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CIRCADIAN and SEASONAL RHYTHMS the Roles of Vasoactive

CIRCADIAN and SEASONAL RHYTHMS the Roles of Vasoactive

7 CIRCADIAN AND SEASONAL RHYTHMS

The roles of vasoactive intestinal polypeptide in the mammalian circadian clock

H D Piggins and D J Cutler School of Biological Sciences, 3.614 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK (Requests for offprints should be addressed toHDPiggins;Email: [email protected])

Abstract Biological oscillations with an endogenous of near both in vivo and in vitro. These resetting actions appear to 24 h (circadian rhythms) are generated by the master be mediated through the VPAC2 (a type of circadian pacemaker or clock located in the supra- receptor for VIP). Unexpectedly, genetically ablating chiasmatic nuclei (SCN) of the . This clock expression of the VPAC2 receptor renders the circadian is synchronised to recurring environmental signals con- clock arrhythmic at the molecular, neurophysiological veyed by selective neural pathways. One of the main and behavioural levels. These findings indicate that this chemical constituents of SCN neurones is vasoactive intrinsic acting through the VPAC2 receptor intestinal polypeptide (VIP). Such neurones are retino- participates in both resetting to light and maintenance of recipient and activated by light. Exogenous application of ongoing rhythmicity of the SCN. VIP resets the SCN circadian clock in a light-like manner, Journal of Endocrinology (2003) 177, 7–15

Introduction the restoration of wheel-running rhythms (Silver et al. 1996). This suggests that paracrine signals convey phase Over the past 30 years, a critical mass of evidence has been information from the graft to the neural structures regu- collected demonstrating that the suprachiasmatic nuclei lating locomotor activity. Two substances, transforming (SCN) of the hypothalamus house the dominant mam- growth factor- (TGF-) (Kramer et al. 2001) and pro- malian circadian clock or pacemaker (Weaver 1998). This kineticin 2 (Cheng et al. 2002) have recently been pacemaker and its synchronisation (entrainment) to the implicated as key messengers in communicating phase environmental light–dark cycle modulates the 24 h organ- information from the SCN to motor control sites in intact isation of physiological and behavioural processes. Studies rodents. in which the rodent SCN is lesioned electrolytically or The SCN clock is reset by light or photic stimuli neurochemically have demonstrated that this leads to the (Meijer 2002) as well as arousal-inducing or non-photic abolition of wheel-running rhythms (although the rodent stimuli (Mrosovsky 1996). Extensive studies in nocturnal can still move freely) and the loss of daily variation in rodents maintained in constant darkness and housed in endocrine function such as the luteinising surge cages equipped with running wheels revealed that light in female rats (Raisman & Brown-Grant 1977) and pulses given during their active phase (their subjective secretion of (Klein & Moore 1979). In humans, night) phase-dependently phase-reset the onset of the damage to the SCN region arising through cranio- wheel-running activity rhythm (Daan & Pittendrigh pharyngioma can lead to loss of –wake and endocrine 1976, Takahashi et al. 1984). A light pulse given during rhythms (Cohen & Albers 1991). Transplantation of fetal the early part of the subjective night slows or phase-delays SCN material can rescue rodent behavioural rhythms the clock, while a similar light pulse given during the latter (Lehman et al. 1987, Ralph et al. 1990), but not endocrine part of the subjective night accelerates or phase-advances rhythms (Meyer-Bernstein et al. 1999), indicating that the clock (Fig. 1A). Pulses of light given during the middle hard-wiring of the SCN input to neural structures of the of the inactive phase or subjective day have no resetting neuroendocrine axis is required for the normal expression effects, even though the animal may be awake at the time of overt neurohormonal rhythms. Surprisingly, neural of the pulse (Meijer 2002). Clock processes therefore gate contacts between SCN graft and host are not required for these actions of light on the circadian clock such that light

Journal of Endocrinology (2003) 177, 7–15 Online version via http://www.endocrinology.org 0022–0795/03/0177–007  2003 Society for Endocrinology Printed in Great Britain

