Pawan Kumar Jha

Hanan Bou Âouda

Andries Kalsbeek

Etienne Challet

Hanan Bouâouda

Pawan K Jha

Distinct feedback actions of behavioural arousal to the master circadian clock in nocturnal and diurnal mammals

Keywords: Behavioural arousal, Circadian rhythm, Diurnal, Entrainment, Nocturnal, Phaseshifts, Sleep, Suprachiasmatic nucleus

Highlights

• Behavioural arousal affects circadian rhythms in mammals by its feedback action on the master clock in the suprachiasmatic nucleus (SCN).

• In nocturnal animals arousing stimuli in the middle of the rest period induce a phase advance and attenuate light-induced phase-shifts.

• Unlike photic signals, the feedback of behavioural arousal to the SCN utilizes a network of connections involving several brain nuclei and neurotransmitters.

• Circadian responses to behavioural feedback in diurnal species differ from those in nocturnal species, indicating distinct circadian windows of sensitivity to arousal.

• It is imperative to understand this disparity in more detail before addressing the question of therapeutic interventions to repair circadian misalignments due to disturbed sleep, shift work, or trans-meridian travel.

Introduction

The 24-h period of Earth's rotation is correlated with oscillations in many critical variables in the environment, such as ambient illumination and temperature, but also the availability of nutrients and activity of predators. The periodicity of these challenges and opportunities permits an anticipation to them that will shape the temporal organization of behaviour and physiology of organisms. Different patterns of rest/activity or sleep/wake cycles segregate organisms into nocturnal, diurnal and crepuscular species. To perform optimally in their respective temporal niche, these organisms display daily oscillations in behaviour, physiology and endocrine function. Such rhythms are generated by endogenous circadian clocks expressed in most cells and tissues that oscillate with a period close to 24 h even in absence of external variations in the environment. The adaptive benefit of having such circadian clocks has been noted in various experimental setups [START_REF] Sharma | Adaptive significance of circadian clocks[END_REF][START_REF] Bloch | Animal activity around the clock with no overt circadian rhythms: patterns, mechanisms and adaptive value[END_REF].

In mammals, the circadian system consists of input pathways, a master pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), extra-SCN oscillators/clocks throughout the brain and body, and output pathways to enforce daily changes in the temporal organization of behaviour and physiology [START_REF] Kalsbeek | SCN outputs and the hypothalamic balance of life[END_REF][START_REF] Golombek | Physiology of circadian entrainment[END_REF]. The SCN is a heterogeneous structure that contains a varied population of neuronal and glial cell types.

A recent single-cell RNA sequencing study describes five distinct neuronal and seven other major cell types in the mouse SCN [START_REF] Wen | Spatiotemporal singlecell analysis of gene expression in the mouse suprachiasmatic nucleus[END_REF]. Anatomically, it can broadly be divided into two sub-regions based on the expression of different neuropeptides. The 'core' in its ventrolateral part is characterized by the vasoactive intestinal polypeptide (VIP) expressing neurons that receive heavy inputs from the retina and other brain areas, whereas the neurons in J o u r n a l P r e -p r o o f the dorso-medial 'shell' predominantly express arginine vasopressin (AVP) and receive fewer extra-SCN innervations [START_REF] Abrahamson | Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections[END_REF][START_REF] Morin | SCN organization reconsidered[END_REF]. The circadian rhythms generated in the SCN are driven by the expression of core clock genes and their intertwining interactions, as well as by the strong intercellular coupling between the SCN cells [START_REF] Ko | Molecular components of the mammalian circadian clock[END_REF][START_REF] Liu | Intercellular coupling confers robustness against mutations in the SCN circadian clock network[END_REF]. Among mammalian species, most daily endocrine, behavioural and physiological rhythms are differently phased depending upon their temporal niche [START_REF] Challet | Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals[END_REF][START_REF] Jha | Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals[END_REF]. These differences are schematically illustrated in Fig. 1A-D. However, the daily pattern of SCN activity is relatively similar across species. In particular, the molecular clockwork in the SCN is similarly phased according to astronomical time. For instance, the daily peak of expression of the clock gene Per1 in the SCN occurs around noon in both nocturnal and diurnal mammals [START_REF] Sun | RIGUI, a putative mammalian ortholog of the Drosophila period gene[END_REF][START_REF] Takumi | A new mammalian period gene predominantly expressed in the suprachiasmatic nucleus[END_REF][START_REF] Mrosovsky | Cycle of period gene expression in a diurnal mammal (Spermophilus tridecemlineatus): implications for nonphotic phase shifting[END_REF][START_REF] Caldelas | Circadian profile and photic regulation of clock genes in the suprachiasmatic nucleus of a diurnal mammal Arvicanthis ansorgei[END_REF][START_REF] Otalora | Period gene expression in the brain of a dual-phasing rodent, the Octodon degus[END_REF]. In the same line, the electrical activity of the SCN is higher during daytime compared to the night in nocturnal as well as diurnal animals [START_REF] Smale | Mammalian diurnality: some facts and gaps[END_REF]. Furthermore, rhythmic outputs from the SCN studied so far are similarly phased according to astronomical time in the two categories of animals (e.g., peak of release of SCN vasopressin always in late daytime). By contrast, brain structures targeted by the SCN efferents, such as the paraventricular nucleus of the hypothalamus, interpret the temporal messages coming from the SCN differently in diurnal and nocturnal species [START_REF] Kalsbeek | Opposite actions of hypothalamic vasopressin on circadian corticosterone rhythm in nocturnal versus diurnal species[END_REF].

For optimal adaptability, the circadian rhythms of an organism must be synchronized with the predictable changes in the environment. Various stimuli, broadly classified into either photic or non-photic cues, have the ability to reset and entrain the circadian system. It is well established that forced wakefulness or induced arousal acts as a non-photic clue that feeds back to the SCN clock in nocturnal animals [START_REF] Turek | Effects of stimulated physical activity on the circadian pacemaker of vertebrates[END_REF][START_REF] Mrosovsky | Locomotor activity and non-photic influences on circadian clocks[END_REF][START_REF] Hughes | Feedback actions of locomotor activity to the circadian clock[END_REF][START_REF] Webb | Regulation of circadian rhythms in mammals by behavioral arousal[END_REF]. Considering that the temporal organization of the sleep and wakefulness cycle is oppositely phased in nocturnal and diurnal species, the feedback action of arousal may not be the same in diurnal and nocturnal species. Indeed, comparative studies suggest that behavioural arousal affects the master clock and its light resetting differently in nocturnal and diurnal mammals. The aim of this review is to discuss how induced arousal, or involuntary wakefulness, feeds back to the SCN clock and exerts its phase resetting and entraining action in nocturnal and diurnal animals.

Light entrainment of the SCN clock

J o u r n a l P r e -p r o o f

Light is the most ubiquitous entraining Zeitgeber (time giver) encountered in the daily life of most organisms. Photic entrainment may influence, and be influenced by, the non-photic phase resetting in mammals. Therefore, we must first discuss photic entrainment in brief here. As by definition the period of endogenous circadian rhythms differs slightly from 24-h in most mammals, therefore rhythms must periodically be shifted either forward or backward in order to maintain an appropriate phase-relationship with the environmental period of exactly 24-h [START_REF] Challet | Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals[END_REF]. Brief pulses of light delivered to animals housed in constant darkness produce phase-dependent shifts in the timing of their rest-activity cycles, thereby defining a so-called phase-response curve (PRC) to light [START_REF] Daan | Functional analysis of circadian pacemakers in nocturnal rodents.2. Variability of phase response curves[END_REF][START_REF] Schwartz | Circadian timekeeping in BALB/c and C57BL/6 inbred mouse strains[END_REF]. Exposure to light during the late day and early night, when nocturnal animals have just become active after dusk and diurnal animals start their resting period, delays the SCN clock.

Consequently, this shift will also delay the SCN-controlled rest/activity rhythm to a slightly later time on subsequent cycles, re-adjusting the rhythm phase with the external world, especially for animals with an endogenous period shorter than 24 h. On the other hand, light exposure during the late night and early morning (i.e., close to activity offsets and onsets in nocturnal and diurnal species, respectively) advances the phase of the SCN clock. As a result, this shift will advance the rest/activity rhythm to a slightly earlier time on subsequent days, readjusting the behaviour and physiology with the external environment, especially for animals with an endogenous period longer than 24 h. Furthermore, during most of the day, light has no phase-shifting effect. These circadian responses to light are roughly similar in both nocturnal and diurnal species (Fig. 2A-D) [START_REF] Caldelas | Circadian profile and photic regulation of clock genes in the suprachiasmatic nucleus of a diurnal mammal Arvicanthis ansorgei[END_REF][START_REF] Slotten | Photic and nonphotic effects on the circadian activity rhythm in the diurnal rodent Arvicanthis ansorgei[END_REF][START_REF] Challet | Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals[END_REF].

