Interactions of the Serotonergic and Circadian Systems in Health and Disease

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Chapter I

Marc Cuesta,1, 2 and Etienne Challet3 1Centre for Study and Treatment of Circadian Rhythms, 2Laboratory of Molecular Chronobiology, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada 3Department Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, University of Strasbourg, Strasbourg, France

Abstract

The serotonergic and circadian systems constitute two of the main regulatory signaling networks of the brain. Each of them consists of a highly localized neuronal population that exerts a widespread influence

 Corresponding author: Marc Cuesta, Ph.D. Centre for Study and Treatment of Circadian Rhythms and Laboratory of Molecular Chronobiology Douglas Mental Health University Institute; Department of Psychiatry, McGill University; 6875 LaSalle Boulevard; Montreal (Quebec) H4H 1R3 CANADA; Phone: (514) 761-6131 ext. 2395; Fax: (514) 888-4099; [email protected]. 2 Marc Cuesta and Etienne Challet

on multiple cognitive, behavioral, physiological and molecular functions. Anatomically, these two systems are tightly interconnected and influence each other. In mammals, the circadian system is composed of a central circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus and peripheral oscillators found in the brain and throughout the body, which are subordinate to the SCN. This circadian organization allows the rhythmic regulation of various physiological functions in a harmonious fashion, including the circadian regulation of serotonin (5-hydroxytryptamine or 5-HT) synthesis and release. The serotonergic system comprises several interconnected nuclei, located in the brainstem, and through its neuronal projections that mainly release 5- HT, regulates numerous functions, such as sleep and wake states, pain, thermoregulation and circadian rhythms. In this chapter, we first define the circadian system and its serotonergic component, as well as the rhythmic regulation of the serotonergic system. Then, we review the serotonergic modulation of the circadian system, including its direct effects as a non-photic factor and its ability to modulate the photic synchronization of the central clock. In the last part, we analyze the potential relationships of the serotonin-circadian interaction with mood disorders.

The Circadian Timing System

From the Earth’s Rotation to Biological Rhythms

Every day, living organisms undergo rhythmic variations of a multitude of biological parameters, such as gene and protein production, physiological functions, behaviors and cognitive processes. These daily variations clearly follow the 24-h light-dark (LD) cycle due to Earth’s rotation. In 1729, the French astronomer de Mairan demonstrated that rhythmic variations are not passive responses to the changing outside world. Indeed, he was the first to report that the daily leaf movements of the sensitive plant (Mimosa pudica) persist in constant darkness (DD), proving their endogenous origin [1].This kind of intrinsic oscillations, ubiquitous in plants and animals, allows species to anticipate environmental rhythmic variations in a coordinated fashion, and is driven by the circadian system (from the Latin circa and dies, meaning “about”and “one day”, respectively). This system is composed of clocks, found in brain and non-brain tissues. Circadian clocks have been identified in most living organisms from cyanobacteria to humans and fulfill the following properties: they have the ability to generate endogenous rhythms under Interactions of the Serotonergic and Circadian Systems ... 3 constant conditions and to convey them to other structures; they are synchronized or entrained by external and internal cues (called zeitgeber or ZT from the German, meaning “time-giver”), the most potent being the light-dark cycle; they are temperature compensated (i.e. the rhythmicity remains constant even if temperature increases or decreases across a physiological range) [2].

The Central Circadian Clock and its Ability to Generate Rhythmicity

In mammals, the main actor of the circadian system is the central or “master” circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. This paired structure, containing around 10,000 neurons per nucleus, comprises a ventral “core” region and a dorsal “shell” region [3]. In most SCN neurons, neuropeptides (e.g. VIP in the core; AVP in the shell) are colocalized with GABA and sometimes with glutamate [3]. The neuroanatomy of the SCN and their neuropeptides composition vary considerably across species, as reviewed elsewhere [4]. The first demonstration of the fundamental role of the SCN as the central clock was provided by two independent studies in 1972. Indeed, a bilateral lesion of the SCN resulted in the loss of the cortisol secretion rhythm [5], as well as rest-activity and drinking behavior rhythms [6]. More than 20 years later, Ralph and collaborators [7] showed that a transplantation of fetal SCN was able to restore behavioral rhythmicity in hamsters bearing SCN lesion. This clearly indicates that the primary function of the SCN is to generate internal rhythmicity. Ten more years were necessary to decrypt the underlying molecular mechanisms responsible for the endogenous rhythmicity. In 2000, Shearman and collaborators [8] proposed a mammalian circadian molecular oscillator model (updated since then; see [2, 9]), based on studies using mostly transgenic mice for different genes, called clock genes. In this model, identical in nocturnal and diurnal species, the self-sustained rhythmicity is generated by positive and negative core clock components that form a feedback core loop with a period of about 24 h per cycle (Figure 1; see Table 1 for full names of the different clock components). Two PAS domain helix-loop-helix proteins, CLOCK and BMAL1 form the positive part of the loop. These transcription factors heterodimerize and then activate the transcription from genes containing an E-box (5’-CACGTG-3’) or an E’-box (5’-CACGTT-3’). Among those genes, three Per (1-2-3) and two Cry (1-2) genes constitute the negative 4 Marc Cuesta and Etienne Challet part of the loop. PER and CRY proteins heterodimerize and form a complex with CK1ε/δ that phosphorylates PER and CRY. This facilitates the complex translocation to the nucleus where its quantity increases, leading to the repression of the transcription of several genes by CLOCK/BMAL1, including Per and Cry. This repression is thought to be driven via the recruitment by PER/CRY of a PTB-associated splicing factor/SIN3-histone deacetylase complex (PSF/Sin3-HDAC complex), which deacetylates histones 3 and 4 [10].

Figure 1. Molecular model of the mammalian cell-autonomous oscillator within a SCN cell as described in the text. Genes are represented in italic and proteins in CAPITAL. Nomenclature for each actor is given in Table 1. Abbreviations: CCG, clock-controlled gene; P, phosphate; U, ubiquitin. Interactions of the Serotonergic and Circadian Systems ... 5

Table 1. Non-exhaustive list of the main core clock genes and associated genes mentioned in the text

Gene Alternatename Full name Clock Circadian locomotor output cycle kaput Npas2 Mop4 Neuronal PAS domain-containingprotein 2 Bmal1 Arntl; Mop3 Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 Per1 Period1 Periodcircadianproteinhomolog 1 Per2 Period2 Periodcircadianproteinhomolog 2 Per3 Period3 Periodcircadianproteinhomolog 3 Cry1 Cryptochrome 1 Cry2 Cryptochrome 2 Rev-erbα Nr1d1 Reverse viral erythroblastis oncogene product alpha Rev-erbβ Nr1d2 Reverse viral erythroblastis oncogene product beta Rorα Rora, Nr1f1 Retinoic acid-related orphan receptor alpha Rorβ Rorb, Nr1f2 Retinoic acid-related orphan receptor beta Rorγ Rorc, Nr1f3 Retinoic acid-related orphan receptor gamma Ck1δ Csnk1d Caseine kinase I delta Ck1ε Csnk1e Caseine kinase I epsilon Ampk AMP-activated protein kinase β-Trcp1 Btrc Beta-transducin repeat containing protein 1 Fbxl3 F-box and leucine-rich repeat protein 3 Fbxl21 F-box and leucine-rich repeat protein 21 Dec1 Bhlhe40 Differentiated embryo chondrocyte protein 1 Dec2 Bhlhe41 Differentiated embryo chondrocyte protein 2 Dbp D-box binding protein Tef Thyrotroph Embryonic Factor Hlf Hepatic leukemia factor E4bp4 E4 promoter-bindingprotein 4 Avp Adh Arginine vasopressin Timeless Tim Timeless Prokr2 Prokineticin 2

Following this step, PER and CRY are targeted by CK1ε/δ and AMPK, respectively. This leads to their polyubiquitylation by β-TRCP1 and FBXL3 or 6 Marc Cuesta and Etienne Challet

FBXL21, respectively, which are proteins constituting an ubiquitin protein ligase complex, named SKP1-cullin-F-box (SCF). Ultimately, PER and CRY are degraded by the 26S proteasome. Other secondary loops, interconnected with the core loop, allow fine-tune regulations of the circadian clock, by multiple layers of control [2, 11]. For instance, the positive CLOCK/BMAL1 complex also regulates its own production via an activation of the transcription of nuclear orphan receptors genes through E-box located on their promoter (Figure 1). The protein products of these genes, namely REV-ERBα/β and RORα/β/γ, inhibit and activate Bmal1 transcription, respectively, by a competitive binding on ROR- specific response elements (RORE) located on Bmal1 promoter. It appears that the different REV-ERB and ROR proteins are not essential to generate the circadian rhythmicity in the SCN [12]. These proteins would also have a stabilizing role, by maintaining high amplitudes oscillations of clock genes, allowing a better response to synchronizing factors. Several other molecules have been identified as playing a role in the regulation of the circadian clock. For instance, the transcription factors DEC1 and DEC2 are able to reduce E- box mediated transcription in the SCN [13]. Other elements of the proline and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factor family (e.g. DBP, TEF, HLF and E4BP4; Table 1) act through a D-box, present on some genes, to form a second accessory feedback loop [2]. Other genes, called clock-controlled genes (ccgs), are not part of any of the different loops but are regulated by them [14]. For instance, some of these genes are directly under the rhythmic control of CLOCK/BMAL1 via E-boxes, such as Avp gene in the SCN [15]. The ccgs are considered as the molecular output of the circadian clock. In other words, they are the link between the basic molecular clock machinery and a multitude of cellular and physiological functions.