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resets the clock predominantly during the subjective night. To date, investigations on the basis of In contrast, non-photic stimuli, such as changing the cage photic and non-photic resetting have focused on the or giving the animal a new running wheel, which promote influence of SCN afferents. Research with neuroanatomi- arousal, lead to an acceleration or phase-advance in the cal tracers such as cholera toxin subunit  and fluorogold clock during the subjective day (Fig. 1B) and have few has demonstrated that photic information is relayed prominent phase-shifting effects during the subjective from the retina directly to the SCN by the monosyn- night (Mrosovsky 1996). Thus, like light, the resetting aptic (RHT) (for reviews see actions of non-photic stimuli are phase-dependently gated Colwell & Menaker 1996, Ebling 1996) (see Fig. 2). by the SCN clock. Immunohistochemical and electron microscopy studies have identified the excitatory glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) as the main of the RHT (Castel et al. 1993, Hannibal et al. 2000, Hannibal & Fahrenkrug 2002). Previously, (SP) had been implicated as a candidate transmitter of the rat RHT (Takatsuji et al. 1991, 1995), but subsequent neuroanatomical studies (Piggins et al. 2001, Hannibal 2002) and functional studies (Piggins & Rusak 1997) have suggested that SP is unlikely to be an RHT neurochemical in many rodent species. Some RHT afferents bifurcate and, together with other retinal fibres, innervate the intergeniculate leaflet of the visual (Pickard 1985, Smith et al. 2000). Cells here project rostrally to the SCN to form the geniculo- hypothalamic tract (GHT), thus providing another path- way (Fig. 2) by which environmental light information can be conveyed to the SCN circadian clock (Harrington 1997). In contrast to the neurochemicals of the RHT, (NPY) and GABA are most readily identified in GHT fibres that innervate the SCN (Harrington 1997). Further, this pathway appears to be more important in relaying non-photic information to the SCN since destruction of the GHT blocks the resetting effects of many arousal-inducing stimuli (Mrosovsky 1996), but only has subtle effects on photic entrainment. Microinjection of NPY into the SCN region phase- advances behavioural rhythms during the subjective day, thus emulating the temporal pattern of phase-resetting by non-photic stimuli (Huhman & Albers 1994). A third major SCN afferent arises from median Raphe cells of the brainstem (Fig. 2). has been identified in this

Figure 1 Resetting effects of photic and non-photic stimuli on nocturnal rodent wheel-running rhythms. (A) Solid rectangles depict running-wheel activity under light–dark and constant dark (DD) conditions. The animal initially entrains to lights off (illustrated by the top bar) and then free-runs with a tau of >24 h when released into DD. Note phase-dependent phase-shifting effects of 15-min light pulses (*) delivered at late subjective night, early subjective night or middle subjective day phases respectively. In contrast, confinement to a novel running wheel during the middle of the projected day (hatched bar) phase-advances the wheel-running rhythm. (B) Phase-response curves for photic (solid line) and non-photic stimuli (broken line) with phase-advances and -delays plotted as positive and negative values respectively. The magnitude of the shift is plotted according to the time of the circadian cycle at which the was delivered.