Phase-shifts such as those described above in response to light pulses are generally evaluated by measurements of daily onsets or offsets of the locomotor activity pattern. As mentioned above, these shifts in rhythmic behaviour correspond to phase-changes of the underlying SCN clock. How does light reset the SCN clock? In 1972 Moore and Lenn discovered terminals of retinal axons in the SCN, strongly suggesting that the mammalian retina could convey photic information to the SCN [START_REF] Moore | A retinohypothalamic projection in the rat[END_REF]. It is now well established that photic signals from the retina are conveyed to the SCN mainly via a direct pathway called the retinohypothalamic tract (RHT), in addition to rods and cones involving photosensitive retinal ganglion cells [START_REF] Moore | A retinohypothalamic projection in the rat[END_REF][START_REF] Rea | Photic entrainment of circadian rhythms in rodents[END_REF][START_REF] Hattar | Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity[END_REF] (Fig. 3). The axons of these retinal ganglion cells project mono-synaptically to the core (ventral) of the SCN [START_REF] Hattar | Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity[END_REF], where they release mainly glutamate and PACAP [START_REF] Castel | Glutamate-like immunoreactivity in retinal terminals of the mouse suprachiasmatic nucleus[END_REF][START_REF] Hannibal | Pituitary adenylate cyclase-activating peptide (PACAP) in the retinohypothalamic tract: a potential daytime regulator of the biological clock[END_REF]. Additionally, an indirect neural pathway courses to the SCN via the J o u r n a l P r e -p r o o f intergeniculate leaflet (IGL) [START_REF] Moore | Intergeniculate leaflet: an anatomically and functionally distinct subdivision of the lateral geniculate complex[END_REF][START_REF] Hattar | Central projections of melanopsin-expressing retinal ganglion cells in the mouse[END_REF]. From the IGL, the geniculohypothalamic tract (GHT) projects to the SCN and thus indirectly conveys light information [START_REF] Pickard | The intergeniculate leaflet partially mediates effects of light on circadian rhythms[END_REF]. The delay between RHT and GHT signals may provide additional information leading to a more differentiated response of the SCN to light cues. Other structures could also transmit light information to the SCN indirectly. For example, the lateral hypothalamic area (LH) is also a target of the RHT [START_REF] Hattar | Central projections of melanopsin-expressing retinal ganglion cells in the mouse[END_REF] and the arousalpromoting orexin neurons in the LH project to the immediate vicinity of the SCN [START_REF] Mcgranaghan | Orexin A-like immunoreactivity in the hypothalamus and thalamus of the Syrian hamster (Mesocricetus auratus) and Siberian hamster (Phodopus sungorus), with special reference to circadian structures[END_REF][START_REF] Brown | Electrophysiological actions of orexins on rat suprachiasmatic neurons in vitro[END_REF]. The downstream signaling of the photic pathways induces acute expression of several immediate early genes, such as c-fos, and the clock genes Per1 and Per2 [START_REF] Kornhauser | Photic and circadian regulation of c-fos gene expression in the hamster suprachiasmatic nucleus[END_REF][START_REF] Albrecht | A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light[END_REF][START_REF] Shigeyoshi | Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript[END_REF].

Moreover, the effect of light is not only limited to these transcriptional changes, but it also impacts on post-transcriptional modifications of core clock components. For example, lightinduced degradation of the clock protein BMAL1 may constitute an important step for photic entrainment [START_REF] Tamaru | Light and glutamate-induced degradation of the circadian oscillating protein BMAL1 during the mammalian clock resetting[END_REF]. The intricacy of photic entrainment is getting even more intensified by epigenetic modifications, such as light-induced chromatic remodeling within SCN cells [START_REF] Crosio | Light induces chromatin modification in cells of the mammalian circadian clock[END_REF].

Reciprocal interactions between homeostatic sleep response and SCN clock

The circadian timing of wake and sleep is one of the characteristics that distinguish diurnal and nocturnal animals. It is noteworthy that the sleep-wake cycle is an extensively studied behavioural rhythm in mammals. In addition to its circadian modulation, homeostatic regulation of sleep is another important physiological process that separately and interactively controls its quality, timing and duration [START_REF] Franken | A role for clock genes in sleep homeostasis[END_REF][START_REF] Borbely | The two-process model of sleep regulation: a reappraisal[END_REF]. The homeostatic process of sleep is regulated by the interactive action of arousal and sleep promoting areas in mammalian brain, primarily located in the hypothalamus and brainstem [START_REF] Saper | Wake-sleep circuitry: an overview[END_REF]. Regarding the circadian modulation of sleep, the SCN is involved in the regulation of the circadian architecture of sleep propensity, sleep onset and its maintenance [START_REF] Dijk | Variation of electroencephalographic activity during non-rapid eye movement and rapid eye movement sleep with phase of circadian melatonin rhythm in humans[END_REF][START_REF] Lavie | Melatonin: role in gating nocturnal rise in sleep propensity[END_REF][START_REF] Sack | Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms?[END_REF][START_REF] Dijk | Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics[END_REF].

The pathways that mainly stimulate wake maintenance consist of glutamatergic inputs from parabrachial and pedunculopontine tegmental nuclei to the basal forebrain, and GABAergic and cholinergic neurons in the basal forebrain that innervate the cerebral cortex. In addition, GABAergic neurons in LH promote wakefulness by inhibiting sleep-promoting neurons in the J o u r n a l P r e -p r o o f thalamus and preoptic area [START_REF] Herrera | Hypothalamic feedforward inhibition of thalamocortical network controls arousal and consciousness[END_REF][START_REF] Venner | A Novel Population of Wake-Promoting GABAergic Neurons in the Ventral Lateral Hypothalamus[END_REF]. On the other hand, circuitries that contribute to promotion of sleep lie mainly in the hypothalamic ventrolateral preoptic (VLPO) and median preoptic (MnPO) areas. Sleep-active GABAergic neurons of preoptic areas project to the above-mentioned wake-active components and inhibit them in a regulated fashion. Furthermore, brainstem GABAergic neurons inhibit glutamatergic arousal neurons and promote sleep [START_REF] Saper | Wake-sleep circuitry: an overview[END_REF]. As such, the wake-sleep regulatory circuit seems to act as self-regulatory loop in which activity in one limb stops input from the other one and vice-versa. How the central pacemaker in the SCN controls the circadian timing of wake and sleep is not fully clear yet. There are possibilities that the SCN communicates to wake and sleep areas in the brain through direct and indirect connections. A sparse input from the SCN to the VLPO implicates a direct influence of the pacemaker on this sleep centre [START_REF] Chou | Afferents to the ventrolateral preoptic nucleus[END_REF]. The SCN also sends major outputs to the subparaventricular zone and to the dorsomedial hypothalamic nucleus (DMH). In turn, the DMH sends GABAergic projections to the VLPO and glutamatergic projections to the LH [START_REF] Chou | Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms[END_REF].

The evidence that emerges from both animal and human studies shows that the homeostatic sleep response (process S) and the circadian process (process C) both act independently, but also interact continuously [START_REF] Borbely | The two-process model of sleep regulation: a reappraisal[END_REF]. Efficient sleep homeostasis in SCN-ablated rats and bright light-induced phase-shifts in human subjects are indicative of independent functioning of both processes [START_REF] Tobler | The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions[END_REF][START_REF] Dijk | Effects of SWS deprivation on subsequent EEG power density and spontaneous sleep duration[END_REF][START_REF] Trachsel | Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration[END_REF]. The SCN clock may interact with sleep homeostasis by influencing the rise and fall of sleep pressure in a time-of-the day dependent manner. The circadian phase during which prolonged waking occurs, modifies the level of subsequent sleep propensity [START_REF] Werth | Brain topography of the human sleep EEG: antero-posterior shifts of spectral power[END_REF][START_REF] Vyazovskiy | Sleep homeostasis in the rat in the light and dark period[END_REF]. At the molecular level, the role of clock genes in sleep homeostasis has been documented [START_REF] Deboer | Technologies of sleep research[END_REF][START_REF] Franken | A role for clock genes in sleep homeostasis[END_REF]. Mice knock-out for clock genes (Per1-3, Clock, Bmal1, Cryptochrome: Cry1 and Cry2, Npas2), show not only disabled circadian clocks, but also an abnormal sleep phenotype and modified sleep homeostasis [START_REF] Franken | A role for clock genes in sleep homeostasis[END_REF]. This indicates that circadian clocks influence sleep homeostasis also at the molecular level.

Most likely, clock genes expressed in extra-SCN brain regions are involved in the homeostatic mechanism of sleep. Results of in situ hybridization experiments revealed that Per2 expression in cortex, forebrain and thalamic nuclei increases in response to sleep loss and returns to control levels within 2-h of sleep recovery [START_REF] Franken | A non-circadian role for clock-genes in sleep homeostasis: a strain comparison[END_REF][START_REF] Franken | A role for clock genes in sleep homeostasis[END_REF]. Remarkably, sleep deprivation does not affect expression of Per2 in the SCN (Curie et al., 2015). How sleep-wake states influence clock genes and other rhythmically expressed genes is not clearly understood Accordingly, a recent study indicates that sleep deprivation abolishes protein oscillations in the mice forebrain [START_REF] Noya | The forebrain synaptic transcriptome is organized by clocks but its proteome is driven by sleep[END_REF]. Now the question arises: does the functioning of the SCN clock change according to sleep homeostasis? Much research has been done in this direction during the last few decades [START_REF] Turek | Effects of stimulated physical activity on the circadian pacemaker of vertebrates[END_REF][START_REF] Mrosovsky | Locomotor activity and non-photic influences on circadian clocks[END_REF][START_REF] Hughes | Feedback actions of locomotor activity to the circadian clock[END_REF][START_REF] Webb | Regulation of circadian rhythms in mammals by behavioral arousal[END_REF]. These studies are based on involuntarily arousal that not only changes the sleep architecture, but also changes the photic response and phase shifting capacity of the SCN pacemaker. As it will be summarised in the following sections, these responses are often very different in nocturnal and diurnal animals.