The Circadian System as a Hierarchical Interconnected Multi-Oscillatory System

Until recently, the SCN were thought to be the one and only central clock, but we know now that many other brain regions (e.g. hypothalamic nuclei, forebrain) and non-neuronal tissues and cell types (e.g. liver, kidney, muscles, leukocytes) harbor autonomous clocks [16, 17]. These secondary clocks are named peripheral clocks as opposed to the central SCN clock. Virtually, every cell of the body contains circadian clocks (18). Both the SCN cells and Interactions of the Serotonergic and Circadian Systems ... 7 peripheral clock cells can independently self-sustain rhythmicity. However, in vitro, while the SCN neurons form a specialized network that can expresses synchronized rhythmsup to several weeks (i.e. pacemaker activity), the oscillations seen in peripheral clocks dampen out after few days due to desynchronization among the peripheral clock cells [19, 20]. This indicates that peripheral clocks need synchronizing stimuli to exhibit robust circadian gene expression at the level of the cellular population. Most of these synchronizing factors originate from the SCN, but feeding-fasting cycles and temperature variations can also directly entrain peripheral clocks [21, 22]. Despite the lack of robust oscillations observed in vitro, there are some peripheral clocks in various brain regions and tissues that can drive local physiological rhythms in the absence of SCN. Two structures have been well characterized, namely the retina [23] and the olfactory bulb [24]. In addition, evidence seems to indicate that the adrenal gland is able to regulate rhythmic parameters, such as steroidogenic acute regulatory protein (StAR) expression, a rate-limiting gene in the regulation of steroidogenesis [25]. Moreover, two SCN-independent oscillators (i.e. food-entrainable oscillator and methamphetamine-sensitive circadian oscillator) can drive circadian behavioral and hormonal rhythms even in SCN-lesioned animals or absence of core clock genes [26-32]. All these major developments in the last decade have started to change the original concept that was shared by chronobiologists for years. The current view of the circadian organization in mammals is that overt rhythms are controlled by a hierarchical system of circadian clocks in the brain and periphery that are subordinate to the central clock in the SCN [33]. This suggests that a system of multiple coupled oscillators is necessary to fine-tune the circadian control of physiology and behavior, including integration of sensory information, metabolic state, social cues, and emotional state. To do so, the SCN convey synchronizing stimuli to the peripheral clocks through a variety of neural and humoral signals. In the central nervous system, the SCN neural projections are very limited and mostly restricted to hypothalamic nuclei (Figure 2A). These nuclei are themselves connected to other brain structures allowing a rhythmic control of peripheral brain clocks. In addition, two neuronal pathways are of particular importance to convey information outside of the brain to peripheral tissues. The first neural pathway connects the SCN to the sympathetic nervous system via the paraventricular nucleus of the hypothalamus (PVN) and the intermediolateral column (IML) to many peripheral organs (Figure 2B). For instance, sympathetic projections 8 Marc Cuesta and Etienne Challet from the IML innervate the adrenal gland, allowing a rhythmic control in its sensitivity to adrenocorticotropic hormone or ACTH [34, 35].

Figure 2. A. Efferent neural projections from the SCN to different brains regions. Abbreviations: AMY, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; DMH, dorsomedial nucleus of the hypothalamus; HB, habenula; IGL, intergeniculate leaflet; LS, lateral septum; POA, preoptic area; PVN, paraventricular nucleus of the hypothalamus; PVT, paraventricular nucleus of the thalamus; SCN, suprachiasmatic nuclei; sPVZ, subparaventricular zone; VMH, ventromedial nucleus of the hypothalamus. B. Efferent neural projections from the SCN to one peripheral clock (i.e. adrenal gland), and humoral signals controlled by the SCN. Two outputs (numerated 1 and 2) are represented that link the central clock to the adrenal clock regulating the release of glucocorticoid hormones. A 3rd output (numerated 3) is represented and links the central clock to the pineal gland regulating the release of melatonin hormone. Neuropeptides and hormones are indicated in italic. Abbreviations: ACTH,adrenocorticotropic hormone; AVP, arginine vasopressine; CRH, corticotropin-releasing hormone; IML; intermediolateral columns; Pin, pineal gland; Pit, pituitary gland; SCG, superior cervical ganglion. Interactions of the Serotonergic and Circadian Systems ... 9

The synthesis of melatonin, a major circadian endocrine factor, is also under the rhythmic control of sympathetic projections. Indeed, from the IML, these projections reach the superior cervical ganglia (SCG), themselves connected to the pineal gland (Figure 2B). Through this pathway, the SCN exert a rhythmic control of the rate-limiting enzyme arylalkylamine N- acetyltransferase (AA-NAT), implicated in melatonin synthesis [36, 37]. The second neural pathway connects the SCN to the parasympathetic nervous system via the PVN and the dorsal motor nucleus of the vagus (DMV) that allows a rhythmic control of a wide range of peripheral tissues functions, such as found in white adipose tissue and liver (for references, see [38, 39]). As we already mentioned, humoral factors represent another link connecting central and peripheral clocks with each other. For instance, the robust rhythm of melatonin is known to facilitate sleep specifically in humans, up-regulate immune parameters and control seasonal functions, such as reproduction [40, 41]. In addition, the synthesis and secretion of glucocorticoids (GCs), another class of hormones, is regulated by the central clock through the hypothalamic-pituitary-adrenal (HPA) axis [25, 42] and thus exhibit a robust circadian rhythm (Figure 2B). This rhythm of GCs (i.e. corticosterone in rats and mice; cortisol in humans) then regulates the synchronization of many peripheral clocks at both molecular and behavioral levels [41, 42]. In peripheral clocks, the circadian rhythmicity relies on the same molecular mechanisms as those found in the SCN clock, although several differences have been identified [43, 44]. For instance, in some brain regions (e.g. striatum, hippocampus), CLOCK is not present and is substituted by one of its analogue, namely NPAS2 (see Table 1). In the liver, both CLOCK and NPAS2 are expressed, but NPAS2 cannot maintain circadian oscillation when CLOCK is missing. RORγ is only expressed in peripheral tissues and would exert the same role than RORα/β. Of note, knowledge of clock gene expression in humans is hampered by the limited possibilities of sampling. Studies must rely on cells that can be easily sampled, or ultimately on post- mortem tissues. Since it is difficult to analyze clock gene expression in the human central clock, several peripheral clocks have been studied instead, such as those present in skin [45], adipose tissue [46, 47], oral mucosa [45], bone marrow [46], colon cells [48, 49], hair follicles [50], and peripheral blood mononuclear cells [51-58]. The results found are relatively similar to those obtained in rodents. In all tissues studied to date, 5 to 10% of the transcriptome displays circadian rhythms, but the subset of rhythmic transcripts is almost entirely 10 Marc Cuesta and Etienne Challet distinct among tissues [14]. This means that the ccgs are not the same in the different clocks found in the SCN and in the different peripheral tissues, implying that the role of these clocks is distinct, and must reflect each structure’s particular functions.

Synchronization of the Central Clock by the Photic Factor

As a relay between the external environment and the internal functions of the body, the SCN regulate the organism’s internal cyclic timing. By this mechanism named “synchronization”, the body can adapt to changes in the environment and thus be in phase with the external world. Among these factors, the 24 h light/dark cycle is the most potent environmental synchronizer of the central clock, but variations in temperature or food availability, for instance, can also affect it [21, 59, 60]. In addition, internal signals, mediating physiological information, can also reach the central clock, which integrates them in conjunction with light cues. These so-called non- photic factors are conveyed in part via serotonergic pathways and will be reviewed later in this chapter. To reach the SCN, the solar light signal or photic factor is mainly detected by the photopigment melanopsin [61], located in a subset of ganglion cells (Figure 3). These melanopsin cells represent 1% to 2.5% of the total number of retinal ganglion cells [61, 62] and project directly to the ventral part of the SCN via the retinohypothalamic tract (RHT) (Figure 3), releasing glutamate and pituitary adenylate cyclase activating peptide (PACAP) [63-65]. In addition, melanopsin cells project to the intergeniculate leaflet (IGL) that is a thalamic structure implicated in the integration of photic and non-photic signals [66-68]. From the IGL, neural projections innervate the ventral part of the SCN through the geniculohypothalamic tract (GHT) (Figure 3) that releases GABA and neuropeptide Y (NPY) [66-68]. From the retina, photic information allows a daily resetting of the central clock. The phase of the SCN can be delayed or advanced up to 2 h per day in most mammalian species, according to the time of day when the retina receives light [69, 70]. By applying discrete light pulses at different time points in animals housed in constant darkness (DD), a phase response curve to light can be defined. Of note, in DD, the period of time when nocturnal animals are awake is considered as the “subjective” night, while it is named “subjective” day when they are asleep. Interactions of the Serotonergic and Circadian Systems ... 11

Figure 3. Main afferent neural projections to the SCN. Grey arrows represent projections that convey photic cues to the SCN, black arrows represent projections that convey non photic cues to the SCN, and the black/grey arrow represent projections that convey photic and/or non-photic cues to the SCN. Neuropeptides and neurotransmitters are indicated in italic. Abbreviations:5-HT, serotonin; DRN, dorsal raphe nucleus; IGL, intergeniculate leaflet; GABA: gamma-aminobutyric acid; GHT, geniculohypothalamic tract; GLU, glutamate; MRN, median raphe nucleus; NPY, neuropeptide Y; PACAP, pituitary adenylatecyclase-activating peptide; RHT, retinohypothalamic tract; SCN, suprachiasmatic nuclei.

