**4. Light-dependent transcription in the mammalian retina**

Dopamine is the major catecholamine in the vertebrate retina and plays a central role in neural adaptation to light. Indeed, light stimulates the synthesis, turnover, and release of retinal dopamine, which makes dopamine an important mediator of light signaling to retinal cellular clocks [35–37]. Among the members of the dopamine-receptor family, the dopamine D2 receptor (D2R) has been shown to control light-induced reset of the circadian clock in the mouse retina [38–40]. At the molecular level, it has been reported that signaling mediated by the D2R enhances the transcriptional capacity of the CLOCK:BMAL complex. This effect involves the extracellular signal-regulated kinase (ERK)/MAPK transduction cascade and is associated with a D2R-induced increase in phosphorylation of the transcriptional coactivator, cAMP-responsive element-binding protein (CREB) and its recruitment to the CLOCK:BMAL complex [40]. Importantly, this activation of CLOCK:BMAL1-dependent transcription is responsible for the induction of the *Per1* gene by light in the retina, which is in turn responsible for the reset of the retinal cellular clock. These findings provide evidence for the physiological links among the ERK/MAPK signaling pathway, dopamine, and the light input pathway of circadian clocks.

### **5. Light-dependent transcription in mammalian SCN**

Light resets the circadian clock by its phase-shifting properties. In particular, the phase-shifting effects of light only occur during the nighttime period of the circadian cycle. In nocturnal mammals kept in darkness, a light pulse during the subjective night (that is, the time of day corresponding to the dark period in a normal light-dark cycle) can reset the clock by evoking changes in the SCN-controlled rhythms [41–43]. If the light pulse is given at an early point in time during the subjective night, it induces a shift in SCN-controlled rhythms to a later time (phase delay). Conversely, if the light pulse is provided at the end of the subjective night, the SCN-controlled rhythms will be shifted to an earlier position in the circadian cycle (phase advance). Photic signals perceived by the retina are conveyed to the SCN through the RHT [32]. Glutamate has been identified as the major neurotransmitter responsible for transducing the photic information to the SCN along the RHT [44] (**Figure 2**). Once glutamate is released by the SCN, it binds to N-methyl-d-aspartate (NMDA) receptors, which in turn leads to the Ca2+ influx, that is, finally responsible for the activation of calcium-/calmodulin-dependent protein kinase (CaMK).

The involvement of the ERK/MAPK pathway in the light-input system of the circadian clock in the SCN has been well established. Mice exposed to light pulses during their subjective night display rapid ERK upregulation (phosphorylation) in the SCN [45]. Furthermore, disruption of the MAPK pathway has been shown to block light-induced phase shifting of the circadian clock at the behavioral level [46]. This finding suggests that the ERK cascade is integrally involved in photic entrainment of mammalian circadian rhythms. Events downstream of the light-induced signaling pathway in the SCN lead to the phosphorylation of cAMPresponse element-binding protein (CREB), which then stimulates expression of Per1 and Per2 genes, which contain a calcium-/cAMP-response element (CRE) in their promoters [6, 47, 48]. Although the exact mechanism by which light induces early gene expression remains to be elucidated, it has been shown that a single light pulse engenders chromatin remodeling via the phosphorylation of histone H3 at Ser10 [49].

**25**

**SCN**

**Figure 2.**

*Light-Dependent Regulation of Circadian Clocks in Vertebrates*

**RHT**

**NMDA receptor**

**CaM Kinase**

**ERK**

Synapse

SCN neuron

*Per1, Per2*

Ca2+ influx

Kinase ?

**6. Light-dependent synchronization of cellular clocks in the mammalian** 

The appropriate synchronization of cellular clocks in tissues and organs is required for the generation of circadian rhythms in a variety of physiological processes, such as sleep and metabolism [50]. In addition, the light-dependent induction of *Per1* and *Per2* is thought to contribute to the synchronization of cellular clocks in the SCN [6, 8]. However, this idea has not been fully elucidated using adequate genetically modified mice. Mouse *Per1* and *Per2* genes are induced by the CLOCK (NPAS2):BMAL complex and by light. In particular, the CLOCK (NPAS2):BMALdependent regulation of *Per1* and *Per2* is essential for establishment of the circadian clock's rhythmicity. Thus, genetic inhibition of both mouse *Per1* and *Per2* genes disrupts the cellular clock, preventing the analysis of synchronization [51, 52]. This

**CRE**

*Signaling cascade transducing photic signal perceived by the retina to the transcription of clock genes in SCN.*

**CREB**

P

problem has been solved by using zebrafish models, as described below.