Arousal: A potent non-photic cue

The concept of non-photic entrainment of circadian rhythms came forward through a series of experiments demonstrating that the rhythms of birds could be entrained to the daily playback of bird's songs (Gwinner, 1966a, b;[START_REF] Menaker | Entrainment of circadian rhythms by sound in Passer domesticus[END_REF]. The early reports of social entrainment in humans [START_REF] Aschoff | Circadian rhythms: influences of internal and external factors on the period measured in constant conditions[END_REF][START_REF] Wever | The circadian system of man. Results of experiments under temporal isolation[END_REF]) also strengthened the notion of lightindependent entrainment of circadian rhythms. Further, it was reported that enhanced locomotion had the ability to act as a potent Zeitgeber in nocturnal rodents and humans [START_REF] Yamada | Change in period of free-running rhythms determined by two different tools in blinded rats[END_REF]Reebs and Mrosovsky, 1989a;[START_REF] Buxton | Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms[END_REF]. In addition to that, meal timing also emerged as a strong synchronizing signal of peripheral circadian clocks in mammals, while scheduled feeding modified the temporal niche of behavioural activity in both nocturnal and diurnal species [START_REF] Challet | Interactions between light, mealtime and calorie restriction to control daily timing in mammals[END_REF]Vivanco et al., 2010b;[START_REF] Patton | Circadian adaptations to meal timing: neuroendocrine mechanisms[END_REF]. Another possible non-photic synchronizer is external temperature, which is very efficient to entrain circadian clocks in heterothermic animals as well as in plants [START_REF] Rensing | Temperature effect on entrainment, phase shifting, and amplitude of circadian clocks and its molecular bases[END_REF]. In most endothermic mammals, episodes of hypothermia can phase-shift secondary clocks with no major effect on the main SCN clock [START_REF] Buhr | Temperature as a universal resetting cue for mammalian circadian oscillators[END_REF]. Of note, entrainment of the master clock by cycles of high ambient temperature has been identified in the diurnal Octodon degus, camel and goat (Vivanco et al., 2010a;[START_REF] El Allali | Entrainment of the circadian clock by daily ambient temperature cycles in the camel (Camelus dromedarius)[END_REF][START_REF] J O U R N A L P R E -P R O O F Farsi | Melatonin rhythm and other outputs of the master circadian clock in the desert goat (Capra hircus) are entrained by daily cycles of ambient temperature[END_REF].

The first evidence of behavioural arousal as a synchronizing factor came from experiments with dark pulses in the nocturnal insectivorous bat, Taphozous melanopogon, housed in constant dim light [START_REF] Subbaraj | Pulses of darkness shift the phase of a circadian rhythm in an insectivorous bat[END_REF]. Exposure to dark pulses in the J o u r n a l P r e -p r o o f resting phase resulted in phase-advances, while dark pulses in their active phase resulted in phase-delays. As in bats, dark pulses in nocturnal rodents housed in constant light produced large advances in the mid-to-late subjective day and smaller phase-delays in late subjective night [START_REF] Challet | Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals[END_REF][START_REF] Webb | Regulation of circadian rhythms in mammals by behavioral arousal[END_REF]. In the dark pulse experiments, clock resetting occurs mostly during the resting period, irrespective of the opposite circadian pattern of locomotor activity between nocturnal and diurnal species [START_REF] Lee | Free-running rhythms and light-and dark-pulse phase response curves for diurnal Octodon degus (Rodentia)[END_REF][START_REF] Mendoza | Shedding light on circadian clock resetting by dark exposure: differential effects between diurnal and nocturnal rodents[END_REF].

Since darkness induces hyperactivity and/or arousal in nocturnal animals, it has been proposed that hyperactivity in these species mediates part of the resetting properties of dark exposure (Reebs et al., 1989;[START_REF] Canal | Resetting of the hamster circadian system by dark pulses[END_REF]. Other procedures that stimulate arousal during the usual daily resting period, such as induced locomotor activity, introduction of a (novel) running wheel or sleep deprivation, produce phase-shifts comparable to those induced by dark pulses (Reebs and Mrosovsky, 1989b;[START_REF] Antle | Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster[END_REF].

On the other hand, our study in the diurnal grass rat, Arvicanthis ansorgei suggests that sleep deprivation in the early rest (night) period induces phase-delays, thus mimicking photic resetting, not dark-induced resetting [START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF]. These findings indicate that circadian sensitivity to non-photic cues may differ greatly between nocturnal and diurnal animals (Fig

4A-B).

Moreover, the cues associated with behavioural activation, such as involuntary physical activity, sleep deprivation, adenosinergic or serotonergic activation, all decrease photic responses of the SCN clock in nocturnal rodents [START_REF] Watanabe | Adenosine A1receptor agonist attenuates the light-induced phase shifts and fos expression in vivo and optic nerve stimulation-evoked field potentials in the suprachiasmatic nucleus in vitro[END_REF][START_REF] Mistlberger | Sleep deprivation can attenuate light-induced phase shifts of circadian rhythms in hamsters[END_REF][START_REF] Challet | Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals[END_REF][START_REF] Elliott | Adenosine A1 receptors regulate the response of the hamster circadian clock to light[END_REF][START_REF] Sigworth | Adenosine A1 receptors regulate the response of the mouse circadian clock to light[END_REF], whereas the same treatments increase photic responses in the diurnal grass rat [START_REF] Cuesta | Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent[END_REF][START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF]. On the other hand, in both diurnal and nocturnal rodents, some other procedures leading to arousal, such as caffeine and modafinil treatment, proved to be ineffective to induce behavioural phase-shifts [START_REF] Webb | Modafinil [-[(diphenylmethyl)sulfinyl]acetamide] and circadian rhythms in syrian hamsters: assessment of the chronobiotic potential of a novel alerting compound[END_REF][START_REF] Vivanco | Drugs that prevent mouse sleep also block light-induced locomotor suppression, circadian rhythm phase shifts and the drop in core temperature[END_REF][START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF].

Arousal can be linked to physical exercise

A number of methods, which include confinement to a novel wheel, injection of benzodiazepine that triggers locomotor activity, and forced treadmill running, were used to study the enhanced levels of locomotor activity and their effects on circadian functions [START_REF] Turek | A benzodiazepine used in the treatment of insomnia phase-shifts the mammalian circadian clock[END_REF][START_REF] Mrosovsky | A behavioural method for accelerating re-entrainment of rhythms to new light-dark cycles[END_REF][START_REF] Mistlberger | Effects of daily schedules of forced activity on free-running rhythms in the rat[END_REF]. It has been shown that single discrete, locomotor activity pulses induced during the mid-to-late part of the subjective day lead to phase-advances of free-running activity rhythms in nocturnal hamsters (Reebs et al., 1989;Reebs and Mrosovsky, 1989b). Triazolam, a short-acting benzodiazepine, and confinement to a novel running wheel also produce this shifting effect in hamsters housed J o u r n a l P r e -p r o o f in constant conditions [START_REF] Turek | A benzodiazepine used in the treatment of insomnia phase-shifts the mammalian circadian clock[END_REF][START_REF] Turek | Dose response curve for the phase-shifting effect of triazolam on the mammalian circadian clock[END_REF]. The PRCs to both triazolam [START_REF] Turek | A benzodiazepine used in the treatment of insomnia phase-shifts the mammalian circadian clock[END_REF]) and novel wheel-induced locomotor activity pulses (Reebs and Mrosovsky, 1989b), similarly define a typical non-photic profile, with maximal phase-advances of 2-3 h, when activity is induced during the mid-to-late subjective day and somewhat smaller phase-delays during the late subjective night (Reebs and Mrosovsky, 1989b;[START_REF] Wickland | Phase-shifting effects of acute increases in activity on circadian locomotor rhythms in hamsters[END_REF][START_REF] Smith | Two families of phase-response curves characterize the resetting of the hamster circadian clock[END_REF]. The magnitude of phaseshifts resulting from induced locomotor activity is dose-dependent (i.e., correlated with the amount of locomotor activity performed) [START_REF] Wickland | Phase-shifting effects of acute increases in activity on circadian locomotor rhythms in hamsters[END_REF][START_REF] Janik | Nonphotically induced phase shifts of circadian rhythms in the golden hamster: activity-response curves at different ambient temperatures[END_REF][START_REF] Weisgerber | Lengthening of circadian period in hamsters by noveltyinduced wheel running[END_REF][START_REF] Bobrzynska | Phase shifting by novelty-induced running: activity dose-response curves at different circadian times[END_REF]. Running during three consecutive hours is necessary to induce maximal responses in hamsters (Reebs and Mrosovsky, 1989a;[START_REF] Wickland | Phase-shifting effects of acute increases in activity on circadian locomotor rhythms in hamsters[END_REF]. The same procedure also leads to sizeable phase-shifts in nocturnal mice housed in constant darkness [START_REF] Challet | Nonphotic phase-shifting in clock mutant mice[END_REF]. Therefore, the circadian system of nocturnal rodents has a relatively high threshold for exercise to alter circadian function, at least compared to light, which produces measurable phase-shifts after as little as a few minutes of exposure to low-intensity light [START_REF] Takahashi | Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms[END_REF][START_REF] Sharma | Rapid phase resetting of a mammalian circadian rhythm by brief light pulses[END_REF]. The relatively low sensitivity to locomotor activity feedback may represent a buffering system to prevent inappropriate phase-shifting to weak arousal or small amounts of motor activity outside the main active period.

The effects of enhanced locomotor activity on the circadian system have not been studied extensively yet in diurnal rodents. Previous studies in the diurnal European ground squirrel and Common marmoset investigated the phase-shifting effect of induced locomotor activity [START_REF] Hut | Nonphotic entrainment in a diurnal mammal, the European ground squirrel (Spermophilus citellus)[END_REF][START_REF] Glass | Photic and nonphotic circadian phase resetting in a diurnal primate, the common marmoset[END_REF]. Because of the small phase-advances observed during the late subjective day, the authors concluded that the responses of the SCN clock to the non-photic stimuli were close to those in nocturnal rodents. This conclusion, however, was based mostly on analysis of the phase-angle of entrainment, not PRC, to single stimuli. Also results from studies with human subjects indicate significant effects of exercise on the circadian system.

Daily exercise facilitates phase-delays of melatonin secretion [START_REF] Barger | Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim light[END_REF]. Van Cauter and colleagues showed that physical activity in early and mid-night induces respective phaseadvances and delays [START_REF] Van Reeth | Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men[END_REF][START_REF] Buxton | Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms[END_REF], highlighting clear phasedependent effects. The study of exercise PRC in humans demonstrated afternoon phaseadvances and early night phase-delays [START_REF] Youngstedt | Human circadian phase-response curves for exercise[END_REF], consistent with our study of sleep deprivation in the diurnal grass rat. Interestingly, chronotype of person influences the circadian rhythm phase shifts cause by timed exercise [START_REF] Thomas | Circadian rhythm phase shifts caused by timed exercise vary with chronotype[END_REF].