The phase response curve to light expresses the magnitude of the phase shift of a central clock marker, such as locomotor activity, as a function of the time of light exposure (Figure 4). In both nocturnal and diurnal species, the phase response curve to light displays a similar pattern with light-induced phase delays or advances occurring mainly during the subjective night (i.e. active and resting period in nocturnal and diurnal species, respectively) [69-72]. This mechanism, for instance, allows the organism to adapt to jetlag: when our body is exposed to a new LD cycle, advanced (i.e westbound travels) or delayed (i.e. eastbound travels) by few hours, the SCN rapidly integrate the timing of the new LD cycle. Then the SCN relay this information, leading to the synchronization of the different rhythmic parameters to the new LD cycle. However, the rate of synchronization differs between the various rhythmic parameters [73], leading to a transient misalignment of the different parts of the circadian system. 12 Marc Cuesta and Etienne Challet

Figure 4. Schematic representation of phase shifts of locomotor activity in response to light pulses in nocturnal rodents and phase response curve to light. At the top of the figure are represented 3 schematic actograms representing the locomotor activity of a nocturnal mouse (A., B. and C). Each row corresponds to 24 h, and 12 days are represented. Animals are kept in constant darkness, as reported by the black and gray bars at the top of each actogram, indicating the subjective night and day, respectively. Hence, mice express their endogenous period (smaller than 24h), explaining why each day, the locomotor activity occurs earlier than the previous day. By convention, in nocturnal species kept in constant darkness, the beginning of the period of activity corresponds to the circadian time 12 or CT12. On the 6th day of recording, a light pulse, represented on the actograms by a grey arrow, is applied at CT6 (A.), CT12 (B.) and CT18 (C.), inducing no effect, a phase delay and a phase advance of the locomotor activity, respectively. The magnitude of the phase shifts is assessed by performing 2 regressions that fit to the onset of activity, represented by gray lines. The first and second regressions are calculated using several days before and after the light pulse, respectively. The phase difference, obtained on the day following the light pulse, gives the value of the phase shift, which is reported on the phase response curve to light, schematized at the bottom of the figure by a gray curve. Each discreet pulse of light, given at a specific time, induces a phase shift with a specific magnitude, and the phase response curve to light represents the integration of all these effects reported on a 24h scale, as represented by the black and gray bars on the x-axis. They are 3 type of response to a light pulse, depending on when it is applied. During the middle of the subjective day (dashed box A), including CT6, no phase shifts are observed. From the end of the subjective day to the middle of the subjective night (dashed box B), including CT12, phase delays are observed. From the middle of the subjective night to the beginning of the subjective day (dashed boxes C), including CT18, phase advances are observed. Abbreviations: CT, circadian time; subj. night, subjective night; subj. day, subjective day. Interactions of the Serotonergic and Circadian Systems ... 13

Retinal illumination leads to glutamate release by RHT terminals, activating N-methyl-D-aspartate (NMDA) receptors present in SCN cells [74]. The subsequent Ca2+ influx induces the synthesis of nitric oxide (NO) [75]. At the beginning of the night, NO activates ryanodine receptors, leading to Ca2+ release from the endoplasmic reticulum [76], while at the end of the night, NO activates guanylate cyclase that produces cGMP [76]. In addition, the cAMP pathway is activated throughout the night in response to photic cues [77]. Together, these 3 pathways induce the phosphorylation of cAMP response element binding (CREB) protein via the activation of the protein kinase A and extracellular signals regulated kinase [78-80]. P-CREB can then translocate to the nucleus and bind to cAMP response element (CRE) present on the promoter of target genes, such as Per1 and Per2 [79-81]. While Per1 transcription is quickly induced throughout the night in response to a light pulse, the induction of Per2 expression is fast at the beginning of the night and slow or even absent at the end of the night [72, 82-84]. In addition, spatial differences have been found. For instance, in response to light, Per1 is induced in the ventral SCN cells, whereas Per2 is expressed in the whole SCN [85, 86]. A causal role of Per1 and Per2 genes in the mediation of light-induced resetting of the central clock has been proposed based on alteration of Per1/2 transcription [87, 88] and studies in Per1/2 mutant mice [89]. In addition, other genes in the SCN are regulated in response to light, such as c-fos [90], Bmal1 [91], Cry2 [72, 92], Rev-erbα and Rorβ [93-95].

The Serotonergic Regulation of the Central Circadian Clock

The Serotonergic Component of the Circadian System

The serotonergic system comprises several nuclei that can be divided in 2 groups, posterior and anterior [96]. Among the anterior group, the median raphe nucleus (MRN) and the dorsal raphe nucleus (DRN) are of particular interest since they are connected with the central clock (Figure 3) [97]. The neural projections from the MRN to the SCN are direct, while the DRN send indirect projections to the SCN via the IGL. Moreover, the MRN and DRN are tightly interconnected [98]. Of note, few studies have described direct projections from the DRN to the SCN in rats and hamsters [99, 100], and retinal fibers connecting raphe nuclei were observed in rats and cats [101, 14 Marc Cuesta and Etienne Challet

102]. These pathways are thought to mediate, at least partially, non-photic information, as reviewed later in this chapter. Hence, the DRM, the MRN, and their input pathways to the SCN can be considered as part of the circadian system. While the raphe nuclei are the primary source of 5-HT in mammal brains, only 50% of the raphe cells that projects to the SCN release 5-HT at their terminals [99, 103, 104]. For instance, in Syrian hamsters, approximately 30% of MRN cells are immunoreactive for vesicular glutamate transporter 3 (VGLUT3) and could then release glutamate [104]. The serotonergic system is with no doubt the neurochemical system that expresses the highest number of 5-HT receptors subtypes. To date, 15 genes coding for those receptors have been described in mammal brains [105]. Among them, 7 different receptors subtypes have been observed in the SCN of the most common rodent species (i.e. rats, mice and hamsters) via immunohistochemistry or autoradiography (Table 2) [106-116]. Less than half of these 5-HT receptors subtypes were described in all 3 species (5-HT1A, 5- HT1B and 5-HT7). The 5-HT2A and 5-HT2Creceptors were only found in rats. To our knowledge, the presence of 5-HT5A receptors in mice was never studied. Importantly, most of these studies did not indicate the pre- or postsynaptic localization of these 5-HT receptors subtypes, as well as the type of neurons on which they are expressed. Of note, the activation of 5-HT3 receptors by different agonists was shown to affect the central clock in rats (see below), but to date, this receptor has only been described in the SCN of Syrian hamsters [116]. It is important to mention that the DRN, MRN and IGL also express 5-HT receptors, such as 5-HT1A (acting as auto-receptors) and 5- HT7 subtypes [108, 117, 118].

Table 2. Localization of 5-HT receptor subtypes in the rat, hamster and mouse SCN

Receptor Rat Hamster Mouse a b c 5-HT1A Yes Yes Yes d e f 5-HT1B Yes Yes Yes g 5-HT2A Yes ? ? g 5-HT2C Yes ? ? k 5-HT3 ? Yes ? h i 5-HT5A Yes Yes ? j a f 5-HT7 Yes Yes Yes ?=Unknown. References as follows: a) [106]; b) [107]; c) [108]; d) [109]; e) [110]; f) [111]; g) [112]; h) [113]; i) [114]; j) [115]; k) [116]. Interactions of the Serotonergic and Circadian Systems ... 15

