Light resets the phase in SCN clocks

Eyes are crucial for vision and daily resetting of the circadian system. Hence enucleated animals are blind and cannot remain synchronized to the photoperiod. Their clocks are therefore free-running with their own endogenous period length (Yamazaki et al., 1999).

Photoreception occurs in the retina. During the few past yers, it has been shown that, unexpectedly, the well known rods’ and cones’ visual phototransduction pathways are dispensable for the synchronizytion of the central clock (Freedman et al., 1999). Entrainment by light can occur in a parallel non-image forming pathway involving a small subset of retinal ganglion cells (RGCs) of the inner retina layer that express melanopsin photopigment and are light sensitive (in contrast to most other RGCs). Melanopsin containing RGCs directly

innervate the SCN through the RHT, and allow the entrainment of the molecular pacemaker by releasing glutamate (Glu) and pituary adenylate cyclase acitvating peptide (PACAP) neurotransmitters. By contrast, the majority of the axonal projections from the other RGCs inervate the late geniculate nucleus (LGN), which transmits the photic information to the visual area of the occipital cortex. Melanopsin knock-out mice only display mild light induced phase-shifting phenotypes and can entrain to a circadian photoperiod. However when melanopsin, rods and cones are absent, mice completely lose circadian photoentrainement and free-run with their internal period length (Hattar et al., 2003; Panda et al., 2003). Thus circadian photoperception is a property of both the cells of the outer retina (rods and cones) and melanopsin-expressing RGCs of the inner retina (Figure 17). The implication of CRY photopigments in addition to melanopsin in circadian photoreception was more difficult to assess, since CRYs play a central role in the core oscillator. A study has shown that CRYs seem to be involved in pupillary reflex, and conceivably they could also participate to nonvisual photoreception in the inner retina. However more investigations are needed to clarify their role in this process (Van Gelder, 2005).

In addition to the SCN, RHT projections also reach the olivary pretectal nucleus (OPN) that participates to pupillary reflex pathways, and the intergeniculate leaflets (IGL) and the subparaventricular zone (SPZ) of the hypothalamus that are believed to contribute to the masking response (rapid SCN-independent inhibition of locomotor activity by light) (Cermakian and Sassone-Corsi, 2002; Gooley et al., 2003; Li et al., 2005; Markwell et al., 2010; Morin and Allen, 2006; Redlin et al., 1999) (Figure 17). The IGL transmits processed light information to the SCN via direct geniculo-hypothalamic tract (GHT) projections that release neuropeptide Y (NPY) and gamma-amino-butyric acid (GABA). Furthermore, it is important to note that the SCN can also be entrained by non photic signals directly from the dorsal and median raphe nuclei (DRN and MRN) and indirectly from the IGL, which is itself inervated by the DRN and MRN. These non-photic signals transmit information resulting

from behavioral arousal and/or stress (Dibner et al., 2010; Webb et al., 2010).

RHT neurons release Glu and PACAP in synapses of the ventrolateral SCN. SCN neuron membrane depolarization initiates then a cascade of events leading ultimately to the induction of immediate-early genes (such as c-fos, Jun-B) and clock genes (such as Per1, Per2) (Albrecht et al., 1997; Zylka et al., 1998b). This is accompagnied by specific chromatin Figure 17. Model of visual and non-visual photoreception (top). Melanopsin containing retinal gaglion cells (RGCs) (full black circles) directly innervate the SCN, the olivary pretectal nucleus (OPN), the intergeniculate leaflets (IGL) and the subparaventricular zone (SPZ) of the hypothalamus through the retino-hypothalamic tract (RHT). INL, inner nuclear layer; LGN, late geniculate nucleus. Continuous or dotted lines represent major or minor projections. Glutamate (Glu), differentially activates Ca2⁺-dependent signaling pathways in a time-of-day-dependent manner. Substance P (SubP) and pituitary adenylate cyclase activating peptide (PACAP) released from the RHT modulate glutamate action. Activated kinases phosphorylate cAMP response element-binding protein (CREB) that in turn activates Per transcription by direct interaction with a calcium/cAMP response element (CRE, blue) in the promoter region of each gene (bottom). C, CLOCK; B, BMAL1; CaMK, calcium calmodulin-dependent kinases; MAPK, MAPkinase; PKA, PKC, PKG, protein kinase A, C, G. This Figure is adapted from (Reppert and Weaver, 2001).

remodelling (such as histone H3 phosphorylation) (Crosio et al., 2000). Per1 and c-fos gene induction is dependent upon the activation of mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and the transcription factor cAMP response element–binding protein (CREB). C-fos, Per1 and Per2 genes contain a cAMP response element (CRE) within their promoter regions. Hence, Per1 and Per2 genes can be activated independently of the CLOCK:BMAL1-controlled E-box activation (Travnickova-Bendova et al., 2002) (Figure 17). The light-dependent induction of Per genes provides thus a plausible way for explaining how a light input can reset the phase of SCN clocks. Thus, a light pulse given at the beginning of the night will cause prolonged PERs expression and phase delay, while a light pulse given at the end of the night will cause precocious PERs expression and phase advance (Daan and Pittendrigh, 1976).

Two observations suggest that intercellular communications in the SCN are important for the generation of rhythmic activity. First, not all neurons of the SCN form synapses with the RHT, and their phase is thus not directly reset by light signals. The ventrolateral SCN is most heavily innervated by RGC fibers, while few innervations reach the dorsomedial SCN (Gooley et al., 2003). In the same perspective, it has been shon that differentially phased neuronal clocks are topographically arranged across the SCN (Yamaguchi et al., 2003). SCN neurons must thus synchronize not only to light/dark cycles but also to one another. Secondly, dissociated SCN neurons in culture loose phase coherence, while neurons within SCN slices keep stable and synchronized rhythms (Liu et al., 2007). In addition, mice with a disrupted Vipr2 gene, coding for the transmembrane receptor of the neuroendocrine hormones VIP (vasoactive intestinal peptid) and PACAP, are completely arrhythmic (Harmar et al., 2002).

Thus, communication between neurons occurs not only via a synaptic network, but also via paracrine secretion, and both play an important role in the maintenance of circadian function within the SCN.