J o u r n a l P r e -p r o o f Arousal can be independent of physical exercise

In the studies that implicate high-intensity locomotor activity (forced or voluntary exercise) as the main phase-shifting stimulus, sleep loss or non-specific arousal may participate in the phase-shifting process as well, independently of locomotion per se. Animals that run little after an arousing stimulus may fail to shift because they do not stay awake, whereas animals that do display a phase-shift after intense running may do so because they remain awake. The possibility of a potential contribution of non-specific arousal to non-photic stimuli was already mentioned in early experiments on non-photic resetting [START_REF] Mrosovsky | Phase response curves for social entrainment[END_REF][START_REF] Rusak | Hamster circadian rhythms are phase-shifted by electrical stimulation of the geniculo-hypothalamic tract[END_REF].

Furthermore, brief arousing episodes induced by an intraperitoneal injection of saline were even able to produce phase-shifts without substantial locomotor activity, though the magnitude of shifts remained much smaller [START_REF] Hastings | Entrainment of the circadian system of mammals by nonphotic cues[END_REF]. [START_REF] Antle | Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster[END_REF] showed in Syrian hamsters that the phase-shifting effects of intense locomotor activity can be fully mimicked by keeping animals awake by gentle handling, with minimal levels of motor activity [START_REF] Antle | Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster[END_REF]. Because sleep deprivation leads to accumulation of extracellular adenosine in the central nervous system, experiments aimed at mimicking sleep deprivation used intracranial or intraperitoneal injection of an adenosine A1 agonist. When administered during the mid-sleep period, these adenosinergic compounds produce dose-dependent shifts similar to those induced by sleep deprivation in nocturnal hamsters. Accordingly, the adenosine antagonist caffeine fails to induce phase-shifts in these animals, but it attenuates the shifts induced by sleep deprivation [START_REF] Antle | Adenosine and caffeine modulate circadian rhythms in the Syrian hamster[END_REF]. Like caffeine, other psychostimulant drugs, such as methamphetamine and modafinil, also show chronobiotic inefficacy in nocturnal rodents [START_REF] Vivanco | Drugs that prevent mouse sleep also block light-induced locomotor suppression, circadian rhythm phase shifts and the drop in core temperature[END_REF].

The behavioural responses to arousing cues that are relatively independent of locomotor activity are largely unknown in the diurnal rodents. Our study in the diurnal grass rat, Arvicanthis ansorgei, suggests that sleep deprivation (provoked by gentle handling) in the early night induces phase-delays, while this awaking procedure in late resting (night) period remained ineffective to shift the SCN clock. Results from human studies indicate that one night of sleep deprivation, during which subjects were asked not to perform physical activity, led to phase-delays of plasma melatonin rhythm [START_REF] Cajochen | Human circadian melatonin rhythm phase delay during a fixed sleep-wake schedule interspersed with nights of sleep deprivation[END_REF]. Consistent with previous reports in nocturnal animals, caffeine treatment alone does not induce any behavioural phaseshift in diurnal rodents either [START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF]. In addition, it is noteworthy that cohabitation, which could have some arousing components, influences the circadian rhythms in diurnal J o u r n a l P r e -p r o o f rodents, such as Octodon degus and Arvicanthis niloticus [START_REF] Goel | Social cues modulate free-running circadian activity rhythms in the diurnal rodent, Octodon degus[END_REF][START_REF] Castillo-Ruiz | Time management in a co-housed social rodent species (Arvicanthis niloticus)[END_REF].

Interactions between arousal and photic entraining stimuli

In laboratory conditions, the environmental variables are tightly controlled in order to determine the responses to specific stimuli. By contrast, in nature it will be more common that different Zeitgebers act in combination. The responses of the mammalian circadian system to both photic and non-photic stimuli are mediated by effects on the central pacemaker. Therefore, it is important to consider the convergent, yet distinct, responses of animals to a combination of non-photic and photic signals. In this section, we describe some findings on the reciprocal interactions of behavioural arousal and photic stimuli on the master clock.

As discussed above, acute arousal due to enhanced physical exercise or sleep deprivation in the middle of rest period induces large phase-advances in nocturnal rodents housed in constant darkness. When the animal is stably entrained to an LD cycle the same stimulus has little or no detectable effect at these daily/circadian phases (daytime), i.e., when the animal is not transferred to constant darkness immediately after the stimulus (Janik et al., 1994). However, in young hamsters that are naïve to wheel running and placed in a wheel for the first time during the light portion of the LD cycle, an extended bout of running may occur. This procedure has been found, in some cases, to markedly phase-advance the rest-activity cycle, which then takes several days to be re-entrained to the LD cycle. Interestingly, if the wheel transfer is performed at the usual time of lights off, no shift is observed [START_REF] Gannon | Twelve-hour phase shifts of hamster circadian rhythms elicited by voluntary wheel running[END_REF].

The question arises why an arousal process during the middle of the light period normally induces little or no shift of the rest-activity rhythm in nocturnal animals housed in an LD cycle? Do arousal and light exposure work antagonistically on the circadian phase? In accordance with this hypothesis, phase-advance shifts induced by light pulses are attenuated if they are concurrent with or followed by arousing stimuli [START_REF] Ralph | Behavioral inhibition of circadian responses to light[END_REF][START_REF] Mistlberger | Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent[END_REF]. Furthermore, sleep deprivation or injection of an adenosine A1 agonist in the middle or late light period also inhibit light-induced phase-shifts of locomotor activity rhythms in mice and hamsters [START_REF] Watanabe | Adenosine A1receptor agonist attenuates the light-induced phase shifts and fos expression in vivo and optic nerve stimulation-evoked field potentials in the suprachiasmatic nucleus in vitro[END_REF][START_REF] Mistlberger | Sleep deprivation can attenuate light-induced phase shifts of circadian rhythms in hamsters[END_REF][START_REF] Challet | Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals[END_REF][START_REF] Elliott | Adenosine A1 receptors regulate the response of the hamster circadian clock to light[END_REF][START_REF] Sigworth | Adenosine A1 receptors regulate the response of the mouse circadian clock to light[END_REF]. In addition, wake-promoting drugs like caffeine, methamphetamine and modafinil, slow down the photic resetting in nocturnal rodents (Moriya et al., 1996;[START_REF] Ono | Methamphetamine modifies the photic entraining responses in the rodent suprachiasmatic nucleus via serotonin release[END_REF][START_REF] Vivanco | Drugs that prevent mouse sleep also block light-induced locomotor suppression, circadian rhythm phase shifts and the drop in core temperature[END_REF]. Among all these wake-promoting molecules, caffeine shows inconsistency in its interaction with photic responses. Contrary to J o u r n a l P r e -p r o o f the attenuation of photic resetting shown by a high dose of caffeine (40 mg/kg) [START_REF] Vivanco | Drugs that prevent mouse sleep also block light-induced locomotor suppression, circadian rhythm phase shifts and the drop in core temperature[END_REF], a moderate dose of caffeine (15 mg/kg) potentiated photic resetting in mice [START_REF] Van Diepen | Caffeine increases light responsiveness of the mouse circadian pacemaker[END_REF][START_REF] Ruby | Caffeine Delays Lightentrained Activity and Potentiates Circadian Photic Phase-resetting in Mice[END_REF]. These findings indicate a dose-dependent, biphasic response of light-induced resetting of the nocturnal SCN clock to caffeine. These inhibitory interactions in nocturnal rodents have been conceptualized as the result of opposite actions of photic and non-photic stimuli on the expression of clock genes in the SCN pacemaker. Accordingly, light and behavioural arousal would respectively activate and repress transcription of the clock genes Per1 and Per2. Arousal thus reverses the cellular and molecular changes that would normally shift the circadian timing loops after exposure to light [START_REF] Maywood | Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock[END_REF][START_REF] Maywood | A molecular explanation of interactions between photic and nonphotic circadian clock-resetting stimuli[END_REF]. However, such a model may not be suitable to explain the shifting effects of arousal during the night in diurnal animals, that is, when the mRNA levels of Per1 and Per2 in the SCN are endogenously low (i.e., precluding a further "non-photic like" down-regulation of their transcription) [START_REF] Challet | Minireview: Entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals[END_REF]. On the other hand, period gene expression is about to start at this time and arousal might thus keep it from initiating its expression. Such a delayed start of its expression should also cause a phase-delay.

In addition to its acute phase-shifting effect, long-term scheduled arousal may also modulate the photic entrainment process. A remarkable example has been obtained by transferring Syrian hamsters from their home cage into a novel wheel for 3 h each day in the middle of the light period, while maintaining the LD cycle [START_REF] Sinclair | Scheduled activity reorganizes circadian phase of Syrian hamsters under full and skeleton photoperiods[END_REF]. This repetition over one week induces a characteristic delay in the onset of nocturnal running that may exceed 6 h. This procedure seemed to split the daily activity cycle into two components when discontinuing the arousal schedule in darkness for few days [START_REF] Mrosovsky | Behavioral decoupling of circadian rhythms[END_REF][START_REF] Gorman | Daily novel wheel running reorganizes and splits hamster circadian activity rhythms[END_REF]. The neural and molecular events associated with such splits are not clearly understood yet.

