone secretion. The clock/StAR relationship has not yet been explored in the mammalian ovary, though in the mouse testis, Bmal1 increases StAR expression (Alvarez et al., 2008). Regulation of the HPG axis by extra-SCN oscillators – testicular rhythms. Unlike data from ovary, the evidence for a functional role of clock genes in the testis is ambiguous. While many species exhibit circadian rhythms in T secretion, this rhythm may not be reflected in local oscillator function within the testis.

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There have been two reports of circadian variation in Per gene expression (Zylka et al., 1998; Guo et al., 2005), but other studies have not detected such rhythms (Miyamoto and Sancar, 1999; Alvarez et al., 2003; Bittman et al., 2003; Morse et al., 2003; Yamamoto et al., 2004; Alvarez and Sehgal, 2005). Additional findings have led to further confusion: although Bmal1 message is not expressed rhythmically, BMAL1 protein oscillates in Leydig cells, and knockout of Bmal1 reduces T production and fertility in mice (Alvarez and Sehgal, 2005; Alvarez et al., 2008). Data from hamsters are also equivocal. Per1, but not Per2, is rhythmic in hamster testes, but Per1’s functional role is unknown; two transcripts exist, both of which are truncated relative to mouse Per1, lack a nuclear localization domain, and cycle in phase (rather than typical antiphase) with Bmal1 (Tong et al., 2004). Finally, the apparent lack of rhythms in testicular clock genes is not limited to mammals. Zebrafish exhibit circadian rhythms in expression of Clock, Bmal1, and Bmal2 in several peripheral tissues, but not in the testis (Whitmore et al., 1998; Cermakian et al., 2000). Quail exhibit Cry1 rhythmicity in several peripheral tissues, not including the testes (Fu et al., 2002). Clock genes may play a noncircadian function in particular stages of sperm development. During the 35-day maturation of mouse sperm, PER1 is only detected in the mid- to late stages and CLOCK is only detected before meiosis (Alvarez et al., 2003; Bittman et al., 2003; Morse et al., 2003). After injection of bromodeoxyuridine, co-localization of this cell division marker and Per1 in newly divided sperm is not evident until 5 days after injection, and is most prevalent 10–21 days after injection (Bittman et al., 2003). Circadian rhythms and differentiation of endocrine tissue. Alvarez et al. (2003) and Alvarez and Sehgal (2005) have suggested that circadian rhythms are suspended during differentiation based on data from testis and thymus. Recent in vitro data using a destabilized luciferase reporter (dluc) driven by the Per2 promoter in rat support this contention (He et al., 2007). Several 24-h cycles of Per2-dluc bioluminescence are induced by medium changes or by DEX in nondifferentiating ovarian luteal cells, proliferative uterine stromal cells, and testicular interstitial cells. In contrast, no rhythms are detected in decidualizing uterine stromal cells, differentiating Leydig cells, or thymocytes. Notably, ovarian granulosa cells displayed a single circadian cycle of bioluminescence; loss of Per2-dluc rhythmicity is concomitant with increased LH-receptor expression, a marker of granulose cell differentiation (He et al., 2007). Whether circadian rhythms interfere with

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differentiation if not inactivated remains an interesting topic for further inquiry. Gonadal hormone feedback – estrogenic feedback to the SCN. Ovarian hormones have profound effects on circadian locomotor activity rhythms. Normally cycling hamsters display a phase advance every fourth day on the day of estrus when E levels are highest (Morin et al., 1977). Continuous administration of E shortens the free-running rhythm compared to OVX controls (Morin et al., 1977), and when such animals are held in constant light, a procedure that normally reduces consolidation of the activity bout and can lead to splitting of activity, continuous E prevents these changes (Morin, 1980). E may act either directly on the SCN, though ERs are sparsely expressed (Shughrue et al., 1997; Hileman et al., 1999; Gundlah et al., 2000), or indirectly though ERa-expressing cells in the POA, amygdala, BNST, and arcuate that provide input to the SCN (de la Iglesia et al., 1999). Estrogens may act by altering gap junction connectivity within the SCN. In female rats, estrogen increased expression of connexin-36, a subunit that makes up interneuronal gap junction channels in the SCN (Shinohara et al., 2001; Rash et al., 2007). Functional gap junctions are revealed in cultured SCN cells by dye and electrical coupling ( Jiang et al., 1997; Colwell, 2000; Long et al., 2005), and gap junction blockers reversibly alter rhythms in electrical activity and hormone release in vitro (Prosser et al., 1994; Shinohara et al., 2000). Locomotor activity rhythms are dampened in male connexin36-knockout mice, suggesting that gap junctions may be important to normal behavioral rhythms in vivo (Long et al., 2005). Further interactions of clock genes with ERa and ERb. Per2, a core clock gene, is regulated both post-transcriptionally and post-translationally by multiple cues, and may be an important link between circadian rhythms and several disease states (reviewed by Albrecht et al. (2007)). Relevant in the present context is a feedback loop comprising ovarian hormones, the ER-signaling network, and Per2. ERb expression is rhythmic in several peripheral tissues in wild-type but not arrhythmic Bmal1 knockout mice. Its promoter region includes an E-box, a target for the CLOCK: BMAL1 complex, suggesting direct regulation by the circadian clock (Cai et al., 2008). Gery et al. (2007) show that Per2 enhances ERa protein degradation, and Per2 suppression leads to ERa stabilization. Estrogen can in turn feedback to induce Per2 expression. While this work was done in a cancer cell model, it is likely to apply to other ERa-containing cells.