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Figure 2 Depiction of the major pathways and their in the mammalian circadian system. PACAP and glutamate relay photic information, while NPY, GABA and serotonin convey non-photic information. Activation of receptors for these neurochemicals impacts on core clock (e.g. per, cry, bmal1, etc.; for review see Albrecht 2002) in SCN neurones to influence the timing of outputs from the circadian clock, including (AVP), 2 and TGF-. brainstem pathway and has been implicated in both non- intestinal polypeptide (VIP) immunoreactive (ir) neurones photic and photic entrainment (for review see Morin 1999). constitute the core of this structure (Fig. 3). Many While much research has been geared to resolving the neurones within the core are retinorecipient, while retinal information conveyed by these pathways as well as the efferents are sparse or absent in the shell. This SCN neurochemical messengers that they utilise, there have neurochemical organisation is also seen in other been comparatively few investigations on the role of including the human where VIP- and AVP-containing endogenous neurochemicals in SCN circadian function. cells are key markers of the SCN (Mai et al. 1991, In this paper, evidence indicating that neurochemicals Moore 1992). In most mammalian species studied, GABA intrinsic to SCN neurones can themselves regulate the is expressed in many SCN neurones and frequently phase of the SCN circadian clock will be reviewed. co-localises with a number of (Buijs et al. Moreover, we also propose that activation of a certain 1995, Castel & Morris 2000). class of neuropeptide receptor may be important in the VIP is synthesised from preproVIP and cleavage of maintenance of ongoing circadian clock function. this molecule forms both VIP and histidine iso- leucine, a peptide found in abundance in the SCN and thought to be co-localised with VIP. VIP and peptide Intrinsic neurochemicals histidine isoleucine are structurally related to PACAP and, in rodents, these three show 68% homology. The neurochemicals synthesised within the rodent SCN Accordingly, these peptides bind to three classes of have been established for a number of years (for review see receptors present in the : VPAC1, VPAC2 and PAC1 Piggins et al. 2002) and, on the basis of these phenotypes (of which there are a number of isoforms). The VPAC1 as well as the neural connections formed by these neuro- and VPAC2 receptors bind VIP/peptide histidine iso- chemically defined cells, it has been hypothesised that the leucine and PACAP with almost equal affinity, while SCN is subdivided into a ‘shell’ and ‘core’ (Moore & Leak PAC1 preferentially binds PACAP over VIP (although 2002). Neurones contained within the shell include AVP- there is an isoform that has similar affinity for PACAP and synthesising cells and (SS)-synthesising cells, VIP, the so-called PAC1short, which is present in the SCN; while -releasing peptide (GRP) and vasoactive Shinohara et al. 2002 but see also Ajpru et al. 2002). www.endocrinology.org Journal of Endocrinology (2003) 177, 7–15

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VIP-ir innervate VIP-ir neurones suggests that VIP may form part of an autofeedback circuit (Fig. 3). Extra-SCN projections of VIP-ir neurones include the hypothalamic subparaventricular zone, gonadotrophin- releasing hormone neurones of the preoptic region (van der Beek et al. 1997), the dorsomedial and posterior hypothalamus, and the paraventricular nucleus of the thalamus (Watts & Swanson 1987, Kalsbeek et al. 1993). The observations that VIP cells receive a direct retinal input (Ibata et al. 1989, Tanaka et al. 1993) and that photic stimulation activates VIP neurones in the SCN (as indi- cated by the presence of cFos protein in such cells; Romijn et al. 1996) implies that VIP neurones interface incoming environmental information and relay it to the circadian clock to adjust its phase accordingly.