In contrast to the findings in nocturnal rodents, results from our experiments in the diurnal grass rat, Arvicanthis ansorgei, indicate that behavioural arousal independent of locomotor activity (i.e., sleep deprivation by gentle handling and caffeine-induced arousal), potentiates the phase-delays and advances induced by light exposure in early and late night, respectively [START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF]. Some studies in humans also reported interactions between arousal and light entrainment. With respect to the chronobiotic effects of sleep deprivation in humans, partial sleep loss combined with bright light reduces light-induced phase-advances (Burgess, 2010), in contrast to the effects in diurnal grass rats in the late night [START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF]. To our J o u r n a l P r e -p r o o f knowledge, the combination of partial sleep deprivation and light in the early night has not been performed in humans yet, thus precluding a precise comparison with the early night data in diurnal grass rats. Also, the effects of caffeine consumption on the human circadian system have been documented. A study in blind patients indicates that daily administration of caffeine (150 mg) is not sufficient to entrain the master clock [START_REF] J O U R N A L P R E -P R O O F St Hilaire | Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms[END_REF]. However, caffeine consumption alone can suppress melatonin release and attenuate the nighttime decrease in body temperature in sleep-deprived subjects [START_REF] Wright | Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans[END_REF]. Furthermore, evening intake of caffeine (3 mg/kg) can produce significant phase-delays of the human SCN clock, while it does not modify significantly the shifting effect of bright light [START_REF] Burke | Effects of caffeine on the human circadian clock in vivo and in vitro[END_REF]. Considering our results in the diurnal grass rat, it could be interesting to test whether caffeine consumption in humans may not potentiate the shifting effects of light exposure with lower intensities.

Brain nuclei and pathways involved in arousal-induced resetting of circadian rhythms

The SCN afferents involved in the non-photic modulation of circadian rhythms have been divided into two major pathways: 1) the GHT originating in the IGL, which contains NPY and GABA amongst others [START_REF] Harrington | Neuropeptide Y immunoreactivity in the hamster geniculosuprachiasmatic tract[END_REF][START_REF] Moore | Intergeniculate leaflet: an anatomically and functionally distinct subdivision of the lateral geniculate complex[END_REF], and 2) an ascending serotonergic pathway originating in the median raphe nucleus (Meyer-Bernstein and [START_REF] Meyer-Bernstein | Differential serotonergic innervation of the suprachiasmatic nucleus and the intergeniculate leaflet and its role in circadian rhythm modulation[END_REF] (Fig. 3). Emerging evidence also relates other neurochemical (e.g. cholinergic and orexinergic) pathways to the non-photic regulatory mechanisms of circadian phase [START_REF] Webb | Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet[END_REF][START_REF] Yamakawa | The cholinergic forebrain arousal system acts directly on the circadian pacemaker[END_REF].

Projections from the intergeniculate leaflet via the GHT

The GHT is a thin elongated fiber tract arising from the IGL that projects to the ventral SCN [START_REF] Morin | Neuroanatomy of the extended circadian rhythm system[END_REF], the IGL itself is situated between the dorsal and ventral lateral geniculate nuclei [START_REF] Hickey | Retinogeniculate projections in hooded and albino rats: an autoradiographic study[END_REF][START_REF] Pickard | Bifurcating axons of retinal ganglion cells terminate in the hypothalamic suprachiasmatic nucleus and the intergeniculate leaflet of the thalamus[END_REF][START_REF] Morin | Intergeniculate leaflet and suprachiasmatic nucleus organization and connections in the golden hamster[END_REF]. Both acute wheel-running activity and sleep deprivation by gentle handling markedly increase c-FOS expression in IGL neurons [START_REF] Janik | Cellular colocalization of Fos and neuropeptide Y in the intergeniculate leaflet after nonphotic phase-shifting events[END_REF][START_REF] Antle | Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster[END_REF]. Electrical stimulation of the IGL produces phase-shifts, as behavioural arousal does [START_REF] Rusak | Hamster circadian rhythms are phase-shifted by electrical stimulation of the geniculo-hypothalamic tract[END_REF]. At the same time, ablation of this region blocks the phase-shifts to various arousing stimuli in hamsters and mice [START_REF] Johnson | Lateral geniculate lesions block circadian phase-shift responses to a benzodiazepine[END_REF]Janik and Mrosovsky, 1994;[START_REF] Wickland | Lesions of the thalamic intergeniculate leaflet block activity-induced phase shifts in the circadian activity rhythm of the golden hamster[END_REF][START_REF] Koletar | Loss of dexras1 alters nonphotic circadian phase shifts and reveals a role for the intergeniculate leaflet (IGL) in gene-targeted mice[END_REF].

These findings suggest that activation of the IGL is necessary for circadian clock resetting mediated by arousal stimuli. In addition to NPY and GABA, the GHT may also contain enkephalin and neurotensin as neuromodulators [START_REF] Morin | Neuromodulator content of hamster intergeniculate leaflet neurons and their projection to the suprachiasmatic nucleus or visual midbrain[END_REF]. Interestingly, J o u r n a l P r e -p r o o f lesions of the IGL also influenced the circadian behaviour of diurnal Nile grass rat, as well as their responses to light and dark pulses [START_REF] Gall | Lesions of the Intergeniculate Leaflet Lead to a Reorganization in Circadian Regulation and a Reversal in Masking Responses to Photic Stimuli in the Nile Grass Rat[END_REF].

Neuropeptide Y: In hamsters, almost 50% of IGL neurons that project to the SCN are immunoreactive for NPY [START_REF] Morin | Neuromodulator content of hamster intergeniculate leaflet neurons and their projection to the suprachiasmatic nucleus or visual midbrain[END_REF]. Wheel confinement in the middle of the rest period markedly increases c-FOS expression in the IGL NPY neurons and increases the release of this peptide in the SCN [START_REF] Janik | Cellular colocalization of Fos and neuropeptide Y in the intergeniculate leaflet after nonphotic phase-shifting events[END_REF][START_REF] Glass | On the intrinsic regulation of neuropeptide Y release in the mammalian suprachiasmatic nucleus circadian clock[END_REF]. Remarkably nocturnal light pulses also induce c-FOS expression in the IGL, but not in NPY neurons [START_REF] Janik | Cellular colocalization of Fos and neuropeptide Y in the intergeniculate leaflet after nonphotic phase-shifting events[END_REF]. Intra-SCN administration of NPY results in a PRC similar to that produced by non-photic behavioural manipulations in hamsters and mice [START_REF] Biello | Neuropeptide Y and behaviorally induced phase shifts[END_REF][START_REF] Huhman | Neuropeptide Y microinjected into the suprachiasmatic region phase shifts circadian rhythms in constant darkness[END_REF][START_REF] Maywood | Opposing actions of neuropeptide Y and light on the expression of circadian clock genes in the mouse suprachiasmatic nuclei[END_REF][START_REF] Soscia | Neuropeptide Y does not reset the circadian clock in NPY Y2-/-mice[END_REF]. Blocking the effect of NPY by injection of NPY antiserum severely attenuates wheel-running-induced phase-advances without reducing the number of wheel revolutions [START_REF] Biello | Neuropeptide Y and behaviorally induced phase shifts[END_REF]. In vitro treatment with NPY during the subjective day dose-dependently phase-advances the peak firing rate of the SCN neurons [START_REF] Medanic | Suprachiasmatic circadian pacemaker of rat shows two windows of sensitivity to neuropeptide Y in vitro[END_REF][START_REF] Shibata | Neuropeptide Y and optic chiasm stimulation affect suprachiasmatic nucleus circadian function in vitro[END_REF][START_REF] Biello | Circadian phase shifts to neuropeptide Y In vitro: cellular communication and signal transduction[END_REF][START_REF] J O U R N A L P R E -P R O O F Harrington | Neuropeptide Y phase advances the in vitro hamster circadian clock during the subjective day with no effect on phase during the subjective night[END_REF]. Furthermore, both in vitro and in vivo application of NPY suppresses Per1 and Per2 expression in the SCN [START_REF] Fukuhara | Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus[END_REF][START_REF] Maywood | Opposing actions of neuropeptide Y and light on the expression of circadian clock genes in the mouse suprachiasmatic nuclei[END_REF]. NPY may also be involved in non-photic inhibition of photic responses, because NPY infusion into the SCN completely blocks light-induced phase-advances [START_REF] Weber | Neuropeptide Y blocks light-induced phase advances but not delays of the circadian activity rhythm in hamsters[END_REF]. In diurnal animals the role of NPY in the arousal-induced resetting of the master clock is largely unknown. However, different patterns of fluctuation of NPY in the SCN and NPY-containing neurons in IGL between nocturnal and diurnal rodents suggest a distinct role in the circadian system of both classes of animals [START_REF] Smale | Patterns of wheel running are related to Fos expression in neuropeptide-Y-containing neurons in the intergeniculate leaflet of Arvicanthis niloticus[END_REF][START_REF] Vidal | Changes in neuropeptide Y immunoreactivity and transcript levels in circadian system structures of the diurnal rodent, the thirteen-lined ground squirrel[END_REF].