Circadian Control of the Serotonergic System

Brain 5-HT is synthetized in two steps from the essential amino acid L- tryptophan (L-Trp). During the first step, tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of this synthesis pathway, allows L-Trp to be transformed into 5-hydroxyptryptophane (5-HTP) [119]. Then, 5-HTP is quickly decarboxylated into 5-HT by 5-HTP decarboxylase. Interestingly, TPH2 expression is under the control of the circadian system. Indeed, in the DRN and MRN of rats kept in DD, both Tph2 mRNA and TPH2 protein levels expressed a circadian rhythm with a peak at the end of the day and the middle of the night, respectively [120, 121]. In addition, a similar rhythm of TPH2 level was found in the SCN [122] and the IGL [120] with a peak occurring at the end of day. The authors mentioned that the delay observed in the TPH2 peak between these structures suggests that TPH2 is first express in the raphe nuclei and then is transported along the axons to reach terminals located in the SCN and IGL. Moreover, TPH2 enzymatic activity was shown to be rhythmic in rats, with a peak during the middle of the day [123], although this remains contradictory [124]. The underlying mechanisms controlling TPH2 rhythmic synthesis have started to be deciphered. Indeed, in adrenalectomized rats [125] or Syrian hamsters [126], TPH2 rhythm was abolished, but restored when animals received exogenous GCs (i.e. corticosterone in rats and cortisol/corticosterone in Syrian hamsters) in drinking water, mimicking the endogenous rhythm. More recently, it was shown that chronic administration of corticosterone in rats also abolishes Tph2 mRNA rhythm in the DRN [127]. Altogether, these data clearly indicate that the circadian rhythm of plasma GCs is responsible for the rhythm of TPH2. In addition, locomotor activity seems to be able to influence Tph2 expression [125]. Variations of 5-HT content in the whole brain are known for a long time [128] and present elevated values during daytime. More recently, 5-HT content in the SCN region was found to be rhythmic in both nocturnal [95, 129] and diurnal [130] rodents, with maximal values at night and day, respectively. In addition, microdialysis studies indicate a rhythmic release of 5-HT in the SCN of Syrian hamsters [131] and rats [122] with a peak occurring in early night. Similar results were found in the IGL of Syrian hamsters [132]. Interestingly, 5-HT release and content express maximal values few hours later than those of TPH2 levels, suggesting that 5-HT rhythmicity is under the control of TPH2 rhythm. In the mouse midbrain, the 5-HT transporter (5-HTT) that reuptakes extracellular 5-HT from the synaptic 16 Marc Cuesta and Etienne Challet cleft is also under the control of the central clock [133, 134] with higher levels observed at night for both 5-htt mRNA and 5-HTT protein. Hence, the subsequent 5-HT uptake expresses a circadian profile [134]. This circadian regulation is thought to be mediate through the rhythmic control of the activating transcription factor-4 (ATF4) that activates 5-htt transcription. The precise role of the 5-HT rhythmic release into the SCN and IGL is still poorly understood. In the SCN, this rhythm appears to be in phase opposition between nocturnal and diurnal species (i.e. high values during the active period for both behaviors), suggesting that one of its functions is to indicate to the central clock when an animal is awake and active. As it will be reviewed in the remaining part of this chapter, the serotonergic system exerts multiple other roles as a regulator of the circadian system, but most of them are related to sleep and wake behaviors, such as induced locomotor activity, arousal and sleep deprivation.

Serotonin and the Sleep-Wake Cycle

During the last decade, progress has been made in our understanding of the neural regulation of the human sleep-wake cycle. The current view is that sleep and wake behaviors are generated by complex interactions between endogenous circadian and sleep homeostatic processes, as well as direct effects of light and dark [135]. Interestingly, the sleep-wake cycle is also closely related to the activity of 5-HT neurons. For instance, the activity of 5- HT neurons in the DRN of cats is slow and regular during the wake period [136]. Then, when animals start their sleep period, this activity decreases and loses its rhythmicity, until complete disappearance during the onset of the first REM sleep episode. In addition, as we previously mentioned, 5-HT release in the SCN region occurs during the waking period of animals and is thus correlated to the electrical activity of 5-HT neurons. More recently, it was shown that an induced transient 5-HT deficiency resulted in a transient loss of circadian rhythmicity of locomotor activity and sleep-wake cycle [137]. Taken together, these results suggest that 5-HT (especially from the DRN) not only promotes wake and inhibit REM sleep [138], but also participates in the circadian regulation of sleep and wake behaviors [137]. This indicates that the sleep-wake cycle, the serotonergic system and the circadian central clock are tightly connected.

Interactions of the Serotonergic and Circadian Systems ... 17

Serotonin and Non-Photic Synchronization

In addition to light, many factors can influence the central clock at both molecular and behavioral levels. To study the influence of these non-photic factors, animals are usually kept in DD to prevent not only the synchronizing effect of light, but also its direct effect, called “masking”. Negative masking is a process that diminishes the expression of a circadian pattern [139]. For instance, in nocturnal animals, light exposure at night inhibits locomotor activity [140]. In opposition, positive masking allows a variable to be expressed in addition to its circadian pattern. In diurnal species, light exposure at night induces a bout of locomotor activity at a time when animals are supposed to sleep [141]. In this context, constant conditions such as DD, allow to “unmask” a given variable.

Figure 5. Phase response curve to non-photic factors in nocturnal species. Each discreet application of a non-photic factor, given at a specific time, induces a phase shift of the locomotor activity with a specific magnitude, and the phase response curve represents the integration of all these effects reported on a 24h scale, as represented by the black and gray bars on the x-axis. Phase advances are mainly observed during the subjective day. Abbreviations: CT, circadian time; subj. night, subjective night; subj. day, subjective day.

Examples of non-photic factors and their effects on both rest-activity rhythm and clock gene expression are summarized in Table 3. Hereafter, we will only focus on those that have been linked to the serotonergic system. In nocturnal species, these non-photic factors are mainly effective when applied during the middle of the subjective day. They induce a phase advance of 18 Marc Cuesta and Etienne Challet locomotor activity rhythm (Figure 5) and inhibit expression of clock genes (i.e. Pers). Some studies have reported little behavioral phase delays during the late subjective night, but usually they are barely detectable. In a way somewhat counter-intuitive, thecircadian molecular oscillator model and the photic synchronization are similar in phase according to the astronomical time (e.g. light-dark cycle) in diurnal animals compared to nocturnal ones. By contrast, the responses of the central clock to most non-photic factors are opposite in astronomical phase (but in phase according to the sleep/wake cycle), highlighting the fundamental role of the serotonergic system in the determination and/or the maintenance of diurnal or nocturnal behavior. More importantly, these differences must be taken into serious consideration in both normal and pathological conditions, since humans are genetically diurnal.

Table 3. Main behavioral and molecular effects of different photic and non-photic factors

Nocturnal rodents Diurnal rodents Type of Locomotor Per1/2 Locomotor Per1/2 Factor activity expression activity expression 1. Phase delays: 1. Phase delays: early night early night Increase Increase (wake) (sleep) Light early and late early and late 2. Phase 2. Phase night night advances: advances: late night late night (sleep) (wake) Phase Phase advances Transitory advances Decrease early night ? hyperactivity midday (sleep) (sleep) Phase Phase advances 5-HT advances Decrease No effect night (sleep) midday (sleep) Phase NPY advances Decrease ? ? midday (sleep) Phase Phase delays GABA advances Decrease Decrease Per2 midday (wake) midday (sleep)

Interactions of the Serotonergic and Circadian Systems ... 19

Transitory Hyperactivity and Sleep Deprivation In nocturnal species, a novel running wheel presented during the sleep period (i.e. subjective day) induces a transient hyperactivity that leads to a phase advance of the locomotor activity rhythm [142] and a transient decrease of Per1 and Per2 mRNA levels in the SCN (Table 3) [143, 144]. Hyperactivity seems to be an essential parameter in phase shift induction. Indeed, in immobilized or light runner animals, behavioral phase advances are very small or even undetectable. It has been suggested that the sleep deprivation caused by the hyperactivity could be responsible for these phase- shifts rather than the degree of activity itself [145]. In line with this argument, phase shifts are only observed during the subjective day, when animals are asleep, although there are discrepancies regarding the studied species. For instance, sleep deprivation is ineffective in shifting the SCN of mice [146] and only induces small phase advances in rats [147]. Interestingly, long bouts of activity (minimum of 3 h) are necessary to induce a significant phase shift. This indicates that the circadian system of nocturnal species has a high threshold for wake/activity behavior to alter the circadian system, especially in comparison to light that can induce phase shifts only after few minutes of exposure even at low intensity [70, 148]. This relatively low sensitivity is thought to prevent uncoordinated resetting of the circadian system in response to small amounts of activity (i.e. Zeitgeber noise) that are not necessarily abnormal outside the main active phase. Very few data on hyperactivity or sleep deprivation are available in diurnal species. In diurnal European ground squirrels confined in a running wheel every day at the end of their active period, a synchronization of the locomotor activity can be observed [149]. The authors suggested that this synchronization is the result of daily phase advances induced by hyperactivity. Hence, diurnal and nocturnal species would similarly react to this non-photic factor independently of the phase of the activity cycle. Another hypothesis suggests that this induced activity could lead to sleep deprivation, since it occurred at the far end of the subjective day for a 3 h period. Thus, this non- photic factor could rather act at early night to induce phase shifts, meaning that its action is dependent of the phase of the activity cycle. Data obtained with other non-photic factors in diurnal species [130] are in line with the latest hypothesis and will be discussed later in this chapter. In humans, however, sustained physical exercise performed at the beginning of the night induces small phase delays [150-152] rather than phase advances. Interestingly, at the cerebral level, hyperactivity was shown to induce an endogenous release of 5-HT from the MRN terminals to the SCN of Syrian 20 Marc Cuesta and Etienne Challet hamsters [131]. In addition, lesion of 5-HT fibers, using the 5,7- dihydroxytryptamine (5,7-DHT) neurotoxin, inhibits the behavioral phase advances normally induced by a novel running wheel access [153]. Although it is still unclear which aspect(s) of locomotor activity is(are) responsible for those effects, these results suggests that the serotonergic system acts as an important link between wake/activity behavior and the circadian system. Hence, serotonin can be considered as a crucial candidate to mediate the non- photic synchronization as it will be now detailed.