VIP and photic entrainment

As noted above, VIP-ir neurones in the core SCN are contacted directly by retinal efferents, and photic stimu- lation induces cFos expression in these VIP cells. In mouse, hamster and rat SCN, some but not all VIP-ir neurones express cFos, a marker of neuronal activation, following retinal illumination during the projected night- time (Romijn et al. 1996, Castel et al. 1997, Aïoun et al. 1998). Expression of VIP mRNA in the rat SCN varies over the light–dark cycle, but not in constant lighting Figure 3 Some intra- and extra-SCN connections of VIP-containing conditions (Zoeller et al. 1992). Similarly, levels of VIP-ir neurones in the rodent SCN. VIP terminals are found on many cell in the adult rat SCN do not show circadian variation, but types including those that synthesise AVP and SS and there is evidence of reciprocal connections among many SCN neurones. are altered by photic stimulation (Shinohara et al. 1993). The subparaventricular zone (sPVNz) and paraventricular nuclei of This suggests that VIP synthesis and/or release in the the thalamus (PVT) are among the many targets of SCN efferents rodent SCN is not under strong circadian control and is including those arising from GRP neurones. The core and shell of instead driven by variations in environmental lighting the SCN are depicted as stippled and unstippled areas levels (although the possibility of circadian-regulated low respectively. amplitude rhythms of VIP synthesis cannot be discounted). Functional studies of VIP in the rodent SCN have indicated a possible role for VIP and VPAC2 signalling in Radioligand studies have demonstrated an abundance of photic entrainment. In rat brain slices, exogenous VIP [125I]VIP-binding sites in the rodent SCN (Robinson & alters the extracellularly recorded firing rate of spon- Fuchs 1993), while in situ hybridisation investigations have taneously active SCN neurones, with suppression of shown that mRNA for VPAC2 and, to a lesser extent, activity being the predominant response (Reed et al. PAC1 mRNA are present in the rodent SCN (Usdin et al. 2002). The selective VPAC2 receptor , Ro 25– 1994, Sheward et al. 1995, Cagampang et al. 1998b,c). By 1553, mimics these suppressive actions of VIP. Consistent contrast, VPAC1 mRNA has not been detected in the with these agonist studies, suppressions to VIP were rodent SCN (Usdin et al. 1994). The heavy expression blocked by the VPAC2 , PG 99–465. of VPAC2 mRNA and intense immunostaining of VIP VIP activates a smaller proportion of rat SCN neurones in SCN neurones suggests that VIP acting through the and the selective PAC1 receptor agonist, maxadilan, VPAC2 receptor may play an important role in circadian mimics these excitatory actions of VIP. By contrast, rhythm processes. equimolar application of the VPAC1 receptor agonist The VIP-ir neurones in the rat SCN have extensive [K15,R16,L27]VIP(1–7)GRF(8–27) has no effect on intra- and inter-SCN projections. Among the intra-SCN SCN neuronal activity; a result consistent with the targets of VIP cells are the AVP-ir and SS-ir neurones in apparent absence of VPAC1 mRNA in the rat SCN. An the shell region, as well as VIP-ir neurones and GRP-ir important observation from these acute neurophysiological neurones in the core (van den Pol & Gorcs 1986, Daikoku studies was that a significantly greater proportion of rat et al. 1992, Romijn et al. 1997). The observation that SCN neurones responded to VIP when tested during the