GABA: Most of the neurons in the IGL (including those projecting to the SCN via the GHT) and SCN are GABAergic [START_REF] Moore | GABA is the principal neurotransmitter of the circadian system[END_REF][START_REF] Moore | Intergeniculate leaflet: an anatomically and functionally distinct subdivision of the lateral geniculate complex[END_REF][START_REF] Morin | Neuromodulator content of hamster intergeniculate leaflet neurons and their projection to the suprachiasmatic nucleus or visual midbrain[END_REF]. GABAA receptor agonists have been shown to perturb the circadian phase in hamsters and mice. Midday central administration of the GABAA agonist muscimol induces phase-advances of the behavioural rhythm [START_REF] Ebihara | The phase-shifting effects of pentobarbital on the circadian rhythm of locomotor activity in the mouse: strain differences[END_REF][START_REF] Smith | Central administration muscimol phase-shifts the mammalian circadian clock[END_REF]. Intra-SCN administration of muscimol in vivo [START_REF] Mintz | GABA interacts with photic signaling in the suprachiasmatic nucleus to regulate circadian phase shifts[END_REF][START_REF] Ehlen | Regulation of light's action in the mammalian circadian clock: role of the extrasynaptic GABAA receptor[END_REF] or application of muscimol in vitro induces non-photic like phase-shifts in rest-activity and SCN electrical activity rhythms [START_REF] Tominaga | GABAA receptor agonist muscimol can reset the phase of neural activity rhythm in the rat suprachiasmatic nucleus in vitro[END_REF][START_REF] Mcelroy | Ethanol modulates mammalian circadian clock phase resetting through extrasynaptic GABA receptor activation[END_REF]. SCN GABAA receptor activation downstream of IGL input is also necessary for NPY-mediated clock resetting since phase-shifts to NPY are blocked by administration of the GABAA receptor antagonist J o u r n a l P r e -p r o o f bicuculline both in vitro and in vivo (Janik et al., 1994;[START_REF] Huhman | Tetrodotoxin blocks NPY-induced but not muscimol-induced phase advances of wheel-running activity in Syrian hamsters[END_REF][START_REF] Gribkoff | Phase shifting of circadian rhythms and depression of neuronal activity in the rat suprachiasmatic nucleus by neuropeptide Y: mediation by different receptor subtypes[END_REF]. In the diurnal unstriped Nile grass rats, Arvicanthis niloticus, SCN GABAergic activation during the mid-subjective day leads to phase-delays [START_REF] Smith | Central administration muscimol phase-shifts the mammalian circadian clock[END_REF][START_REF] Novak | Novel phase-shifting effects of GABAA receptor activation in the suprachiasmatic nucleus of a diurnal rodent[END_REF]. Such behavioural shifts induced by GABAA activation during the mid-subjective day have been associated with a down-regulation of Per1 and Per2 in the SCN of nocturnal rodents and only of Per2 in the SCN of diurnal Arvicanthis [START_REF] Ehlen | GABAA receptor activation suppresses Period 1 mRNA and Period 2 mRNA in the suprachiasmatic nucleus during the midsubjective day[END_REF][START_REF] Novak | Light and GABA (A) receptor activation alter period mRNA levels in the SCN of diurnal Nile grass rats[END_REF]. Moreover, GABAergic stimulation inhibits light-induced phase-shifts in both nocturnal and diurnal rodents [START_REF] Gillespie | GABA(A) and GABA(B) agonists and antagonists alter the phase-shifting effects of light when microinjected into the suprachiasmatic region[END_REF][START_REF] Novak | Novel phase-shifting effects of GABAA receptor activation in the suprachiasmatic nucleus of a diurnal rodent[END_REF].

Enkephalin: Enkephalin-containing neurons in the IGL have been reported in several species and these neurons also contribute to the GHT [START_REF] Card | Organization of lateral geniculate-hypothalamic connections in the rat[END_REF][START_REF] Smale | Immunocytochemical characterization of the suprachiasmatic nucleus and the intergeniculate leaflet in the diurnal ground squirrel, Spermophilus lateralis[END_REF][START_REF] Moore | GABA is the principal neurotransmitter of the circadian system[END_REF][START_REF] Morin | Organization of the hamster intergeniculate leaflet: NPY and ENK projections to the suprachiasmatic nucleus, intergeniculate leaflet and posterior limitans nucleus[END_REF][START_REF] Morin | Neuromodulator content of hamster intergeniculate leaflet neurons and their projection to the suprachiasmatic nucleus or visual midbrain[END_REF]. In vivo systemic administration of fentanyl, a relatively selective µ receptor agonist, induces large phase-advances in hamsters when administered during the mid-to late light period. Like fentanyl treatment, similar phase-advances have been reported after morphine treatment [START_REF] Chen | The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine[END_REF][START_REF] Marchant | Morphine phase-shifts circadian rhythms in mice: role of behavioural activation[END_REF][START_REF] Meijer | Fentanyl, a upsilon-opioid receptor agonist, phase shifts the hamster circadian pacemaker[END_REF][START_REF] Vansteensel | Differential responses of circadian activity onset and offset following GABA-ergic and opioid receptor activation[END_REF][START_REF] Vansteensel | The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei[END_REF]. Enkephalinergic cells have also been found in the dorsomedial SCN [START_REF] Abrahamson | Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections[END_REF][START_REF] Morin | The circadian visual system, 2005[END_REF], suggesting that release of this neuropeptide from SCN neurons may also contribute to the control of circadian phase.

Neurotensin:

The hamster IGL also contains neurotensin-positive cells that project to the SCN [START_REF] Morin | Neuromodulator content of hamster intergeniculate leaflet neurons and their projection to the suprachiasmatic nucleus or visual midbrain[END_REF]. Neurotensin-expressing cells also have been described in the mouse ventral SCN [START_REF] Abrahamson | Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections[END_REF], as well as in the human SCN [START_REF] Goncharuk | Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock[END_REF]. In vitro midday application of this neuropeptide to the rat SCN induces large phase-advances in neuronal firing rhythm [START_REF] Meyer-Spasche | Neurotensin phase-shifts the firing rate rhythm of neurons in the rat suprachiasmatic nuclei in vitro[END_REF].

Serotoninergic projections from the raphe nuclei

Serotonin (5-HT) has long been reported to modulate circadian responses. 5-HT transmission has been proposed as a potential mediator of behavioural phase-shifts and modulation of photic synchronization by arousal (Moriya et al., 1996;[START_REF] Sumova | Serotonergic antagonists impair arousal-induced phase shifts of the circadian system of the syrian hamster[END_REF][START_REF] Watanabe | Adenosine A1receptor agonist attenuates the light-induced phase shifts and fos expression in vivo and optic nerve stimulation-evoked field potentials in the suprachiasmatic nucleus in vitro[END_REF][START_REF] Morin | Serotonin and the regulation of mammalian circadian rhythmicity[END_REF][START_REF] Grossman | Sleep deprivation stimulates serotonin release in the suprachiasmatic nucleus[END_REF][START_REF] Challet | Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals[END_REF]. The release of 5-HT associated with arousal and arousal-induced behavioural shifts most often has an inhibitory effect on photic resetting or entrainment in nocturnal rodents (Moriya et al., 1996;[START_REF] Sumova | Serotonergic antagonists impair arousal-induced phase shifts of the circadian system of the syrian hamster[END_REF][START_REF] Mistlberger | Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent[END_REF][START_REF] Grossman | Sleep deprivation stimulates serotonin release in the suprachiasmatic nucleus[END_REF][START_REF] Cuesta | New light on the serotonergic paradox in the rat circadian system[END_REF]. In the rat, phase-shifts induced by arousal are attenuated by pre-treatment with a serotonin antagonist (Sumova et al., J o u r n a l P r e -p r o o f 1996). In hamsters, however, phase-shifts induced by stimulated running are not blocked by 5-HT receptor antagonists or serotonin depletion in SCN [START_REF] Bobrzynska | Serotonergic stimulation and nonphotic phaseshifting in hamsters[END_REF][START_REF] Antle | Serotonin antagonists do not attenuate activityinduced phase shifts of circadian rhythms in the Syrian hamster[END_REF], but triazolam-induced phase-shifts are blocked by removal of the SCN 5HT input, despite the lack of c-fos expression in the raphe nuclei [START_REF] Cutrera | No triazolam-induced expression of Fos protein in raphe nuclei of the male Syrian hamster[END_REF][START_REF] Cutrera | Specific destruction of the serotonergic afferents to the suprachiasmatic nuclei prevents triazolam-induced phase advances of hamster activity rhythms[END_REF]. On the other hand, stimulated locomotor activity and sleep deprivation lead to release of serotonin in the SCN of nocturnal rodents [START_REF] Dudley | Endogenous regulation of serotonin release in the hamster suprachiasmatic nucleus[END_REF][START_REF] Grossman | Sleep deprivation stimulates serotonin release in the suprachiasmatic nucleus[END_REF].

The serotonergic projection from the median raphe innervates the SCN, while the IGL receives a serotonergic projection from the dorsal raphe [START_REF] Hughes | Feedback actions of locomotor activity to the circadian clock[END_REF]. Waking is associated with increased firing rate of serotonergic neurons in the raphe nuclei and increased 5-HT release in the SCN and IGL [START_REF] Dudley | Endogenous regulation of serotonin release in the hamster suprachiasmatic nucleus[END_REF][START_REF] Jacobs | Activity of serotonergic neurons in behaving animals[END_REF][START_REF] Barassin | Circadian tryptophan hydroxylase levels and serotonin release in the suprachiasmatic nucleus of the rat[END_REF][START_REF] Grossman | Regulation of serotonin release in the Syrian hamster intergeniculate leaflet region[END_REF]. Electrical stimulation of the raphe nuclei leads to behavioural phase-shifts with increased levels of serotonin and suppressed c-FOS expression in the SCN of nocturnal species [START_REF] Meyer-Bernstein | Differential serotonergic innervation of the suprachiasmatic nucleus and the intergeniculate leaflet and its role in circadian rhythm modulation[END_REF][START_REF] Dudley | In vivo assessment of the midbrain raphe nuclear regulation of serotonin release in the hamster suprachiasmatic nucleus[END_REF]. Serotonin release in the SCN associated with arousal-induced phase-shifts is blocked by intra-dorsal raphe injections of 5-HT1,2,7 and 5-HT7 antagonists, indicating the role of dorsal raphe output in the phase-resetting response to arousal [START_REF] Glass | Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus[END_REF]. It has been reported that arousal attenuates photic resetting of the SCN clock via associated serotonergic changes (Moriya et al., 1996;[START_REF] Ono | Methamphetamine modifies the photic entraining responses in the rodent suprachiasmatic nucleus via serotonin release[END_REF][START_REF] Challet | Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals[END_REF]. Furthermore, in general administration of 5-HT and 5-HT1A /7 agonists to SCN slices in vitro, as well as in animals in vivo produces typical nonphotic-like PRCs, with large phase-advances during the day and small, if any, phase-delays in late night [START_REF] Prosser | A serotonin agonist phase-shifts the circadian clock in the suprachiasmatic nuclei in vitro[END_REF][START_REF] Medanic | Serotonin regulates the phase of the rat suprachiasmatic circadian pacemaker in vitro only during the subjective day[END_REF][START_REF] Tominaga | Effects of 5-HT1A receptor agonists on the circadian rhythm of wheel-running activity in hamsters[END_REF][START_REF] Edgar | Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists[END_REF][START_REF] Shibata | Neuropeptide Y and optic chiasm stimulation affect suprachiasmatic nucleus circadian function in vitro[END_REF][START_REF] Bobrzynska | Serotonergic stimulation and nonphotic phaseshifting in hamsters[END_REF][START_REF] Challet | Roles of suprachiasmatic nuclei and intergeniculate leaflets in mediating the phase-shifting effects of a serotonergic agonist and their photic modulation during subjective day[END_REF][START_REF] Ehlen | In vivo resetting of the hamster circadian clock by 5-HT7 receptors in the suprachiasmatic nucleus[END_REF][START_REF] Horikawa | Phase-resetting response to (+)8-OH-DPAT, a serotonin 1A/7 receptor agonist, in the mouse in vivo[END_REF]. SCN serotonin levels follow the daily pattern of activity/rest in nocturnal and diurnal rodents, with higher values during the active period [START_REF] Poncet | Daily variations in in vivo tryptophan hydroxylation and in the contents of serotonin and 5-hydroxyindoleacetic acid in discrete brain areas of the rat[END_REF][START_REF] Cuesta | Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent[END_REF][START_REF] Cuesta | New light on the serotonergic paradox in the rat circadian system[END_REF]. Injections of serotonin, both in vitro and in vivo, are capable of phase-advancing the SCN clock during the mid-subjective day in nocturnal rodents [START_REF] Shibata | Phase-resetting effect of 8-OH-DPAT, a serotonin1A receptor agonist, on the circadian rhythm of firing rate in the rat suprachiasmatic nuclei in vitro[END_REF][START_REF] Bobrzynska | Serotonergic stimulation and nonphotic phaseshifting in hamsters[END_REF].