Serotonin, Serotonergic Agonists and Selective Serotonin Reuptake Inhibitors In nocturnal species, serotonergic influence on the synchronization of the central clock has been extensively studied, both in vitro and in vivo, using different methods of acute administration (systemic or local) and a wide range of agonists, such as serotonin itself, 8-hydroxy-2-di-n-propylaminotetralin (8- OH-DPAT), the most used 5-HT agonist, and fluoxetine, a selective serotonin reuptake inhibitor (SSRI) [95, 154-163]. When administered during the middle of the subjective day, these molecules induce phase-advances of the locomotor activity and transitory inhibition of Per1 and Per2 transcription in the SCN of mice, rats and Syrian hamsters. Interestingly, these effects are similar to those observed in response to transitory hyperactivity. Of note, in rats, it has been shown that mRNA levels of Rev-erbα and Rorβ are increased and decreased, respectively, in response to fluoxetine injection [95]. In addition, in vitro studies indicate that application of 8-OH-DPAT and fluoxetine on SCN slices during the subjective day induce phase advance of the SCN electrical activity [164, 165]. Moreover, by causing a state of serotonin-hypersensitivity (i.e. suppression of the endogenous serotonergic tone), it is possible to induce very large phase shifts in response to 5-HT agonists in vitro [165] and hyperactivity in vivo [166, 167]. Interestingly, in nocturnal species, recreational drugs, such as cocaine or 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), known to act on the serotonergic system by different mechanisms, can mimic [168] or alter [169] the non-photic synchronization of the central clock, respectively. To date, there is only one study that examined the serotonergic modulation on the central clock of Arvicanthisansorgei, also known as Sudanian grass rats [130], a diurnal rodent model [170]. Strikingly, the temporal window of circadian sensitivity of this rodent to (+)8-OH-DPAT (i.e. positive enantiomer of 8-OH-DPAT) and fluoxetine is opposed to that observed in nocturnal rodents. In other words, this agonist induces phase advances of the locomotor Interactions of the Serotonergic and Circadian Systems ... 21 activity essentially during the subjective night, meaning that such phase-shifts are dependent on the sleep-wake cycle. Indeed, for both nocturnal and diurnal rodents, phase advances are observed during their rest period. This result highlights one more time the pivotal role of the serotonergic system in the transmission of wake/activity information to the central clock. Surprisingly, systemic injections of (+)8-OH-DPAT and fluoxetine at subjective dawn and dusk failed to modify Per1 and Per2 mRNA expression in the SCN of Sudanian grass rats, as it was observed in nocturnal rodents. This suggests that other clock genes could be modified in response to acute serotonergic input in diurnal species, since Per1 and Per2 mRNA levels are relatively low at dawn and dusk. Another hypothesis suggests that Per1 and Per2 expression could be influenced on a different time scale in diurnal rodents. Indeed, a change in the expression of these genes was measured one hour after the treatment, while in some nocturnal rodents (i.e. Syrian hamster), the effects on Per expression were only observed 2 hours after a serotonergic injection [160]. Several studies have explored the different 5-HT receptor subtypes that could be responsible for the non-photic effects observed in response to a serotonergic stimulation. Since 8-OH-DPAT binds to 5-HT1A and 5-HT7 receptors, two subtypes of receptors present in the SCN (Table 2), extensive research has been performed to delineate their respective role. Apparently, both receptors subtypes are needed to observed non-photic effects. Indeed, both 5-HT1A antagonists (e.g. pindolol) [171] and 5-HT7 antagonists (e.g. 2a- [4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydro- bezo[cd]indol-2(1H)-one or DR404 and (2R)-1-[(3-hydroxyphenyl)sulfonyl]- 2[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine or SB269970) [159, 172] block phase shift induced by 8-OH-DPAT treatment and mutant mice lacking either 5-HT1A [173] or 5-HT7 [174] receptors subtype do not express behavioral phase shifts in response to 8-OH-DPAT. Of note, 5-HT5A receptors could also be implicated, at least in rats [175], but this in vitro result needs to be confirmed with in vivo studies. No data are yet available in diurnal species, but it is reasonable to suggest that both type of receptors are implicated, since (+)8-OH-DPAT induces behavioral phase shifts [130]. Besides their presence in the SCN, 5-HT1A and 5-HT7 receptors are also expressed in the DRM, NRM and IGL [108, 117, 118]. Electrical stimulation of the DRN and MRN, and local injections of 8-OH-DPAT into the DRN and IGL induce phase advances of the locomotor activity rhythm [155, 172, 176]. However, these structures and their 5-HT receptors are not essential to elicit these effects, since a local injection of 8-OH-DPAT into the SCN leads to behavioral phase advances [155, 159]. 22 Marc Cuesta and Etienne Challet

While 5-HT1A and 5-HT7 receptors seem to act in synergy, the intracellular pathways they activate are opposed: 5-HT1A and 5-HT7 receptors activation leads to inhibition [177] and activation [178] of the adenylatecyclase (AC) pathway, respectively. It is possible that within the SCN, these receptors are expressed in different neuronal subtypes. According to this hypothesis, 5-HT7 receptors activation inhibits GABA release and GABA-activated current into the SCN of rats [179] and the DRN of guinea- pigs [180], and 5-HT1A receptors activation leads to a decrease of glutamate release into the SCN of Syrian hamsters [181]. In addition, in vivo local applications of 5-HT and 8-OH-DPAT inhibit the SCN electrical activity [182, 183]. Based on these results, 5-HT1A and 5-HT7 receptors could be localized in glutamatergic and GABAergic neurons in the SCN, respectively, but further investigations are required to confirm this hypothesis and delineate the respective functions of these neuronal subtypes in the mediation of non-photic information to the central clock.

Neuropeptide Y, GABA and the IGL As an integrator of photic and serotonergic non-photic cues that are then conveyed to the SCN via NPY and GABA release, the IGL represents an additional modulator in the synchronization of the central clock. In nocturnal species, local NPY injections into the SCN [184], electrical stimulations of the geniculo-hypothalamic projections [185], and in vitro NPY application on SCN slices [186] induce phase shifts similar to those observed in response to hyperactivity and 5-HT agonist treatments. In addition, intra- cerebroventricular injections of anti-NPY antibodies [187], as well as IGL lesions [188] lead to an inhibitory effect on behavioral phase shifts induced by an access to a novel wheel. More recently, it was shown that increased locomotor activity and local injections of 8-OH-DPAT in the IGL induce an increased NPY release in the SCN [189]. At the cellular level, NPY is thought to bind to Y2 receptors [190, 191], which activate the protein kinase C [192], leading to a transitory inhibition of Per1 and Per2 mRNA level in the SCN [193, 194], similar to that observed for the other non-photic factors. In addition to NPY, IGL neurons are known to release GABA. Interestingly, local injections into the SCN of GABAergic agonists for

GABAA receptors (e.g. muscimol) induce non-photic phase-shifting responses and an inhibition of Per1 and Per2 mRNA level in the SCN of Syrian hamsters [195-197], similar to those observed in response to hyperactivity, and 5-HT and NPY agonist treatments in nocturnal species. In contrast, data obtained in response to muscimol in the diurnal Nile grass rat [197, 198] are Interactions of the Serotonergic and Circadian Systems ... 23 different than those obtained in response to serotonergic drugs in the diurnal Sudanian grass rat [130]. Indeed, when injected during the subjective day, muscimol induces behavioral phase delays and a transitory inhibition of Per2 expression. This suggests that GABAergic input from the IGL and/or GABAergic neurons into the SCN could have a different role in the synchronization of the central clock between nocturnal and diurnal species. Collectively, all the above results indicate that the serotonergic system, directly from the DRN and MRN, and indirectly through the IGL releasing NPY and GABA, act in mediating locomotor activity-induced phase-shifting effects on the central clock. The challenge in the future years will be to delineate the exact pathway linking the locomotor activity to the serotonergic system, and the cellular and molecular mechanisms regulating the non-photic synchronization in diurnal species. This will represent valuable informationthat could lead to innovative therapies in “diurnal humans” suffering from jet-lag, insomnia or shift-work related alterations.

Serotonin as a Photic Factor

As we mentioned, serotonin is clearly implicated in the non-photic synchronization of the central clock. Surprisingly, only 2 in vivo studies showed this type of effect on the circadian system of rats [95, 158], while there are plenty of in vitro data available in this rodent [158, 162, 165, 171, 199, 200]. The lack of in vivo observations might be due to a specificity found in rats that has not yet been described in mice and Syrian hamsters. Indeed, during the subjective night, systemic and local injections of non-specific serotonergic agonists, such as quipazine (5-HT3> 5-HT1A> 5-HT1B), (±)-2,5- dimethoxy-4-iodoamphetamine or DOI (5-HT2A> 5-HT2C> 5-HT2B), 1-(3- chlorophenyl)piperazine or mCPP (5-HT2C> 5-HT2B> 5-HT2A> 5-HT1), and specific agonists for 5-HT3 (1-(m-chlorophenyl)biguanide or mCPBG) and 5- HT2C (8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quin oxalin-5(6H)- one or WAY-161503) receptors, produce phase shifts of the locomotor activity that are similar to those observed in response to light [95, 201-205]. In addition, most of these compounds induce an increase of Per1 and Per2 mRNA, and FOS protein levels in the SCN when applied at night [202, 206, 207]. The serotonergic modulation of the central clock in rats is thus paradoxical, since both photic-like and non-photic effects can be observed. The different 5-HT receptors subtypes present in the SCN could partially explain why such opposite responses can be observed after a serotonergic 24 Marc Cuesta and Etienne Challet stimulation. First, a global activation of all 5-HT receptors present in the SCN, through an increase of endogenous 5-HT in response to fluoxetine, leads to non-photic rather than photic-like response [95]. This suggests that the serotonergic system mediates mainly non-photic information in rats. Second, as it was previously described, 5-HT1A and 5-HT7 receptors are thought to mediate non-photic effects observed during daytime in nocturnal rodents, including rats. However, these receptors are not implicated in the photic-like effects, since both (+)8-OH-DPAT and (2S)-(+)-5-(1,3,5-trimethylpyrazol-

4yl)-2-(dimethylamino)tetralin (AS19), a potent 5-HT7 agonist, failed to mimic the effect of light when applied at the end of the subjective night [95]. Third, 5-HT3 and 5-HT2C receptors were described as responsible for the induction of photic-like responses. Indeed, injection of specific 5-HT2C (WAY-161503) [95] and 5-HT3 (mCPBG) [95, 202] agonists mimic the effects of light on the central clock.