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Downloaded from Bioscientifica.com at 09/24/2021 07:11:40PM via free access VIP and the circadian clock · H D PIGGINS and D J CUTLER 11 projected night phase as compared with the projected resembles that of light pulses on hamster wheel run- day phase, suggesting that the actions of VIP on the ning, suggesting that VIP participates in photic resetting. SCN circadian clock may be more prevalent during the Moreover, application of VIP during the late projected projected night. night increases the expression of the core clock genes, rper1 A very useful model for determining the phase of adult and rper2, in the rat SCN in vitro (Nielsen et al. 2002) SCN brain slices in vitro is to monitor the spontaneous indicating that VIP can invoke the molecular machinery electrical activity of SCN neurones across the projected necessary to phase-reset the circadian clock. day and night. Early studies demonstrated that rat SCN The notion that VIP acting through the VPAC2 neuronal activity peaks during the middle of the projected receptor is important in photic entrainment is supported day phase (around time (ZT) 6–7, where by a recent study in which mice were transgenically ff ZT0=lights on and ZT12=lights o ) and declined to manipulated to overexpress the VPAC2 receptor gene. In reach a nadir during the middle of the projected night comparison with control wild-types, these mutant mice phase (around ZT18–19) (Green & Gillette 1982, Groos show a shortened circadian period when maintained & Hendriks 1982, Shibata et al. 1982). The timing of the in constant dim red light and an increased rate of peak in this firing-rate rhythm can be reset in a phase- re-entrainment when the light–dark cycle is reset (Shen dependent and predictable direction by exogenous appli- et al. 2000). Moreover, Watanabe et al. (2000) demon- cation of neurochemicals associated with the RHT such as strated that exogenous VIP reset the secretion of AVP from glutamate and PACAP (Ding et al. 1994, Chen et al. 1999) organotypic SCN cultures with a temporal pattern of and the GHT such as NPY (Biello et al. 1997). Using this sensitivity resembling that of a photic phase-response model, application of VIP (at a concentration shown to be curve. These results suggest that VIP and the activation of ff e ective in altering rat SCN activity – see above) phase- the VPAC2 receptor are important in resetting to light. advances the firing-rate rhythm when applied during the late projected night, but has little effect when given during the middle of the projected day phase (Reed VIP and VPAC2 receptor activation in et al. 2001). Application of VIP during the early projected maintenance of circadian clock phase night causes small phase delays. The phase-advancing actions of VIP are dose-dependent and are mimicked by The idea that the VIP–VPAC2 signalling system may equimolar doses of the VPAC2 receptor agonist Ro be necessary for maintaining the rhythmic function of 25–1553, but neither the VPAC1 receptor agonist the SCN is supported by studies on mice in which [K15,R16,L27]VIP(1–7)GRF(8–27) nor PACAP alter the the expression of the VPAC2 receptor gene has timing in the peak of the rat SCN neuronal firing-rate been genetically altered (Harmar et al. 2002). In these rhythm. These long-term neurophysiological investiga- Vipr2/ mice, a LacZ-Neor cassette was inserted in the tions show that VIP acting presumably through the start site of the VPAC2 receptor gene (Vipr2) VPAC2 receptor can reset the rat SCN neuronal activity such that this gene is not expressed, as indicated by the rhythm during the projected night in a manner resembling absence of Ro 25–1553 binding. Under light–dark con- the actions of light pulses on nocturnal rodent behavioural ditions, Vipr2/ mice show apparent normal entrain- rhythms. This night-time phase of sensitivity is coincident ment of locomotor rhythms, with pronounced bouts of with the phase when a greater proportion of rat SCN wheel running coincident with lights off. When the neurones are responsive to VIP, indicating circadian gating light–dark cycle was shifted by 8 h, Vipr2/ mice in the SCN clock to the actions of VIP. The precise re-entrain almost immediately and more quickly than mechanism(s) underpinning this altered sensitivity is wild-type mice. Unexpectedly, these mice fail to exhibit unknown, but may be related to temporal variation in the robust behavioural rhythms when released into constant expression of the VPAC2 receptor (Cagampang et al. dim red light conditions. The core clock genes (mper1, 1998c) and/or coupling of this receptor complex to second mper2, mcry1 and bmal1) and the clock-controlled AVP messenger systems that influence clock gene expression at gene are expressed at significantly lower levels in the this phase of the circadian cycle (Cagampang et al. 1998a). Vipr2/ mouse SCN compared with wild-type mouse These in vitro studies are remarkably consistent with an SCN, and the pattern of expression of these genes does not earlier in vivo investigation of the influence of VIP on the vary significantly over the circadian cycle. This study hamster SCN circadian clock. The hamster shows a robust suggests that the SCN circadian clock function is severely in this measure of locomotor activity and impaired in Vipr2/ mice. the circadian clock regulates the onset of this rhythm. In recent in vivo and in vitro investigations, we have Microinjection of VIP alone or in combination with confirmed the findings of Harmar et al. (2002). Under other endogenous neuropeptides into the SCN region of light–dark conditions, Vipr2/ and wild-type mice hamsters free-running in constant dark or constant light show apparent entrainment of locomotor activity to lights was found to reset the clock during the projected night- off. However, when maintained in constant darkness, time (Piggins et al. 1995). This pattern of resetting Vipr2/ mice are behaviourally arrhythmic, while www.endocrinology.org Journal of Endocrinology (2003) 177, 7–15