In sharp contrast, in the diurnal rat Arvicanthis, serotonergic receptor activation produces phase-advances essentially during the subjective night, but not during the mid-subjective day [START_REF] Cuesta | Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent[END_REF]. In nocturnal rodents, the phase-shifts induced by serotonergic activation are consistently associated with reduced expression of Per1 and Per2 in the SCN. However, in the diurnal Arvicanthis, Per expression is unchanged after such treatment, suggesting distinct J o u r n a l P r e -p r o o f molecular mechanisms in diurnal species that remain to be identified [START_REF] Horikawa | Nonphotic entrainment by 5-HT1A/7 receptor agonists accompanied by reduced Per1 and Per2 mRNA levels in the suprachiasmatic nuclei[END_REF][START_REF] Glass | Photic and nonphotic circadian phase resetting in a diurnal primate, the common marmoset[END_REF][START_REF] Cuesta | Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent[END_REF]. In our recent experiments in Arvicanthis ansorgei where sleep deprivation and caffeine treatment enhanced photic resetting of SCN clock, we reported no change of 5-HT levels in the SCN and midbrain, whereas caffeine treatment increased midbrain serotonin [START_REF] Jha | Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent[END_REF]. Furthermore, serotonin modulates photic resetting differently between nocturnal and diurnal rodents. Serotonergic activation reduces lightinduced shifts in nocturnal rodents, while this treatment potentiates light-induced phase-shifts in the diurnal Arvicanthis [START_REF] Challet | Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals[END_REF][START_REF] Cuesta | Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent[END_REF]. Consistently, a serotonergic activation induced by a single dose of citalopram, a serotonin reuptake inhibitor, increases photic sensitivity of the circadian system in humans [START_REF] Mcglashan | The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose[END_REF]. These results indicate that arousal feedback mediated by serotonin acts differently in nocturnal and diurnal animals.

Orexinergic projections from the lateral hypothalamic area

As already mentioned earlier, orexin-expressing neurons in the LH are important for the appropriate control of arousal [START_REF] Sakurai | The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness[END_REF], and innervate a number of structures implicated in arousal-mediated circadian resetting, such as IGL, median raphe and the peri-SCN region [START_REF] Hughes | Feedback actions of locomotor activity to the circadian clock[END_REF] (Fig. 3). In turn, orexinergic neurons receive indirect afferent projections from the SCN [START_REF] Abrahamson | Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections[END_REF][START_REF] Deurveilher | Indirect projections from the suprachiasmatic nucleus to major arousalpromoting cell groups in rat: implications for the circadian control of behavioural state[END_REF], suggesting reciprocal modulation between circadian and arousal-promoting circuits. It has been reported that novel wheel-running, sleep deprivation by gentle handling and dark pulses elevate c-FOS expression in orexin-expressing cells [START_REF] Marston | Circadian and dark-pulse activation of orexin/hypocretin neurons[END_REF][START_REF] Webb | Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet[END_REF]. Moreover, orexin acutely alters both SCN and IGL neuronal activity in vitro [START_REF] Farkas | Effect of orexin-A on discharge rate of rat suprachiasmatic nucleus neurons in vitro[END_REF][START_REF] Brown | Electrophysiological actions of orexins on rat suprachiasmatic neurons in vitro[END_REF][START_REF] Klisch | Orexin A modulates neuronal activity of the rodent suprachiasmatic nucleus in vitro[END_REF][START_REF] Pekala | The influence of orexins on the firing rate and pattern of rat intergeniculate leaflet neurons--electrophysiological and immunohistological studies[END_REF]. Of note, activation of orexinergic neurons in the LH precedes the onset of the main activity bout [START_REF] Marston | Circadian and dark-pulse activation of orexin/hypocretin neurons[END_REF]. So far, it is not fully clear whether activation of LH neurons is a consequence of nonphotic-like phase-shifts or part of the upstream mechanisms controlling them.

Acetylcholinergic pathways

Two populations of cholinergic neurons project to the SCN, one from the midbrain tegmentum and another one from the basal forebrain [START_REF] Bina | Localization of cholinergic neurons in the forebrain and brainstem that project to the suprachiasmatic nucleus of the hypothalamus in rat[END_REF]. Since cholinergic neurons are involved in the regulation of sleep and arousal, these projections may well transmit behavioural cues to the SCN. Acetylcholine and cholinergic agonists applied in vivo or in vitro led to phaseadvances of the SCN clock, especially at night [START_REF] Trachsel | Nicotine phase-advances the circadian neuronal activity rhythm in rat suprachiasmatic nuclei explants[END_REF][START_REF] Liu | Cholinergic regulation of the suprachiasmatic nucleus circadian rhythm via a muscarinic mechanism at night[END_REF].

J o u r n a l P r e -p r o o f

In rats, damage of cholinergic projections to the SCN reduces and increases light-induced phase-advances and delays, respectively, thus indicating that cholinergic cues modulate photic resetting [START_REF] Erhardt | Modulation of photic resetting in rats by lesions of projections to the suprachiasmatic nuclei expressing p75 neurotrophin receptor[END_REF]. In addition, a more recent study in Syrian hamsters suggests that cholinergic cells in the basal forebrain are necessary for arousal-induced phase-shifting [START_REF] Yamakawa | The cholinergic forebrain arousal system acts directly on the circadian pacemaker[END_REF].

Molecular bases of arousal-induced resetting of circadian rhythms

Arousing stimuli modify expression of immediate early genes in the circadian system. In particular, these non-photic manipulations decrease rhythmic c-FOS expression in the SCN, while they induce its expression in the IGL of nocturnal rodents [START_REF] Janik | Gene expression in the geniculate induced by a nonphotic circadian phase shifting stimulus[END_REF]Mistlberger et al., 1998;[START_REF] Antle | Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster[END_REF][START_REF] Coogan | Dark pulse suppression of P-ERK and c-Fos in the hamster suprachiasmatic nuclei[END_REF]. In response to behavioural arousal, c-FOS expression is triggered specifically in NPYergic cells of the IGL [START_REF] Janik | Cellular colocalization of Fos and neuropeptide Y in the intergeniculate leaflet after nonphotic phase-shifting events[END_REF], whereas a light pulse activates non-NPYergic cells in the IGL. Thus, although the IGL is involved in both non-photic and photic entrainment, it does so through separate cell populations.

As already mentioned, the levels of Per1 and Per2 mRNA are rapidly down-regulated following daytime wheel-confinement in nocturnal hamsters [START_REF] Maywood | Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock[END_REF][START_REF] Maywood | A molecular explanation of interactions between photic and nonphotic circadian clock-resetting stimuli[END_REF]. Similarly, Per1 levels in the SCN decrease after sleep deprivation [START_REF] Webb | Regulation of circadian rhythms in mammals by behavioral arousal[END_REF]. Other non-photic stimuli such as systemic injections of 5-HT1A /7 agonist, intra-SCN NPY and dark pulses, also decrease Per1 and Per2 expression in the SCN [START_REF] Horikawa | Nonphotic entrainment by 5-HT1A/7 receptor agonists accompanied by reduced Per1 and Per2 mRNA levels in the suprachiasmatic nuclei[END_REF][START_REF] Fukuhara | Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus[END_REF][START_REF] Mendoza | Dark pulse resetting of the suprachiasmatic clock in Syrian hamsters: behavioral phase-shifts and clock gene expression[END_REF]. In diurnal rodents the levels of Per1 and Per2 mRNA are reduced in response to dark pulses, but their expression remains unchanged after serotonergic activation [START_REF] Mendoza | Shedding light on circadian clock resetting by dark exposure: differential effects between diurnal and nocturnal rodents[END_REF][START_REF] Cuesta | Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent[END_REF], indicating distinct molecular mechanisms from those reported above in nocturnal rodents.