*DOI: http://dx.doi.org/10.5772/intechopen.86524*

**Glutamate**

*Light-Dependent Regulation of Circadian Clocks in Vertebrates DOI: http://dx.doi.org/10.5772/intechopen.86524*

*Chronobiology - The Science of Biological Time Structure*

of circadian clocks.

protein kinase (CaMK).

**4. Light-dependent transcription in the mammalian retina**

**5. Light-dependent transcription in mammalian SCN**

Light resets the circadian clock by its phase-shifting properties. In particular, the phase-shifting effects of light only occur during the nighttime period of the circadian cycle. In nocturnal mammals kept in darkness, a light pulse during the subjective night (that is, the time of day corresponding to the dark period in a normal light-dark cycle) can reset the clock by evoking changes in the SCN-controlled rhythms [41–43]. If the light pulse is given at an early point in time during the subjective night, it induces a shift in SCN-controlled rhythms to a later time (phase delay). Conversely, if the light pulse is provided at the end of the subjective night, the SCN-controlled rhythms will be shifted to an earlier position in the circadian cycle (phase advance). Photic signals perceived by the retina are conveyed to the SCN through the RHT [32]. Glutamate has been identified as the major neurotransmitter responsible for transducing the photic information to the SCN along the RHT [44] (**Figure 2**). Once glutamate is released by the SCN, it binds to N-methyl-d-aspartate (NMDA) receptors, which in turn leads to the Ca2+ influx, that is, finally responsible for the activation of calcium-/calmodulin-dependent

The involvement of the ERK/MAPK pathway in the light-input system of the circadian clock in the SCN has been well established. Mice exposed to light pulses during their subjective night display rapid ERK upregulation (phosphorylation) in the SCN [45]. Furthermore, disruption of the MAPK pathway has been shown to block light-induced phase shifting of the circadian clock at the behavioral level [46]. This finding suggests that the ERK cascade is integrally involved in photic entrainment of mammalian circadian rhythms. Events downstream of the light-induced signaling pathway in the SCN lead to the phosphorylation of cAMPresponse element-binding protein (CREB), which then stimulates expression of Per1 and Per2 genes, which contain a calcium-/cAMP-response element (CRE) in their promoters [6, 47, 48]. Although the exact mechanism by which light induces early gene expression remains to be elucidated, it has been shown that a single light pulse engenders chromatin remodeling via the phosphorylation of histone H3

Dopamine is the major catecholamine in the vertebrate retina and plays a central role in neural adaptation to light. Indeed, light stimulates the synthesis, turnover, and release of retinal dopamine, which makes dopamine an important mediator of light signaling to retinal cellular clocks [35–37]. Among the members of the dopamine-receptor family, the dopamine D2 receptor (D2R) has been shown to control light-induced reset of the circadian clock in the mouse retina [38–40]. At the molecular level, it has been reported that signaling mediated by the D2R enhances the transcriptional capacity of the CLOCK:BMAL complex. This effect involves the extracellular signal-regulated kinase (ERK)/MAPK transduction cascade and is associated with a D2R-induced increase in phosphorylation of the transcriptional coactivator, cAMP-responsive element-binding protein (CREB) and its recruitment to the CLOCK:BMAL complex [40]. Importantly, this activation of CLOCK:BMAL1-dependent transcription is responsible for the induction of the *Per1* gene by light in the retina, which is in turn responsible for the reset of the retinal cellular clock. These findings provide evidence for the physiological links among the ERK/MAPK signaling pathway, dopamine, and the light input pathway

**24**

at Ser10 [49].
