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subject to changes in their environment such as during travel across time
zones. The entrainment process takes days to week, temporarily involving
desynchronization between the central clock and the peripheral organs. For
example, the disruption of the circadian clock during travel across time
zones produces jet lag, as homeostatic and circadian cues temporarily are
out of sync. The endogenous circadian clock must reentrain, a process that
relies on distinct signaling transduction pathways that lie upstream of the
transcriptional translational loops of the clock machinery already described.
The clock proteins are required to maintain circadian oscillations in the
SCN (i.e., Bmal1 knockout animals and Clock mutant mice have altered cir-
cadian rhythms in SCN tissue). The clock system uses both photic and non-
photic inputs to transduce the signals necessary for alterations in chromatin
structure. Specifically, photic and nonphotic inputs are integrated in the
SCN by various signal transduction pathways which result in epigenetic
changes which alter gene expression. For example, neurons of the SCN
respond to pituitary adenylyl cyclase-activating peptide during the subjec-
tive day, 50 while at night they respond to acetylcholine as well as other
cGMP-activating analogs. 51 While nonphotic SCN resetting can occur
via serotonergic innervation, 52 light exposure during the subjective night
can also reset the SCN clock by inducing the release of glutamate from ret-
inal ganglion cells, leading to activation of NMDA receptors on SCN neu-
rons. NMDA-induced depolarization of SCN neurons causes an activation
of calcium-sensitive adenylyl cyclases in the SCN and the production of
cAMP. In turn, cAMP activates proteins such as the guanine nucleotide
exchange factors (EPAC proteins) as well as the mitogen-activated protein
kinase (MAPK) signaling cascade, which in neuronal cells couples depolar-
ization to transcription via activation of CREB. Indeed, organisms exposed
to a light pulse at night show a rapid and robust MAPK phosphorylation in
the SCN as well as phosphorylation of CREB and activation of cAMP
response element (CRE)-mediated gene transcription. 53,54 cAMP oscilla-
tions are necessary for circadian rhythmicity in the SCN. 55 Inhibition of
cAMP-producing adenylyl cyclase enzymes prolongs period length, an
event which is abrogated by mutations in the central clock machinery.
Understanding of the central pathways involved in SCN plasticity provides
an essential framework for understand how chromatin remodeling in the
brain participates in cellular and systems-wide level timekeeping.
Initial studies looking at the role of epigenetic processes in circadian gene
expression revealed that a pulse of light administered to a nocturnal rodent
during its subjective night period can induce phosphorylation as H3S10. 56
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