Gonadal hormone feedback – androgenic feedback to the SCN. Castration of mice lengthens the free-running period, decreases the precision of activity onset, and reduces consolidation of activity (Daan et al., 1975; Karatsoreos et al., 2007). Both T and dihydrotestosterone (DHT: a nonaromatizable androgen) restore the gonadally intact phenotype, suggesting that the effects of T are mediated by androgen receptors (ARs) rather than by ERs. While it is likely that androgens modulate locomotor behavior at multiple sites, AR is concentrated in the core region of the SCN of mice suggesting the possibility of a direct effect on the circadian clock in this species (Figure 8; Karatsoreos et al., 2007). More diffuse AR expression has also been detected in other species (see Karatsoreos and Silver (2007) for review). T may exert its effects on activity through conversion to E. In rats, where activity levels are potently reduced by castration and increased by T, conversion of T to E may be important in determining activity level (Roy and Wade, 1975). E is nearly 100times as effective at increasing activity as is T, and DHT has no effect on wheel-running activity (Roy and Wade, 1975). Comparison of AR expression indicates sex differences in the SCN in humans (Fernandez-Guasti et al., 2000) and in rodents (Iwahana et al., 2008). Western blots and immunohistochemistry indicate that ARs are more highly expressed in male than in female mice; gonadectomy eliminates and androgen treatment restores these sex differences. At the behavioral level, gonadectomy produces a dramatic loss of the evening activity onset bout in males but has no such effect in females. Treatment with T or DHT restores male locomotor activity and eliminates sex differences in the behavioral response (Iwahana et al., 2008). 13.4.3 Circadian Regulation of Melatonin and Seasonality Overview. The local environment varies considerably throughout the seasons and animals have evolved to restrict breeding and lactation to times of year when food availability and environmental conditions are optimal. Because day length (photoperiod) is the most reliable predictor of changing seasons, most temperate species use this cue to forecast local conditions and initiate adaptations to the coming season. Photoperiod is transduced to a melatonin signal that is inversely proportional to day length, providing a hormonal system for communicating photoperiodic information to the reproductive axis (reviewed in Goldman (2001)).

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Figure 8 Androgen receptors are expressed in the mouse SCN core (red), and there is little overlap with the AVP cells in the shell (green). The presence of these receptors and the changes in circadian locomotor activity rhythms of castrated mice suggest a neuroendocrine feedback loop in which the SCN plays a role in determining the rhythm of androgen secretion, and androgens then act on the SCN to modulate period and phase of rhythms. 3v, third ventricle; oc, optic chiasm. Scale bar¼ 150mm. Adapted from Karatsoreos IN, Wang A, Sasanian J, and Silver R (2007) A role for androgens in regulating circadian behavior and the suprachiasmatic nucleus. Endocrinology 148: 5487–5495.