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Figure 4 Spontaneous SCN firing rate activity in wild-type (C57BL/6J or 129/Ola) and Vipr2/ mice across the projected lights-on phase in vitro. In each scatterplot, the firing of individual SCN neurone is shown by open diamonds, while fitted smoothing function of the sampled population firing rate is shown by solid symbols. Note the absence of cells with high firing rates (>4 Hz) and a prominent peak in Vipr2/ SCN neuronal activity compared with that of wild-type SCN cells.

C57BL/6J and Ola/129 wild-type mice display robust the paucity of responses to Ro 25–1553, indicate that wheel-running activity rhythms with endogenous periods residual responses to VIP are mediated through receptors (taus) of 23·8 h and 23·7 h respectively (Cutler et al. 2003). other than VPAC2. The identity of such receptors is Verification of the absence of functional VPAC2 receptors unknown but they are likely to be isoforms of the PAC1 / in Vipr2 mice came from the observation in vitro that receptor, as opposed to the VPAC1 receptor which has not a significantly lower proportion of SCN neurones from been detected in the rodent SCN. It is noteworthy that / Vipr2 mice respond to VIP, compared with wild- while these non-VPAC2 receptors mediate some cellular type SCN neurones. Moreover, 60% of wild-type SCN actions of VIP within the SCN, their activation by VIP is neurones maintained in vitro respond to the selective insufficient to sustain overt circadian clock function. These VPAC receptor agonist, Ro 25–1553, compared with studies reveal that the absence of behavioural and molecu- 2 only 4% of SCN neurones from Vipr2/ mice. The lar rhythms also manifests at the level of neuronal activity, proportion of SCN neurones responding to other results that show remarkable consistency in the circadian G-protein-coupled receptor (AVP and GRP) was phenotype of these mice. similar in Vipr2/ and wild-type mice, indicating that inactivation of the Vipr2 gene does not appear to impact generally on neuropeptide receptor function in the murine Summary and model SCN. Remarkably, when the firing-rate rhythm of SCN slices in vitro were assessed, we found that SCN neuronal Thus, unexpectedly, these studies show novel, unique activity in Vipr2/ mice is very low and does not show functions for an intrinsic neurochemical in SCN circadian pronounced circadian variation (Fig. 4). In contrast, wild- time-keeping processes. Neurophysiological studies in rat type mice show significant circadian variation in SCN SCN brain slices in vitro established that VIP alters SCN electrical activity, with a readily discernible peak in the neuronal activity via the VPAC2 receptor and that more firing-rate rhythm detected during the middle of the SCN cells respond to VIP during the projected night subjective day (ZT 6·5–7·5) (Fig. 4). The peak to peak phase. During the late night phase, VIP and the VPAC2 interval between the peak on day 1 in vitro and day 2 receptor agonist Ro 25–1553 phase-advance the SCN in vitro was 23·9 h in C57BL/6J mice and 23·8 h in circadian clock. Similarly, microinjection of VIP into the 129/Ola mice (Cutler et al. 2003). Thus, firing-rate SCN region during the late subjective night phase-shifts rhythm, the most proximal of physiological measures of hamster wheel-running rhythms. Overexpression of the SCN clock function, strongly resembles the circadian VPAC2 receptor in mice shortens tau and accelerates behavioural phenotype of mutant and wild-type mice. re-entrainment to the light–dark cycle. In the absence of The reduced cellular responsiveness to VIP, coupled with functional VPAC2 receptors, the mouse circadian clock