While 5-HT2C receptors were described in the SCN of rats [112] at the post-synaptic level [207], 5-HT3 receptors were localized only in the SCN of Syrian hamsters [116]. However, it was shown in rats that enucleation, leading to RHT degeneration, prevents the behavioral phase advances induced by quipazine [201]. This indirect evidence suggests that 5-HT3 receptors would be localized at the presynaptic level on RHT terminals. Their activation would lead to a release of glutamate from RHT terminals inducing photic phase shifts. Of note, since 5-HT2A receptor subtype is present in the SCN of rats [112] and has an affinity for DOI, a serotonergic agonist that induces photic- like effects, we cannot exclude its possible involvement in these effects. While there is extensive literature on the photic-like effects observed in rats, there are almost no data available in mice or Syrian hamsters.The localization of 5-HT3 and 5-HT2C receptors in the SCN of these species has not yet been fully described and to our knowledge, only one study used a 5-HT2C receptor agonist (Ro-600175) in Syrian hamsters, but in order to study the modulation of the photic synchronization rather than to test possible photic- like effects [208]. To date, the only study showing possible photic-like effects in Syrian hamsters used an agonist with particular properties, named 8-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione or

BMY 7378 [209]. This mixed compound act on 5-HT1A receptors, but as an antagonist when they are located at the postsynaptic level, and as an agonist in presynaptic receptors. BMY 7378 induces phase shifts only when administered at the end of the subjective night. These effects would be a consequence of the pharmacological properties of this agonist rather than a real photic-like effect observable in rats. Interactions of the Serotonergic and Circadian Systems ... 25

Serotonin as a Modulator of the Photic Synchronization

In this chapter, we previously described the well-characterized effects of light, as well as those related to non-photic factors, on the synchronization of the central clock in rodents kept in laboratory conditions. These conditions allow the study of one specific stimulus by a rigorous control of different variables that could influence the circadian system. In the wild, however, it seems obvious that different synchronizing factors simultaneously reach the SCN. Responses of the circadian system to the combination of these factors are mediated by the central clock and can sometimes be complex. Hereafter, the different effects observed in response to the interaction of photic and serotonergic non-photic factors will be reviewed.

Negative Modulationof the Photic Synchronization in Nocturnal Species As for others non-photic factors, such as novel wheel access [210], NPY [211, 212] and GABA agonists [213, 214], the serotonergic modulation of the photic synchronization of the central clock has been extensively studied in mice and Syrian hamsters, and more recently in rats, providing similar results. In these 3 nocturnal species, systemic or local injections of 8-OH-DPAT and fluoxetine performed during the subjective night and preceding light pulses, inhibits light-induced phase shifts of the locomotor activity (Figure 6) [95, 146, 215-218]. Surprisingly, 8-OH-DPAT was described as less effective in mice compared to Syrian hamster [218], and in rats, its positive enantiomer was used to test only the modulation of light-induced phase advances [95]. Other serotonergic related compounds were shown to affect the photic synchronization. For instance, in Syrian hamsters, light-induced electrical activity of SCN neurons is inhibited by pre-treatment with 8-OH-DPAT, but also with 5-carboxamidotryptamine (5-CT) and 5-HT itself [182, 183]. Of note, light, when applied during the subjective day, is able to reduce behavioral phase advance induced by the most common non-photic factors [154, 155, 194, 195, 219-221]. At the molecular level, it has been shown that 8-OH-DPAT and quipazine inhibit light-induced FOS expression in the SCN [216, 222-224], with a stronger inhibition observed in Syrian hamsters compared to rats. To date, there is only one study that described the modulation of clock gene expression in response to serotonergic stimulation associated with light pulse [95]. 26 Marc Cuesta and Etienne Challet

Figure 6. Schematic representation of the serotonergic modulation of the photic synchronization at the level of the locomotor activity of nocturnal animals. Schematic actograms representing the locomotor activity of a nocturnal mouse in response to a light pulse (A.), an injection of a serotonergic agonist (i.e. 8-OH-DPAT) followed by a light pulse (B.) and an injection of 8-OH-DPAT (C), performed at CT12 (left panel in A., B., and C.) and CT18 (right panel in A., B., and C.). Each row corresponds to 24 h, and 12 days are represented. Animals are kept in constant darkness, as reported by the black and gray bars at the top of each actogram, indicating the subjective night and day, respectively. Hence, mice express their endogenous period (smaller than 24h), explaining why each day, the locomotor activity occurs earlier than the previous day. By convention, in nocturnal species kept in constant darkness, the beginning of the period of activity corresponds to the circadian time 12 or CT12. On the 6th day of recording, the treatment, represented on the actograms by a grey arrow, is applied at CT12 or CT18, to test the effects of 8-OH-DPAT on light-induced phase delays and advances, respectively. The magnitude of the phase shifts is assessed by performing 2 regressions that fit to the onset of activity, represented by gray lines. The first and second regressions are calculated using several days before and after the light pulse, respectively. The phase difference, obtained on the day following the light pulse, gives the value of the phase shift. The light-induced phase advance and delay (A.) are both reduced when animals receive an injection of 8-OH-DPAT prior to the light pulse (B.), while 8-OH-DPAT alone does not induce phase shift at CT12 and CT18 (C.) Abbreviations: CT, circadian time; subj. night, subjective night; subj. day, subjective day. Interactions of the Serotonergic and Circadian Systems ... 27

When applied at the end of the subjective night, systemic injections of fluoxetine enhance the light-induced increase of clock gene expression in the SCN, strongly for Per1, and slightly for Per2 and Rorβ. These results challenge the unifying theory established to explain the molecular responses to the interactions between photic and non-photic factors [144]. In this theory, non-photic factors are supposed to inhibit the light-induced increase of clock gene expression. Although this theory was confirmed for some non-photic factors, such as NPY and GABA [225-227], contradictory results were found in response to novel wheel access, behavioral arousal and fluoxetine injection [95, 228, 229]. Thus, despite similar behavioral responses, the molecular mechanisms implicated in the interaction between photic and non-photic factors are variables, complex, and probably not limited to modifications of core clock gene expression in the SCN. As for the non-photic synchronization, 8-OH-DPAT is the most effective agonist used in nocturnal rodents to study the serotonergic modulation of the photic synchronization [95, 216, 217]. Both 5-HT1A and 5-HT7 receptors subtypes have been described as responsible for the responses observed. Indeed, 8-OH-DPAT application is able to inhibit light-induced electrical activity of SCN slices [182, 183], but this inhibition is more or less counteracted by pre-treatment using 5-HT1A [182] receptors antagonists, and strongly reduced with 5-HT7 receptors antagonists [183]. In addition, glutamate release from RHT in response to optic nerve stimulation was shown to be reduced after an activation of 5-HT7 receptors [230]. Another study showed that in Syrian hamsters, 5-HT1A and 5-HT2C antagonist injections are able to increase the inhibition of light-induced behavioral phase shifts elicited by the SSRI citalopram, while 5-HT7 antagonist is ineffective [231]. Mutant mice lacking either 5-HT1A [173] or 5-HT7 [174] receptors subtype also provide us some insights on the role of these receptors. While phase advances are normally observed in response to a light pulse given at the end of the subjective night, phase delays were observed in mutant mice for 5-HT7 receptors. In mutant mice for 5-HT1A receptors, light-induced phase advances are larger than those observed in wild-type animals. Of note, injection of the potent 5-HT7 agonist, AS19, failed to inhibit light-induced phase advance, suggesting a more important role for 5-HT1A receptors in rats [95]. This result, however, has to be interpreted carefully, since AS19 is a relatively new compound and its specificity to 5-HT7receptors is still controversial [232]. Recently, one study showed that the blockade of 5-HT1B and 5-HT5A receptors subtypes using specific antagonists lead to an inhibition of light-induced behavioral phase advances in Syrian hamsters [231]. While this is the first 28 Marc Cuesta and Etienne Challet

demonstration of the implication of 5-HT5A receptors in these effects, data showing the role of 5-HT1B receptors on the negative modulation of the photic synchronization were already available [110, 181, 230, 233, 234]. Briefly, once activated, 5-HT1B receptors induces a decrease in the release of glutamate from the RHT, normally induced in response to light. While all these receptors subtypes have been described in the SCN (Table 2), most of them are also present in the DRN, MRN and IGL and their activation could participate in the behavioral response observed. For instance,

5-HT5A receptors are thought to be localized presynaptically in the raphe nuclei, and their blockade would lead to an increase of 5-HT release into the SCN, explaining why a negative modulation of the photic synchronization was observed in the study of Gannon and collaborators [231]. There are at least five 5-HT receptors subtypes (5-HT1A, 5-HT1B, 5-HT2C, 5-HT5A and 5-HT7) that are involved in the negative modulation of the photic synchronization of the central clock. This demonstrates how important is the role of the serotonergic system on the mechanisms regulating the circadian system. Nevertheless, since local injections of 8-OH-DPAT in the SCN inhibit light-induced phase shifts of the locomotor activity rhythm [217], 5-HT1A and 5-HT7 receptors localized in the SCN are thought to be the predominant actors. More studies are needed to delineate the respective role of these different subtypes of receptors in function of their localization in one or several parts of the serotonergic component of the circadian system. Indeed, association of the right pharmacological compounds with bright-light therapy could prevent circadian rhythms from becoming pathologically modified, as it can be observed in mood disorders (see below).