SCN regulation of melatonin secretion. The neural circuit by which day length information is conveyed to the pineal gland has been well characterized (Moore and Klein, 1974). Light information from the retina is received at the SCN and thence transmitted to the pineal gland via a pathway with synapses in the PVN, the medial forebrain bundle, and the superior cervical ganglion of the spinal cord. From the superior cervical ganglion, b-adrenergic neurons drive pineal melatonin secretion during the dark but not during the light when their activity is inhibited (Cassone et al., 1990; Larsen et al., 1998; Larsen, 1999; Teclemariam-Mesbah et al., 1999; Card, 2000). The transduction of day length to melatonin duration begins in the SCN, where spontaneous electrical activity mirrors day length, with elevated electrical activity through the light portion of the day (VanderLeest et al., 2007). Day length is also represented in the SCN by spatio-temporal expression patterns of clock genes (Hazlerigg et al., 2005; Johnston et al., 2005). Both stimulatory and inhibitory outputs of the SCN are implicated in controlling the final noradrenergic stimulation of the pineal gland at night. During the day, GABAergic projections to the PVN inhibit excitatory output to the pineal

(Kalsbeek et al., 2000b). During the night, stimulatory glutamatergic output from the SCN to the PVN stimulates melatonin synthesis (Perreau-Lenz et al., 2004). As with other hormonal systems, lesions of the SCN abolish circadian rhythms in melatonin production and secretion (Scott et al., 1995; Tessonneaud et al., 1995). The nature of the melatonin signal and its neural targets. Numerous lines of evidence indicate that the duration of melatonin secretion drives seasonal changes in the reproductive system (Carter and Goldman, 1983; Nelson et al., 1990; Bartness et al., 1993). Melatonin receptors are highly localized in the rodent brain (Weaver et al., 1989; Drew et al., 2001). Although melatonin ultimately influences GnRH secretion, it does not appear to act directly on GnRH neurons. The neural loci and peptidergic systems upstream of GnRH that act to decode the melatonin signal and relay this information to the reproductive axis is an active area of investigation. In the Syrian hamster, the DMH is an important melatonin target tissue; lesions of the DMH block short-day (SD) and melatonin-induced regression of the reproductive system (Maywood and Hastings, 1995; Maywood et al., 1996; Lewis et al., 2002).

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The DMH also expresses AR and thus may be a site at which photoperiod modulates sensitivity to T negative feedback, enabling low-steroid titers in reproductively quiescent animals to restrict GnRH secretion. A potential candidate mediating the effect of melatonin on steroid negative feedback is GnIH, a potent inhibitor of GnRH and gonadotropin secretion. GnIH cells are localized to the DMH and participate in sex-steroid negative feedback (Kriegsfeld et al., 2006). GnIH may be an intermediary between melatonin signaling and seasonally changing negative feedback. Contrary to expectation, however, extended exposure to inhibitory day lengths leads to suppression of GnIH immunostaining and mRNA in this species (Mason et al., 2007; Revel et al., 2008). Likewise, 60 days of melatonin administration to long-day (LD) animals suppresses GnIH (Revel et al., 2008). It is possible that Syrian hamsters require GnIHenhanced negative feedback to suppress GnRH during the initial period of regression, but this inhibition is not necessary in hamsters with a fully regressed reproductive axis and low T concentrations. Future studies examining the pattern of GnIH expression throughout the development of reproductive quiescence are necessary to resolve this apparent discrepancy. In Siberian hamsters, in contrast to Syrian hamsters, the SCN is a critical melatonin target tissue necessary for SD-induced regression of the reproductive system (Bartness et al., 1991; Bittman et al., 1991). This finding suggests that the circuit beginning with the SCN also requires the SCN as a target. Presumably, the SCN then communicates melatonin duration information directly to GnRH neurons or to intermediate sites upstream of GnRH, such as kisspeptin, an RFamide peptide that stimulates GnRH (reviewed in Smith and Clarke (2007)). In male and female Siberian hamsters, photoperioddriven changes in reproduction are associated with marked changes in kisspeptin immunoreactivity (Greives et al., 2007; Mason et al., 2007). Kisspeptin immunoreactivity is reduced in the AVPV in animals held in SD (reproductively inactive) compared with hamsters housed in LD (reproductively active). Patterns in the arcuate are reversed, however, with kisspeptin significantly elevated by SD and relatively low in LD (Greives et al., 2007; Mason et al., 2007). Seasonal changes in kisspeptin have been observed in Syrian hamsters. In this species, arcuate Kiss-1 mRNA is increased in LD and decreased in SD; Kiss-1 mRNA is not observed in the AVPV

