34 The nocturnal melatonin signal is also crucial for the rhythmic expression in the PT of several cAMP-responsive genes, including the transcriptional inhibitor-inducible cAMP early repressor (ICRR), and of several clock genes.36,37 Indeed, two components of the molecular clock, namely Perl and Cry 1, are TWS119 manufacturer rhythmically expressed in the FT Furthermore, other components of the clock like Timeless, Clock, and Perl (Pévet P et al, unpublished observations) are also expressed in the PT, at least in the PT of some

rodents, raising the possibility that Inhibitors,research,lifescience,medical the PT might contain a complete set of clock genes.33,36,38-41 However, the clock gene expression in the PT differs from what is observed in the SCN or other peripheral tissues (peripheral oscillators) because it appears to be directly driven by

melatonin. Removal of the pineal Inhibitors,research,lifescience,medical gland abolishes rhythmic PT gene expression, and extension of the dark phase of the LD cycle dampens the amplitude of the Perl in PT cells.39 Cry1 is rapidly and very strongly induced by melatonin administration. In nontrcated animals, a peak of expression occurs during the dark phase (ie, at a time when melatonin is present in the bloodstream). This indicates that melatonin may gate the expression of Cry1 in the PT, suggesting that these clock genes are involved in the melatonin readout mechanism. Cry1 expression Inhibitors,research,lifescience,medical appears to be anchored to the onset of melatonin secretion. It acts as a sensor of melatonin onset, rather than a marker of the duration Inhibitors,research,lifescience,medical of the melatonin signal. Per1 mRNA peaks early in the day, when blood plasma melatonin levels are back to low levels. Per1 expression thus appears

to be linked to the offset of melatonin secretion. This dual effect of melatonin together with its photoperiod-dependent pattern in plasma levels may provide the basis of a time measurement mechanism. This model may help understand how the PT is involved in the seasonal control of prolactin secretion by the PT. The validation of such a model will, however, require Inhibitors,research,lifescience,medical further experiments and the complete understanding of the melatonin and photoperiodic readout requires a link with identified downstream response in the PR This is still difficult. It is through the production of a prolactin-releasing (or release inhibitor) factor that the photoperiodic and melatonin information to lactotroph cells in the pituitary Chlormezanone arc relayed. This factor, termed “tubcralin,”30,42 has not yet been identified. Photoperiod-induced changes in prolactin secretion, however, are not enough to explain the seasonal sexual cycle. This implies that in order to mediate photoperiodic information melatonin must act on other target sites. This view is supported by the fact that Syrian hamsters bearing lesions to the dorsomedial hypothalamus (DMH) and infused with melatonin to mimic short photoperiod (SP), display differential responses in terms of prolactin and luteinizing hormone (LH).