Positive Modulation of the Photic Synchronization in Nocturnal Species In nocturnal rodents, as we just described, the serotonergic system mainly exerts negative modulation on the photic synchronization of the central clock.

In rats, however, it was shown that an activation of 5-HT2C receptors at the end of the subjective night, using the specific agonist WAY-161503, leads to the potentiation of light-induced behavioral phase advances [95]. This receptor subtype is also responsible for the photic-like effects observed in that species [95, 202] and it is thus not surprising to observe such an additional effect in response to the association of this photic-like factor with the photic factor. Strikingly, 5-HT3 receptors that are also implicated in the photic-like effects do not participate in the positive modulation of the photic synchronization [95]. This lack of effect could be due to the localization of this subtype of Interactions of the Serotonergic and Circadian Systems ... 29 receptor. Indeed, they are supposed to be localized on RHT terminals and to mimic the effect of light, their activation induces a release of glutamate from RHT terminals. It is possible that this release is negligible in comparison to the massive release induced by a light pulse, explaining why an additional effect is not observed. In the case of the 5-HT2C receptors activation, since they are thought to be localized postsynaptically in the SCN and the intracellular pathway they activate is independent of glutamate release, they could potentiate light-induced phase shifts of the locomotor activity rhythm. In mice and Syrian hamsters they are almost no data available on a possible positive modulation of the photic synchronization through the activation of 5-HT receptors. One study described that 5-HT2C receptors activation does not modify light-induced phase advance in Syrian hamsters [208]. In contrast, 5-HT2C antagonist injections were shown to increase the inhibition of light-induced phase advances elicited by the SSRI citalopram [231]. Taken together, these results suggest a different role for 5- HT2C receptors activation in Syrian hamster compared to the effects seen in rats. It has been proposed that in Syrian hamsters, the blockade of 5-HT2C receptors at the level of the raphe nuclei would lead to an increase of 5-HT release into the SCN [231], thus reinforcing the elevation of extracellular 5-HT in the SCN, elicited by citalopram. More data are needed to confirm this hypothesis, but it is clear that 5-HT2C receptors, as a function of their localization, regulate the synchronization of the circadian system in very different ways between rats and Syrian hamsters. It is possible, however, to observe a positive modulation of the photic synchronization in Syrian hamsters. Indeed injections of mixed agonists, such as 1-(2-methoxyphenyl)- 4(4-(2-phtalimido)butyl)piperazine or NAN-190, were shown to potentiate light-induced phase shifts [208, 209, 235-240]. The critical involvement of 5-

HT1A receptors in this effect was described [240], meaning that the effects observed are due to the specific pharmacological properties of these mixed agonists. In addition, Smith and collaborators [240] found that the potentiation effects of NAN-190 were due, at least in part, to a down-regulation of some genes and biochemical pathways involved in the molecular responses of the central clock to light.

Positive Modulation of the Photic Synchronization in Diurnal Species Interactions between photic and non-photic factors have not been extensively studied in diurnal rodents. To date, there are few publications on the inhibitory effects of GABAA and GABAB agonists on the light-induced 30 Marc Cuesta and Etienne Challet behavioral phase advances obtained in Nile grass rats [198, 226, 241]. These results are similar to those obtained in the nocturnal Syrian hamster [213, 214]. This suggests that, in contrast to what has been observed for GABA agonists as a non-photic factor, these compounds act on the photic synchronization in a similar way between nocturnal and diurnal species, despite some differences at the molecular level [197, 226] Interestingly, in the diurnal Sudanian grass rat, systemic injections of (+)8-OH-DPAT and fluoxetine were shown to potentiate both light-induced behavioral phase advances and delays [130]. This result highlights an opposed serotonergic modulation of the photic synchronization between nocturnal and diurnal species, as it was described for the serotonergic non-photic modulation of the central clock. Moreover, it appears that the non-photic regulation of the photic synchronization varies in function of a given non-photic factor (GABA vs. 5-HT agonists) between nocturnal and diurnal species, as it was also described for the non-photic modulation of the central clock. Taken together, it is thus tempting to hypothesize that the differential effects observed in response to these non-photic factors are linked to the mechanisms underlying diurnal and nocturnal behaviors. We already mentioned that the serotonergic system conveys information on wake/arousal behavior to the central clock. Hence, it is not surprising that the responses of the SCN to serotonergic cues differ between nocturnal and diurnal species, since their respective sleep-wake patterns are in phase opposition. The differences observed for GABA agonists suggest that the IGL (that release GABA) or the SCN GABAergic neurons could provide differential information to the SCN in function of the diurnal or nocturnal behavior. At the beginning of the subjective night, systemic injections of (+)8-OH- DPAT and fluoxetine coupled with light pulses induce an increase of Per1 and Rev-erbα mRNA levels in the SCN, while light pulse alone does not modify the expression of these genes [130]. At the end of the subjective night, these injections potentiate and inhibit the light-induced expression of Per1 and Rorβ mRNA in the SCN, respectively [130]. Interestingly, while these results are similar for Per1 at the end of the subjective night in diurnal and nocturnal species, they are in opposition for Rorβ [95]. This suggests an important differential role for Rorβ in response to the serotonergic modulation of the photic synchronization between diurnal and nocturnal species. Of note, the molecular effects observed in response to a serotonergic stimulation are different than those seen after a GABAergic injection, confirming the differential role of these 2 non-photic factors in diurnal species. Once again, these results have to be interpreted carefully, since translational and post- Interactions of the Serotonergic and Circadian Systems ... 31 translational modification could occur in response to the association of photic and non-photic factors. As for the serotonergic non-photic synchronization of the central clock, the serotonergic modulation of the photic synchronization differs greatly between nocturnal and diurnal species, thus reinforcing the need to obtain more data on diurnal species that could then be used in humans for the treatment of different pathologies affecting the circadian system.

Interactions of the Serotonergic and Circadian Systems in Pathological Conditions

As a fundamental coordinator of various biological functions, the endogenous circadian system strongly participates in overall health and longevity. For optimal function, circadian rhythms should be aligned with respect to the sleep-wake cycle. Accordingly, a temporal misalignment between the circadian system and the sleep-wake cycle could have deleterious effects as seen in many disorders, including mental disorders. In addition, several therapeutic approaches based on manipulation of circadian synchronizers have been used successfullyto treat symptoms of several of these disorders. Interestingly, the symptomatic presence of irregular or disrupted sleep-wake cycleinmood disorders, associated with perturbation in the level of different neurotransmitters, including serotonin, raises the question whether these alterations are a consequence of a dysfunctional circadian system. In the last part of this chapter, we first present the impact of a deficiency of the serotonergic neurotransmission on the circadian system and then we review the sleep, circadian rhythms and serotonergic disturbances observed in mood disorders.