(Revel et al., 2006), a region where kisspeptin is seen in other rodent species (Smith et al., 2005; Greives et al., 2007; Kauffman et al., 2007). The role of kisspeptin neurons in each of these nuclei remains unclear. It is also unclear whether melatonin acts directly, or upstream of, kisspeptin cells in the AVPV and arcuate nucleus. Clock genes in decoding melatonin signaling. In seasonally breeding species, the pars tuberalis (PT) consistently exhibits high melatonin binding in autoradiographic studies (Bittman and Weaver, 1990; Weaver and Reppert, 1990). In hypothalamic– pituitary transected sheep, melatonin implants in the region of the PT reduce prolactin (PRL) secretion in a manner similar to SDs, but do not affect gonadotropin secretion, suggesting that the PT may regulate photoperiodic effects on the lactotropic, but not gonadotropic, axis (Lincoln and Clarke, 1997). A number of studies suggest a role for PT clock genes in the control of seasonality ( Johnston et al., 2003; Lincoln et al., 2003; Hofman, 2004). In Syrian and Siberian hamsters, photoperiod alters the duration and amplitude of clock and clock-controlled gene expression in the PT (Messager et al., 2000; Johnston et al., 2003). In sheep, the relative timing of the clock genes Per and Cry is altered by photoperiod in the PT, providing a mechanism of temporal encoding and downstream control (Lincoln et al., 2002, 2003, 2005; Hazlerigg et al., 2004). These results are intriguing and suggest that phase and/or amplitude of clock and clockcontrolled genes in SCN brain targets and endocrine glands may predict their responsiveness to upstream signals on a daily schedule (Figure 9). 13.4.4

Circadian Regulation of Prolactin

Prolactin rhythms. A pronounced daily rhythm in PRL secretion has been reported for a number of species, including both human and nonhuman primates (Spies et al., 1979; Van Cauter et al., 1981). PRL has a robust diurnal rhythm with plasma concentrations being highest during sleep and the lowest during the waking hours in humans, and with a higher amplitude in women than in men (reviewed in Freeman et al. (2000)). In humans maintained in constant conditions, this rhythm persists and is independent of sleep per se (Waldstreicher et al., 1996). Likewise, in rats, PRL secretion has a robust circadian pattern that persists in constant conditions and is abolished by lesions of the SCN (Bethea and Neill, 1979; Mai et al., 1994). In addition to baseline circadian rhythms, PRL surges occur in mice and rats around

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Figure 9 The duration of melatonin (mel) secretion, the critical variable that drives photoperiodic responses in many species, may be decoded in melatonin target tissues by spatial and temporal changes in clock-gene expression. In each panel, the light–dark cycle is shown at the bottom in zeitgeber time (ZT), and the period of elevated melatonin duration is shown at the top. (a) In the model based on work in the hamster, photoperiod is encoded in the amplitude (A–B: a) of gene expression in melatonin target tissues (Per and inducible cAMP early repressor, ICER). (b) In the model based on work in sheep, photoperiod is encoded in the phase relationship between Per and Cry expression rhythms (A–B:C). Given the importance of PER:CRY interactions in regulating transcriptional activity, the change in their phase relationship may alter the strength of their interactions, and the timing of their activity. Reproduced from Lincoln GA, Andersson H, and Loudon A (2003) Clock genes in calendar cells as the basis of annual timekeeping in mammals – a unifying hypothesis. Journal of Endocrinology 179: 1–13, with permission from # Society for Endocrinology (2003).

the time of the proestrous LH surge, and this too appears to be under circadian control (Blake, 1976; Bethea and Neill, 1980). PRL rhythm regulation by the SCN. PRL secretion is modulated by both releasing and inhibiting factors, but the primary control is inhibition by dopamine (DA), synthesized and released in three groups of neurons of the hypothalamus: the tuberoinfundibular DA-ergic (TIDA), tuberohypophyseal DA-ergic (THDA), and periventricular tuberohypophyseal DA-ergic (PHDA) neurons (reviewed in Freeman et al. (2000)). Rhythmic PRL release is associated with rhythms in activity of TIDA and PHDA neurons, but not THDA neurons