Serotonergic resetting of the SCN clock in nocturnal rodents is mainly mediated by 5-HT7 and 5-HT1A receptors [START_REF] Lovenberg | Cloning of new 5-HT receptors[END_REF][START_REF] Cuesta | New light on the serotonergic paradox in the rat circadian system[END_REF]. Activation of 5-HT7 receptors leads to an increase in cyclic adenosine monophosphate (cAMP) production [START_REF] Lovenberg | Cloning of new 5-HT receptors[END_REF]. In vitro the circadian rhythm in electrical firing rate of the rat SCN can be shifted in a non-photic manner by activation of the cAMP cascade [START_REF] Prosser | The mammalian circadian clock in the suprachiasmatic nuclei is reset in vitro by cAMP[END_REF]. Protein kinase A (PKA) is activated by cAMP. In in vitro SCN preparations phase-shifts induced by 5-HT1A agonist can be inhibited by pretreatment of the slice with a PKA inhibitor [START_REF] Prosser | Serotonergic phase advances of the mammalian circadian clock involve protein kinase A and K+ channel opening[END_REF]. The non-photic-like phase-shift induced by NPY is mediated by the NPY Y2 receptor [START_REF] Golombek | Neuropeptide Y phase shifts the circadian clock in vitro via a Y2 receptor[END_REF]. Activation of this receptor leads to activation of phospholipase C and J o u r n a l P r e -p r o o f production of inositol triphosphate and diacyl-glycerol, which then leads to release of intracellular Ca 2+ and activation of protein kinase C (PKC). Pretreatment of SCN slices with PKC inhibitors blocks the NPY-induced phase-shifts of the circadian rhythm of electrical firing rate [START_REF] Biello | Circadian phase shifts to neuropeptide Y In vitro: cellular communication and signal transduction[END_REF].

The MAPK family has also been implicated in non-photic and dark pulse-induced phaseshifting. Dark pulses during the subjective day and sleep deprivation suppress ERK phosphorylation in the hamster SCN [START_REF] Coogan | Dark pulse suppression of P-ERK and c-Fos in the hamster suprachiasmatic nuclei[END_REF]. ERK activation may regulate transcription factors, which could lead to changes in clock gene expression. The activated form of ERK is decreased by sleep deprivation in most of the SCN cells. On the other hand, sleep deprivation activates ERK in a small dorsolateral cluster of cells in the caudal SCN [START_REF] Antle | Non-photic phase shifting of the circadian clock: role of the extracellular signal-responsive kinases I/II/mitogen-activated protein kinase pathway[END_REF].

SCN electrical activity and clock resetting

Electrical activity of the SCN is correlated with the rest/activity cycle in both diurnal and nocturnal mammals, i.e. with a positive correlation in diurnal animals and a negative correlation in nocturnal species [START_REF] Inouye | Persistence of circadian rhythmicity in a mammalian hypothalamic "island" containing the suprachiasmatic nucleus[END_REF][START_REF] J O U R N A L P R E -P R O O F Meijer | Multiunit activity recordings in the suprachiasmatic nuclei: in vivo versus in vitro models[END_REF][START_REF] Meijer | Light responsiveness of the suprachiasmatic nucleus: long-term multiunit and single-unit recordings in freely moving rats[END_REF][START_REF] Deboer | Sleep states alter activity of suprachiasmatic nucleus neurons[END_REF]. Behavioural arousal that leads to phase-shifts of the master circadian clock of nocturnal animals is associated with an acute inhibition of SCN neuronal activity, as assessed by suppression of c-FOS expression [START_REF] Antle | Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster[END_REF]. Also, in freely-moving nocturnal rats and hamsters, increased locomotor activity bouts are linked with a transient reduction of SCN firing rate, which recovers when the activity bout ceases [START_REF] J O U R N A L P R E -P R O O F Meijer | Multiunit activity recordings in the suprachiasmatic nuclei: in vivo versus in vitro models[END_REF][START_REF] Yamazaki | Rhythmic properties of the hamster suprachiasmatic nucleus in vivo[END_REF][START_REF] Schaap | Opposing effects of behavioural activity and light on neurons of the suprachiasmatic nucleus[END_REF]. This suppression of SCN firing rate is not induced when animals perform less vigorous activities, such as grooming and feeding. The magnitude of the suppression is thus correlated with the intensity of wheel running [START_REF] Yamazaki | Rhythmic properties of the hamster suprachiasmatic nucleus in vivo[END_REF][START_REF] Schaap | Opposing effects of behavioural activity and light on neurons of the suprachiasmatic nucleus[END_REF][START_REF] Van Oosterhout | Amplitude of the SCN clock enhanced by the behavioral activity rhythm[END_REF]. Moreover, NPY, GABA and serotonin predominantly suppress SCN firing rate [START_REF] Webb | Regulation of circadian rhythms in mammals by behavioral arousal[END_REF]. It would be interesting to study whether behavioural arousal that phase-shifts the circadian clock in nocturnal species independently of locomotor activity, also suppresses SCN firing rate.

Furthermore, the ability of these stimuli to suppress neural activity may be crucial for resetting the molecular clock mechanism in nocturnal mice. Indeed, NPY-induced phase-advances of SCN Per2 expression in vitro are blocked by K + mediated depolarization even 2 h after NPY washout [START_REF] Besing | Neuropeptide Y-induced phase shifts of PER2::LUC rhythms are mediated by long-term suppression of neuronal excitability in a phase-specific manner[END_REF]. Thus, long-term inhibition of SCN neural firing may be necessary to induce non-photic circadian resetting in nocturnal mammals. Because the firing J o u r n a l P r e -p r o o f rate of the SCN is higher during the active phase in diurnal mammals, the feedback effects of behavioural arousal are expected to be quite different from those described above in nocturnal animals. Such a hypothesis deserves to be investigated in future studies.

Conclusion and future directions

Ambient light is the dominant synchronizer of the master clock in the SCN of mammals. SCN responsiveness to light is very similar in terms of circadian phase and direction of induced phase-shifts in nocturnal and diurnal species. In addition to light, behavioural arousal is another potent clock resetting stimulus. Behavioural arousal in the middle of the rest period induces characteristic phase-advances in nocturnal rodents, with arousing stimuli with or without a locomotor activity component showing a similar feedback to the SCN clock. Since the sleep/wake cycle is oppositely phased between nocturnal and diurnal species, it is important to determine the circadian sensitivity of arousal over a 24 h cycle also in diurnal species. It appears that unlike photic entrainment, arousal leads to different responses as compared to nocturnal mammals, both in humans and diurnal rodents. Moreover, interactions of arousing stimuli with photic entrainment involve different pathways or mechanisms because behavioural arousal antagonizes or potentiates the effects of light on the SCN respectively in nocturnal and diurnal mammals. Thus, various studies strengthen the notion that behavioural arousal modulates the master clock differently in nocturnal and diurnal animals to maintain their respective temporal niche. Most likely these disparities are a manifestation of their different temporal activity/rest period, species difference or cumulative effect of both. Most of the studies on mammalian circadian entrainment so far have been done with standard laboratory nocturnal rodents. Further inclusion of diurnal rodents and more studies in human subjects would help to conclude with more certainty whether circadian entrainment follows distinct patterns between these two categories of species. Furthermore, ddetermining how arousal-promoting areas in the brain interact with the SCN and whether this wiring is different between nocturnal and diurnal animals should be studied in more detail in future experiments. Therefore, at the circuit level, new research of wake promoting areas connected to the SCN needs to be performed. In addition, further investigations of how wake-promoting molecules, like caffeine and modafinil, modulate circadian rhythms in a time-of-day dependent manner in diurnal animal models could also be helpful to develop chronotherapies and other biomedical applications to counteract or prevent circadian misalignment commonly induced by disturbed sleep, shift work, or transmeridian travels.

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  o u r n a l P r e -p r o o f yet. New experiments aiming to study gene expression in the SCN and elsewhere in the brain during sleep deprivation and recovery sleep over a few circadian cycles would help to better understand how the sleep homeostasis interacts with the circadian pacemaker in the SCN.

Fig. 1 .

 1 Fig. 1. Temporal organization of daily rhythms of (A) sleep, (B) body temperature, (C) blood glucose and (D) plasma glucocorticoids in nocturnal (blue line) and diurnal (red line) mammals.

Fig. 2 .

 2 Fig. 2. Schematic representation of effects of light-induced phase shifts in nocturnal and diurnal mammals housed in constant darkness. (A-B) Actograms of wheel-running activity of nocturnal (A) and diurnal (B) rodents. Yellow circles represent time-points of brief light exposure. (C-D) Phase-response curves to light in nocturnal (C) and (D) diurnal animals.

Fig. 3 .

 3 Fig. 3. Schematic network of brain nuclei and neurotransmitters involved in photic and nonphotic entrainments. Photic signals transmitted to the SCN directly via RHT releasing glutamate and PACAP. Non-photic signals utilize network of neural connections involving DRand MR, the IGL, BF and the LH to reach the SCN. These networks use serotonin, NPY, GABA, enkephalin, neurotensin, acetylcholine and orexin to transmit arousal-related information to the SCN. BF, basal forebrain; DR, dorsal raphe; Enk, enkephalin; GABA, gamino butyric acid; GHT, geniculohypothalamic tract; Glu, glutamate; IGL, intergeniculate leaflet; LH, lateral hypothalamic area; MR, median raphe; Neur, neurotensin; PACAP, pituitary adenylate-cyclase-activating peptide; RHT, retinohypothalamic tract; SCN, suprachiasmatic nucleus..

Fig. 4 .

 4 Fig. 4. Schematic representation of phase-shifts induced by sleep deprivation (SD), light pulse and a combination of both for nocturnal and diurnal mammals kept in constant darkness. (A-B) Actograms of wheel-running activity of nocturnal (A) and diurnal (B) rodents. Gray rectangular bars represents timelines of sleep deprivation and yellow circles represent timepoints of brief light exposure. Phase advances and delays are represented by positive and negative signs, respectively.

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The authors have no conflict of interest to declare. This review is based partly on the PhD thesis introduction of Pawan Kumar Jha entitled "Sleep deprivation and its impact on circadian rhythms and glucose metabolism" from the University of Strasbourg, Strasbourg, France and the University of Amsterdam, Amsterdam, the Netherlands.

Conflict of Interest

J o u r n a l P r e -p r o o f