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Downloaded from Bioscientifica.com at 09/24/2021 07:11:40PM via free access VIP and the circadian clock · H D PIGGINS and D J CUTLER 13 appears to stop such that there is no circadian rhythm in be part of the SCN output signal, determining how they core clock gene expression, cellular activity or wheel- alter activity in brain areas that regulate the neuroendo- running behaviour. crine axis will also be essential to elucidate the nature of The notion that VIP, an intrinsic SCN neurochemical, SCN control of neurohormonal rhythms. plays key roles in circadian clock processes is not without precedence. We have shown previously that GRP, an intrinsic neurochemical of the core SCN, potently alters Acknowledgements rodent SCN electrical activity, phase-shifts rat and hamster SCN neuronal rhythms, and phase-resets hamster wheel- We are indebted to our collaborators Professors A J running rhythms in a pattern like light (Piggins & Rusak Harmar andCWCoenandtothecontributions from our 1993, Piggins et al. 1994, 1995, McArthur et al. 2000). colleagues H E Reed, M Haraura, J Brown and T Brown. These resetting effects of GRP appear to be mediated The authors are supported by project grants from the BBSRC. We also thank Professor Robberecht for by the type 2 (BB2) receptor. BB2 receptor mRNA is heavily expressed in the rodent SCN (Battey & supplying selective VIP receptor compounds. Wada 1991) and antagonists to this receptor block these actions of GRP on the SCN clock. Like VIP-ir neurones, References rat GRP-containing neurones are directly contacted by retinal efferents (Tanaka et al. 1997) and some GRP-ir Aida R, Moriya T, Araki M, Akiyama M, Wada K, Wada E & cells express cFos in response to a nocturnal light pulse Shibata S 2002 Gastrin-releasing peptide mediates photic (Aïoun et al. 1998). Further, night-time GRP microinjec- entrainable signals to dorsal subsets of via tion induces mper1 expression, particularly in the dorsal induction of period gene in mice. Molecular Pharmacology 61 26–34. SCN. However, unlike Vipr2/ mice, genetically Aïoun J, Chambille I, PeytevinJ&Martinet L 1998 containing gastrin-releasing peptide and vasoactive intestinal deleting the BB2 receptor in the SCN does not dramati- polypeptide are involved in the reception of the photic signal in the cally alter murine circadian activity, but does diminish the suprachiasmatic nucleus of the Syrian hamster: an immunohisto- magnitude of phase-shifts to light pulses (Aida et al. 2002). chemical ultrastructural study. Cell and Research 291 These findings suggest that both VIP and GRP neurones 239–253. are important in photic entrainment, but that activation Ajpru S, McArthur AJ, Piggins HD & Sugden D 2002 Identification of PAC1 receptor isoform mRNAs by real-time PCR in rat of VPAC2 receptors is critical to the maintenance of suprachiasmatic nucleus. Molecular Brain Research 105 29–37. circadian phase. The co-localisation of these peptides with Albrecht U 2002 Regulation of mammalian circadian clock genes. GABA in SCN neurones indicates possible modulatory Journal of Applied Physiology 92 1348–1355. interactions between these intrinsic neurochemicals BatteyJ&WadaE1991 Two distinct receptor subtypes for mammalian bombesin-like peptides. Trends in Neuroscience 14 (Gillespie et al. 1996). 524–528. Conceptually, the VIP- and GRP-containing neurones van der Beek EM, Horvath TL, Wiegant VM, van den Hurk & Buijs appear to interface between photic inputs and central RM 1997 Evidence for a direct neuronal pathway from the clock activity. These VIP and GRP neurones receive suprachiasmatic nucleus to the gonadotrophin-releasing hormone direct retinal innervation and levels of these peptides in the system: combined tracing and light and electron microscopic immunocytochemical studies. Journal of Comparative Neurology 384 SCN appear to be dependent on the photic environment: 569–579. neither VIP mRNA nor GRP mRNA in the SCN appear Biello SM, Golombek DA & Harrington ME 1997 Neuropeptide Y to cycle with a circadian rhythm in animals maintained in and glutamate block each other’s phase shifts in the suprachiasmatic constant photic conditions. These neurones are activated nucleus in vitro. Neuroscience 77 1049–1058. Buijs RM, WortelJ&HouY-X1995Colocalization of -amino acid by RHT input and release VIP/GRP into the shell and with vasopressin, vasoactive intestinal peptide, and somatostatin. core SCN where their targets include AVP and VIP/GRP Journal of Comparative Neurology 358 343–352. neurones respectively. VIP or a VIP-like peptide is Cagampang FRA, Antoni FA, Smith SM, Piggins HD & Coen CW 1998a Circadian changes of type II mRNA in the secreted to stimulate VPAC2 receptors and this is involved in the maintenance of circadian phase. rat suprachiasmatic nuclei. Brain Research 810 279–282. Cagampang FRA, Piggins HD, Sheward WJ, Harmar AJ & Coen Collectively, the above studies indicate that neuro- CW 1998b Circadian changes in PACAP type 1 (PAC1) receptor chemicals synthesised by SCN neurones may play a role in mRNA in the rat suprachiasmatic and supraoptic nuclei. Brain both the maintenance of circadian phase in constant Research 813 218–222. conditions as well as mediating the resetting actions Cagampang FRA, Sheward AJ, Harmar AJ, Piggins HD & Coen CW 1998c Circadian changes in the expression of vasoactive intestinal of some environmental . Further studies are peptide 2 receptor mRNA in the rat suprachiasmatic nuclei. required to determine the intracellular pathways linking Molecular Brain Research 54 108–112. activation of receptors of GRP or VIP to the regulation CastelM&Morris JF 2000 Morphological heterogeneity of the of core clock genes, as well as determining which popu- GABAergic network in the suprachiasmatic nucleus, the brain’s lation of SCN neurones represents the necessary targets circadian pacemaker. Journal of Anatomy 196 1–13. Castel M, Belenky M, Cohen S, Ottersen OP & Storm-Mathisen J to mediate the phase-shifting actions of these intrinsic 1993 Glutamate-like immunoreactivity in retinal terminals of mouse neuropeptides. Moreover, as both peptides are thought to suprachiasmatic nucleus. European Journal of Neuroscience 5 368–381. www.endocrinology.org Journal of Endocrinology (2003) 177, 7–15

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