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(Sellix and Freeman, 2003; Sellix et al., 2004). Efferents from the SCN make synaptic contacts with tyrosinehydroxylase immunoreactive, presumably DAergic, neurons (Horvath, 1997). PRL release exhibits a strong E dependence, as revealed by the single PRL surge on the afternoon of proestrus in mice and rats (Smith et al., 1975; Michael, 1976). Rising E levels increase TIDA activity (Neill et al., 1971). The precise mechanisms underlying the PRL surge are complex, with both DA tone and PRL-releasing factors playing important roles (Freeman et al., 2000). The circadian system may play a role in establishing the timing of the PRL surge, as it does in the similarly timed LH surge. The phase of the PRL surge is altered by shifts in the light–dark cycle (Blake, 1976; Pieper and Gala, 1979). In conditions of constant darkness or constant dim light, PRL surges display a free-running rhythm in OVX E-treated rats that are abolished after ablation of the SCN (Blake, 1976; Bethea and Neill, 1980). VIP projections from the SCN to oxytocin neurons (OT: the primary PRL-releasing factor) are also important (Kennett et al., 2008). Using OVX Etreated rats, the authors show that administering VIP antisense oligodeoxynucleotides phase advances the peak of FOS expression in periventricular OT neurons and the peak of the PRL surge on the third day after treatment (Kennett et al., 2008). PRL rhythm regulation by extra-SCN clocks. Rhythmic clock-gene expression has recently been observed in tyrosine-hydroxylase-immunoreactive neurons, including TIDA and PHDA neurons (Kriegsfeld et al., 2003; Sellix et al., 2006). In OVX rats in a 12L:12D schedule, both PER1 and PER2 are rhythmic in these cell groups but with different phases, peaking in the middle of the night in TIDA neurons and at the beginning of the night in PHDA neurons (Sellix et al., 2006). In mice, PER1 immunoreactivity in arcuate tyrosine-hydroxylase neurons was high at the end of the day and low at the end of the night (Kriegsfeld et al., 2003). Together, these data suggest the possibility of local control of neuroendocrine DA cells by clock-mediated mechanisms.

13.5 Rhythms in Aging Overview. Aging is accompanied by changes in each major endocrine system. Some of these changes such as declines in insulin sensitivity or thyroid hormone availability are considered indicative of disease, while others such as menopause/andropause, somatopause,

Circadian Regulation of Endocrine Functions

and adrenopause are considered normal aspects of healthy aging (Lamberts et al., 1997). From the perspective of circadian biology, aging is associated with decreased amplitude of many rhythms, altered phase, and changes in free-running period (Brock, 1991; Turek et al., 1995). In this section, we examine several examples of how endocrine rhythms and function change with age. These changes may stem from master-clock organization itself, its outputs, or the sensitivity and phase of target tissues. Evidence for SCN aging and rejuvenation. In old rats, SCN rhythms are blunted, with lower and more aberrant single-unit firing rates (Satinoff et al., 1993; Aujard et al., 2001) and an attenuated and phaseadvanced rhythm of local cerebral glucose utilization (Wise et al., 1988). Aging disrupts either coupling among SCN pacemaker cells or their output, or causes a deterioration of the pacemaking properties of SCN cells (Satinoff et al., 1993). Surprisingly, transplants of fetal SCN tissue can restore young circadian rhythms and SCN responsiveness to environmental signals in old rats. Fetal SCN tissue transplanted into SCN-intact aged rats restores deteriorated circadian rhythms (Li and Satinoff, 1998). Only those grafts that express VIP are able to restore rhythms of activity, drinking, and eating, notable given the importance of VIP as a withinSCN synchronizer of neural activity (Aton et al., 2005). Moreover, these transplants restore lightinduced Fos expression in the host SCN back to normal levels observed in young animals (Cai et al., 1997a). Finally, such grafts also restore rhythms of hypothalamic CRH (which controls the ACTH/ glucocorticoid rhythm) and anterior pituitary proopiomelanocortin (POMC: precursor of b-endorphin) mRNA in rats that have lost such rhythms in middle age (Figure 10). This is noteworthy for these are elements of endocrine rhythms that are not restored by grafts in young, SCN-lesioned animals. This finding suggests that the graft signals help restore rhythm robustness in the host as opposed to driving rhythms in the brain itself (Cai et al., 1997b). Aging in female reproductive rhythms. Female reproductive rhythms require precise coordination of many endocrine factors, ranging from ultradian pulsatility of GnRH release to infradian rhythms of estrous cyclicity and seasonality. The causes of reproductive senescence are varied and differ among species. The course of menopause traces a trajectory from regular cycling through arrhythmic and sporadic cycles to loss of cyclicity. Changes in both the brain and in the ovaries play major roles in reproductive aging

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Figure 10 The amplitude of endocrine rhythms generally declines with age. Transplantation of fetal SCN tissue into SCN-intact hosts restores the amplitude of the CRH mRNA rhythm in middle-aged rats. Video count area denotes the total area of 4 fixed area windows through the PVN covered by silver grains. Reproduced from Cai A, Scarbrough K, Hinkle DA, and Wise PM (1997b) Fetal grafts containing suprachiasmatic nuclei restore the diurnal rhythm of CRH and POMC mRNA in aging rats. American Journal of Physiology 273: R1764–R1770, with permission from The American Physiological Society.