Effects of Chronic Serotonergic Deficiency or Input on the Central Clock

While there is an extensive literature on the effects of discrete serotonergic cues on the central clock, studies describing the impact of a deficiency of the serotonergic system or the chronic effects of serotonergic drugs used in the 32 Marc Cuesta and Etienne Challet treatment of mood disorders on the circadian system are more limited. In Syrian hamsters, destruction of 5-HT fibers, using 5,7-DHT, a toxin that selectively kills serotonergic neurons, leads to a lengthening of the active period in LD and DD [242, 243]. Interestingly, in constant light conditions (LL), the lengthening of the endogenous period observed in response to this regimen, disappears in 5,7-DHT treated animals [242]. In mice, 5-HT fiber lesion associated with enucleation lead to a lengthening of the active phase and the endogenous period, as wells as increased total activity and peculiar patterns of activity during the active phase [244]. In addition, destruction of 5- HT fibers results in the loss of observable behavioral phase advances in response to a novel wheel access given during the middle of the subjective day [153]. More recently, the serotonin transporter knockout (5-HTT KO) mouse model was used to study the effects of lifelong elevated 5-HT levels on circadian rhythms [245]. Unexpectedly, while some alterations of sleep architecture present in patients suffering from mood disorders were previously described in 5-HTT KO mice [246, 247], no differences in the set of locomotor activity parameters (i.e. amplitude, period, acrophase and total activity) were found in those mice compared to wild-type mice, when kept in LD or DD. Interestingly, 5-HTT KO mice presented attenuated light-induced behavioral phase delay compared to wild-type mice. The authors suggested that the constant elevated level of extracellular 5-HT, which is supposed to induce a downregulation of the different 5-HT receptors, could have been inefficient to downregulate 5-HT1B receptors located in the RHT terminals, resulting in elevated 5-HT1B activation that would be responsible of the inhibition of the light-induced phase shifts. Despite this result, the lack of circadian perturbations in 5-HTT KO mice might be explained with compensatory changes. Several studies explored the effects of a chronic treatment of fluoxetine, an antidepressant that increases levels of extracellular 5-HT, as seen in 5-HHT KO mice. While some studies showed an absence of effect on the locomotor activity rhythm of rats [248], others reported a shortening of the endogenous period in mice in response to fluoxetine [249]. Chronic fluoxetine treatment would also lead to a downregulation of 5-HT7 receptors [250], as well as 5-HT1B receptors but only at night [251]. The latest result is then in opposition with the hypothesis proposed to explain the effect seen in 5-HTT KO mice. Another recent study investigated the effect of a developmental disruption of the serotonin system [252]. This disruption was obtained by knocking down PC12 ETS domain-containing transcription factor 1 or Pet-1, a transcription Interactions of the Serotonergic and Circadian Systems ... 33 factor that colocalizes with TPH neurons from embryonic day 12.5. Pet-1 was shown to be necessary for the maintenance of a serotonergic phenotype in adults [253] and mice lacking this gene express increased aggression and anxiety-like behavior [254]. Pet-1 KO mice show a significant disruption of the 5-HT with a loss of around 70% of 5-HT cells and a very little expression of the key molecules of the 5-HT system (e.g. TPH, 5-HTT) in the remaining 30%. In addition, Pet-1 KO mice show virtually no-5-HT labeling in the SCN and a very small number of 5-HT labeling in the MRN and DRN. At the circadian level, Pet-1 KO mice express a lengthening of the endogenous period of locomotor activity in DD, as seen in mice treated with 5,7-DHT. This suggests a possible slowing down of the central clock in absence of serotonin. If this was true, this effect would not be mediated by 5-HT1A, 5- HT1B nor 5-HT7 receptors, since mice lacking one of these receptors do not show a lengthening of their endogenous period [173, 174, 255]. Pet-1 KO mice also express a redistribution of their active period in different light dark cycles, with a significant shift of activity from early to late night, leading to a bimodal pattern. Taken together, the results indicate a clear role for 5-HT in the regulation of the timing of locomotor activity, and 5-HT deficiency results in alteration of the circadian system.

Interaction of the Serotonergic and Circadian Systems in Mood Disorders

Mood disorders are a consequence of genetic, environmental, physiological, and psychological factors. This group of complex and multifactorial disorders essentially comprises recurrent unipolar depressive disorder (also known as major depressive disorders or MDD), seasonal affective disorders (SAD) and bipolar affective disorders (BPD).

Major Depressive Disorders In most countries, the number of people who will suffer from MDD during their life is estimated between 8 and 12%. Alteration of the serotonergic system, such as its under-activation, has long been implicated in the pathophysiology of depression [256, 257]. In addition pharmacological treatments using SSRIs have been shown to be efficient in the treatment of depression. Interestingly, another overarching feature of depression is the systematic presence of sleep and circadian disruptions. Indeed, up to 90% of depressed patients suffer from insomnia, which additionally represents a risk 34 Marc Cuesta and Etienne Challet factor for developing and relapsing into MDD. Depressed patients also often present advanced rhythms, as evidenced by reduced rapid eye movement (REM) sleep latency, earlier distribution of REM sleep during the night, and early morning awakenings [258, 259]. Other circadian disturbances have been observed such as greater nocturnal core body temperature, higher overall mean temperature, greater plasma cortisol and lower plasma melatonin levels, although this remains controversial [258, 260-262]. Abnormal phase advances of the circadian system compared to the sleep-wake cycle were also reported. Based on the systematic presence of circadian disturbances in many psychiatric diseases, including mood disorders, many scientific publications over the past years started to focus on the possible association of various clock gene polymorphisms (e.g. single-nucleotide polymorphisms or SNPs) with mental illnesses in humans. However, the results of most of these studies have to be interpreted keeping in mind the limitations commonly related to candidate gene association studies, such as population stratification, sample size and multiple testing issues. Some of these studies revealed that variants of several core clock genes, namely CRY1 and NPAS2 [263], as well as other circadian genes, such as TIM [264] are associated with MDD. Moreover, variants of PROKR2, which is implicated in circadian and homeostatic regulation of sleep in rodents, were found to be moderately associated with MDD [265]. In addition to association studies, a higher expression of CLOCK, PER1, and BMAL1 mRNA in peripheral blood leukocytes among individuals with a history of depression compared to healthy subjects was described [266]. Interestingly, manipulation of the circadian clock can be effective as a treatment for mood disorders [267, 268]. Indeed, chronotherapies, such as bright light exposure can reset circadian phase (depending on the time of application) and be useful for correcting the state of misalignment between the endogenous circadian system and the sleep schedule.Another chronotherapy, named sleep phase advance therapy, could act in the same way by reducing this temporal misalignment. Other non-pharmacological interventions such as sleep deprivation (partial, total, or selective for REM sleep) have been successfully used for MDD on a short-term scale, but would rely on homeostatic rather than circadian processes.As reviewed earlier in this chapter, the serotonergic and circadian systems are extensively intertwined and both systems are altered in MDD. The linkage of these two systems is also apparent clinically, since bright light therapy was described to accelerate and enhance therapeutic effects of SSRIs in MDD [269-271]. In addition, agomelatine, a new promising drug to treat mood disorders, act on both systems at the same time [272]. As a melatonin agonist, it influences the circadian system by a Interactions of the Serotonergic and Circadian Systems ... 35

possible stabilization of the sleep-wake cycle and as a 5-HT2C receptor antagonist, it acts on different parts of the serotonergic system.

Seasonal Affective Disorder SAD is another common mood disorder in which the linkage between serotonergic and circadian system and its clinical relevance might be best illustrated. SAD affects around 10% of the population living in non-tropical zones. The winter form of SAD is characterized by depressive symptoms occurring during the fall and winter months. This might be linked to altered secretion of melatonin, although this remains controversial [258, 273]. According to another model, the phase shift hypothesis, SAD patients become depressed because a misalignment occurs between their circadian system and their sleep schedule [258]. Most of the time, this misalignment is caused by a circadian phase delay associated with the later dawn in winter. In addition, SAD patients complaints of disturbed sleep (e.g. hypersomnia), and present increased non-REM sleep duration and greater slow-wave activity per minute of non-REM sleep [259, 274]. Association studies indicate that variants of PER2, NPAS2 and BMAL1 are significantly associated with SAD [259, 275, 276]. Moreover, certain allelic combinations of SNPs of these 3 genes have an additive effect, leading to an increased risk of developing SAD by 4.43 over other genotypes and 10.67 over the most protective haplotypes [275]. In addition, prior studies such as that of Johansson and colleagues [276] showed a relationship between the PER3 p.Val647Gly genotypeand morningness /eveningness, reinforcing the association between clock genes polymorphism and chronotype. While SAD is considered as a circadian disorder, there is evidence involving the serotonergic system. Polymorphism of the short-repeat allele of 5-HTT gene (5-HTTLPR) is associated with increased seasonality in mood and with atypical depressive symptoms present in SAD [277, 278]. In addition, variants of the gene coding for 5-HT2A receptors are directly associated with increased risk of developing SAD [279, 280]. Interestingly, tph2 gene expression in the raphe nuclei of Syrian hamsters is variable according to the season, with winter-like light cycles suppressing the circadian rhythm of its mRNA expression [126, 281]. This suggests an effect of the photoperiod on a key component of the serotonergic system that could be seen in SAD patients. In accordance with this hypothesis, 5-HT turnover, obtained by measuring 5-HT and its metabolites in blood, is lowest in winter and the rate of its production is increased in response to the duration of bright light [96]. Moreover, in vivo measures of serotonin transporter binding in the human brain are higher at the fall and winter and decreases as the day length 36 Marc Cuesta and Etienne Challet increases [282-284]. Bright light exposure and/or exogenous melatonin administration have been successfully used as attempts to correct abnormal phase position present in SAD [285, 286]. In addition, pharmacotherapy with SSRIs and agomelatine is also effective to alleviate SAD [272, 285, 286]. Overall, seasonal light cues, mediated by the circadian system, influence the serotonergic system in the brain, and both systems contribute to seasonal regulation of mood at the physiological level.

Conclusion

Etiological determinants of mood disorders are still poorly understood although several pieces of evidence point toward fundamental alterations of circadian rhythmicity in addition to a deficiency of the serotonergic system. A model has been proposed for bipolar disorders [287] that could also be used for MDD and SAD. In this model, variants of certain genes, especially clock genes, would affect the ability of the circadian system to adapt to environmental changes and would predispose to sleep-wake disturbances. Considering the interconnections between the circadian and serotonergic systems, it is reasonable to suggest that sleep disturbances and circadian deficits could alter the serotonergic system (as wells as other system such as dopaminergic system), in turn affecting mood regulation. A vicious cycle would then begin, where mood deregulation would affect sleep quality and quantity, which would reinforce the temporal misalignment between the sleep- wake cycle and the circadian system. The convergence of these two systems in mood regulation is well illustrated, especially in SAD, in which there is evidence for perturbation of both systems, and manipulation of each of these systems is amenable to therapeutic strategies. The challenge in the near future will be to better understand the pathophysiology of this serotonergic/circadian cycle that could help to find most appropriate treatments.

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