(Wise et al., 1996). The exhaustion of the ovarian follicular supply has long been accepted as the single, most important cause of the transition from fertility to menopause (vom Saal et al., 1994). Follicular depletion may not always be the limiting factor, because aged ovaries can ovulate when implanted in young rats (Krohn, 1955). A gradual loss of coordination of brain rhythms is also observed around the time of menopause, often preceding cycle shortening or complete follicular loss (Wise et al., 1996, 1997). In the brain, aging alters sensitivity to steroid negative feedback, pulse frequency and amplitude of both GnRH and LH, and structural and functional changes occur in the GnRH neurons themselves (Yin and Gore, 2006). Older females manifest alterations in the pattern of the LH surge, including delays in phase and attenuated peak values, and these changes occur before any loss of overt rhythmicity (Cooper et al., 1980; Wise, 1982a; Nass et al., 1984). The timing of the preovulatory LH surge also loses precision in middle age: the critical period during which barbiturates can block the LH surge is extended 1–2h longer in middle-aged rats as compared to young rats (van der Schoot, 1976). Changes in the GnRH-pulse generator, as detected by changes in the frequency and duration of ultradian LH pulses, similarly precede the transition from regular to irregular cycling in both middle-aged women and rats (10–12months old; Cooper et al., 1980; Wise, 1982a; Nass et al., 1984; Matt et al., 1998). In middle-aged rats, GnRH

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neurons are less active than in young rats (Rubin and Bridges, 1989; Rubin et al., 1994). Fewer GnRH neurons express FOS around the time of the preovulatory period, and the interval during which the number of FOS/GnRH double-labeled cells are observed is shorter in middle-aged compared to young rats (Rubin et al., 1994). The time course of FOS expression by GnRH neurons is delayed also , in keeping with the delay in the LH surge above. These data indicate that hypothalamic endocrine regulation may begin to weaken or become desynchronized before the initiation of the perimenopausal transition. Evidence for an SCN role in female reproductive aging. The mechanisms associated with the decreased amplitude and precision of circadian regulation with aging are likely to be numerous. Two possible mechanisms are circadian changes in VIP or in norepinephrine (NE) signaling. VIP is expressed and secreted from the SCN rhythmically, and may communicate phase information to GnRH cells of the POA (van der Beek et al., 1993, 1994). Forty percent of all GnRH neurons contain VIP2 receptor and VIP-containing processes occur in close apposition to VIP2 receptor-positive GnRH neurons (Smith et al., 2000). VIP mRNA is expressed rhythmically in young female rats, but this rhythm disappears in middle-aged rats (Krajnak et al., 1998). In parallel, the number of VIPimmunoreactive cells in the SCN decreases with age (Chee et al., 1988). Injecting VIP antisense in the peri-SCN region mimics the effect of age on the E-induced LH surge, delaying and attenuating peak LH levels (Harney et al., 1996). NE exhibits a diurnal rhythm that is characterized by elevated turnover stimulating the LH surge (Wise et al., 1997). Suppression of the afternoon rise in NE prevents the expected LH surge (Kalra and McCann, 1974) and administration of NE agonists induces preovulatory-like LH surges (Krieg and Sawyer, 1976). Middle-aged proestrous rats fail to show a daily rhythm in NE turnover in the SCN (Wise, 1982b) and the peak in NE release is markedly attenuated, although the average NE release is increased compared to that in the young proestrous animals (Mohankumar et al., 1994). The stimulatory effects of NE on the LH surge are thought to be mediated through a1-adrenergic receptors (Drouva et al., 1982). Young rats display a daily rhythm in the SCN and other anterior regions of the hypothalamus, with the density of receptors peaking during the evening (Weiland and Wise, 1990). There is a progressive disappearance in this rhythm with age, even though the

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average density of receptors is maintained until very old age. Male reproductive aging. Reproductive aging in males appears more gradual than in females, and apparently does not involve changes in the circadian system. As with many other hormones, T rhythms are blunted with age; in healthy men over 50years of age, afternoon T concentrations are similar to those of younger men, but the nocturnal increase is attenuated or absent (Bremner et al., 1983). Some changes may be associated with altered sleep. Sleep fragmentation reduces nocturnal T secretion in young men (22–26years old; Luboshitzky et al., 2001). Middleaged men have less nocturnal T secretion than young men, and this may be associated with gradual loss of synchrony between LH and T pulses and between rapid eye movement (REM) sleep and T secretion (Luboshitzky et al., 2003). In addition, in a recent study of 12 elderly men, the amount of nighttime sleep predicted morning T concentrations (Penev, 2007). Circadian rhythms, sleep, and melatonin in aging. With age, the amplitude of the sleep–wake cycle decreases: individuals are awake more often and have more difficulty sleeping during the rest period, and have more difficulty staying awake during the wake period (Van Gool and Mirmiran, 1986). Exogenous melatonin may be a useful therapy in improving sleep quality in aged humans (Cajochen et al., 2003; Brzezinski et al., 2005; Pandi-Perumal et al., 2005). Daytime administration of melatonin increases subjective sleepiness (Barchas et al., 1967), and this effect can be seen in increased theta activity in EEG recordings (Cajochen et al., 1997). In elderly insomniacs, low doses of exogenous melatonin improve several measures of sleep including latency to sleep onset and awakenings per night (Wurtman and Zhdanova, 1995). Melatonin may also confer benefits to elderly patients with disrupted sleep–wake cycles in association with Alzheimer’s disease (Wu and Swaab, 2007). Data from nonmammalian vertebrates also support the therapeutic value of melatonin treatment in aged individuals. In old ring doves, melatonin rhythms are attenuated; treatment with acute melatonin before lights off for 3days restores peak melatonin values and increased several measures of immune function (Paredes et al., 2007). In aged zebra fish that manifest fragmented circadian rhythms, melatonin promotes entrainment, and can partially ameliorate the cognitive deficits associated with a lack of circadian timing (Zhdanova et al., 2008). Given the efficacy of exogenous melatonin in decreasing sleep-onset latency, and promoting sleep

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consolidation (Cajochen et al., 2003; Zisapel, 2007), it has been suggested that changes in sleep patterns with age might be associated with changes in endogenous melatonin rhythms (Pandi-Perumal et al., 2005). Nevertheless, the relationship between endogenous melatonin, sleep, and age is unclear. Zeitzer et al. (2007) reviewed work since 1979 on age effects on melatonin rhythm amplitude; just over half of the work documents decreased amplitude while the other reports indicate no change or mixed results. The evidence is also mixed regarding melatonin’s role in altered sleep quality in the elderly. Some studies have found correlations between melatonin, sleep quality, and insomnia, but others have not (Youngstedt et al., 1998; Leger et al., 2004). Differences between studies may stem from high interindividual variability in melatonin secretion (Bergiannaki et al., 1995).

13.6 The Circadian System: From Bench to Bedside One of the advantages of studying circadian clocks is that circadian time and the expression of clock genes can be assessed in numerous tissues and cells. For research aimed at understanding the coordination of responses within the body, an attraction of the circadian system is the ability to study events at multiple levels of analysis (molecular, genetic, neural, behavioral) and to integrate our understanding of processes at various temporal and spatial scales while taking into consideration normal and abnormal function. A second promise of circadian research is that it provides protocols for high-throughput screening, important for development of biomarkers and drugs. The availability of tools for analyzing cells and their time-stamp throughout the body, using molecular and imaging tools, along with powerful methods for analysis of large data bases, enables such research. One aspect of the circadian system that has been hard to explore is individual differences. The extent of such differences in the temporal patterns of hormone secretion is not well characterized, but may be consistent within individuals (Schulz et al., 2008). In this study, eight hormones were measured over two different nights. The temporal organization of hormone secretion into the blood was highly individual, the intra-individual patterns were conserved. Colloquially, we have similar intuitive experiences and can often categorize ourselves as larks or owls. A major breakthrough for circadian biologists has been the use of cells of peripheral tissues as proxies

for oscillators of the SCN. Interindividual genetic differences appear to be manifest similarly in central and peripheral oscillators (Yagita et al., 2001; Pando et al., 2002). Several strategies for assessing individual differences in timing, with the potential for optimizing medical treatment, are promising. Molecular gene cycling is useful for determining body time with important applications in personalized medicine, including cardiovascular disease and cancer, our leading causes of death (Liu et al., 2007). Detection of an individual’s body time via a single-timepoint assay can be achieved by a molecular timetable composed of hundreds of time-indicating genes (Ueda et al., 2004). Diurnal protein cycling in blood using high-throughput proteomics is also an attractive possibility; blood draws are minimally invasive, and the proteomic profile can indicate what is happening elsewhere in the body in health and disease (Martino et al., 2007). Rhythms in fibroblasts also vary among individuals, and the correlation between activity patterns and fibroblast rhythms suggests that these cells accurately indicate circadian properties (Brown et al., 2005). Because peripheral cells oscillate and are easily accessible, it has also been possible to introduce genetic materials into such cells by transfection or transduction; this holds promise for the analysis of biochemical mechanisms of oscillation, quantitative trait mapping, and the search for individual chronotypes (Brown et al., 2008; Cuninkova and Brown, 2008). These cell-based clock models are ideal for target discovery and chemical biology and some of the screening principles and measuring technologies may be useful in the study of relationships between hormones, clock genes, and clock-controlled genes at various levels of the neuraxis. We have emphasized in this review the significance of the circadian system in the brain and periphery in studies of endocrine physiology and behavior. Circadian regulation and dysregulation have profound consequences in health and in disease. An improved understanding of tissue-specific rhythms should help to refine clinical diagnosis and hasten the development of individualized timed courses of treatment.

Acknowledgments The authors would like to thank Susan Strider and Ben Meltzer for invaluable assistance in preparing this manuscript. This work is supported by NIH grants MH075045 and NS37919 (RS), T32DK07328 (MPB), and HD050470 (LJK).

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Biographical Sketch

Matthew P. Butler received his doctorate in 2007 in integrative biology from the University of California, Berkeley, where he worked on seasonal timing mechanisms under Dr. Irving Zucker. He is presently a postdoctoral research fellow at Columbia University in Dr. Rae Silver’s chronobiology laboratory, where he is studying the circadian regulation of the neuroendocrine system. His present work focuses on the timing of signals that emanate from the circadian clock in the brain, and the pathways by which these cues communicate time to the body.

Lance Kriegsfeld received his PhD from Johns Hopkins University where his graduate work focused on the neuroendocrine mechanisms controlling seasonal changes in reproductive functioning. He then continued his education as a postdoctoral fellow at Columbia University investigating the organization of the circadian system in rhythm generation and the control of timed physiology and behavior. He is presently an assistant professor at the University of California, Berkeley where he has merged his two interests to study the role of neuroendocrine timing in reproduction, health, and disease prevention. His present work focuses on the neural circuits and neurochemical systems by which the circadian clock impacts ovulatory function. His recent findings have uncovered a novel neural circuit by which the brain clock temporally coordinates the balance of positive and negative feedback influences of estradiol to allow for the preovulatory luteinizing hormone surge and, ultimately, ovulation.

Rae Silver is Helene N and Mark N Kaplan Professor of Natural and Physical Sciences and holds a joint appointment at Barnard College and at Columbia University. She received her undergraduate degree in honors psychology at McGill University, and her PhD with Dr. Daniel S Lehrman at Rutgers University. Rae Silver’s service to the community includes terms as senior advisor in the Office of the Director at the National Science Foundation, US representative to the Council of Scientists of the Human Frontiers Science Program, on the Program and Education Committees of the Society for Neuroscience, as chair or panel member on external evaluation committees of academic university departments and programs, and on grant review panels at NIH, NSF, and NASA. She chaired NASA’s REMAP committee that reviewed research priorities on the International Space Station. She serves on the editorial and advisory board of Hormones and Behavior, European Journal of Neuroscience, Journal of Biological Rhythms, and Chronobiology International. At Columbia University and Barnard College, she has been Department Chair, Director of the Graduate Program, and Director of the Undergraduate Program in Neuroscience. Rae Silver’s research focuses on the neural basis of circadian timing, the regulatory system that organizes our daily sleep alertness and is responsible for jet lag and numerous sleep abnormalities. Initial studies definitively showed the brain clock’s locus by demonstrating that transplantation of the suprachiasmatic nucleus (SCN) restored temporal organization in animals lacking such a clock. Importantly, 95% of such transplants are successful, indicating a robust diffusible signal which is sufficient to sustain circadian responses. An elegant aspect of studies of the brain’s circadian clock is that it can be successfully examined at the subcellular, cellular circuit, and systems levels. Current studies involve behavioral, genetic, electrophysiological, and modeling work, showing that clock function is an emergent property of the underlying circuit. Furthermore, the circuit is modified (at the electrical, genetic, and behavioral levels) by direct input from external signals (photic input from the eye), and internal cues (hormones) to specific identifiable cellular elements of the clock, which are then communicated to the rest of the network. In a second line of research, the laboratory is working on neuro-immune interactions, specifically on the role of mast cells in the brain. The population of brain mast cells changes with behavioral and endocrine state of the animal under normal physiological conditions, and also is sensitive to disease states. This work focuses on the contribution of mast-cell mediators on neural and vascular signaling in the CNS, and on the consequences of such signals on behavior and physiology.