The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle

Abstract

Daily behavioral and physiological rhythms are linked to circadian oscillations of clock genes in the brain and periphery that are synchronized by the master clock in the suprachiasmatic nucleus. In addition, there are a number of inputs that can influence circadian oscillations in clock gene expression in a tissue-specific manner. Here we identify an influence on the circadian oscillation of the clock protein PER2, endogenous changes in ovarian steroids, within two nuclei of the limbic forebrain: the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala. We show that the daily rhythm of PER2 expression within these nuclei but not in the suprachiasmatic nucleus, dentate gyrus, or basolateral amygdala is blunted in the metestrus and diestrus phases of the estrus cycle. The blunting of the PER2 rhythm at these phases of the cycle is abolished by ovariectomy and restored by phasic estrogen replacement suggesting that fluctuations in estrogen levels or their sequelae are necessary to produce these effects. The finding that fluctuations in ovarian hormones have area-specific effects on clock gene expression in the brain introduces a new level of organizational complexity in the control of circadian rhythms of behavior and physiology.circadian clock ͉ circadian rhythm ͉ estrogen T he core molecular mechanism generating circadian rhythms within the suprachiasmatic nucleus (SCN), the master circadian clock, is based on feedback loops among several rhythmically expressed clock genes and their protein products (1, 2). Circadian rhythms in clock gene expression are observed not only in the SCN but also in other brain areas as well as peripheral tissues. These include but are not limited to the olfactory bulb, several hypothalamic nuclei, the eyes, pituitary gland, heart, and lung (3-13). Because synchronized expression of clock genes in these tissues requires an intact SCN, it has been proposed that these oscillations in clock gene expression serve to gate circadian signals from the SCN into tissue-specific rhythmic outputs (10,12,13).In addition, there is growing evidence to suggest that circulating hormones as well as metabolic signals can modulate circadian oscillations of clock gene expression in some brain regions and peripheral structures (14). For example, the pineal hormone melatonin modulates the rhythm of the clock gene Per1 in the pituitary gland, striatum, and adrenal cortex (15-17). Furthermore, adrenal glucocorticoids induce Per1 expression in peripheral tissues such as the liver (18,19) and modulate the rhythm of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminal (BNST-OV) and central nucleus of the amygdala (CEA) (12, 13). By contrast, adrenalectomy has no effect on PER2 expression in the SCN, basolateral amygdala (BLA), or dentate gyrus (DG) (12, 13), and melatonin does not affect rhythms of clock gene expression in the SCN, limbic forebrain, eye, or heart (20). The ability of circulating hormones to modulate clock gene ...

Up-regulation of Per1 expression by estradiol and progesterone in the rat uterus

“…The finding of up-regulation of Per1 expression by E 2 may contribute to understand how ER functions to phase shift the circadian rhythms of clock gene expression and to alter the behavior and endocrine rhythms (Morin et al 1977, Thomas & Armstrong 1989, Nakamura et al 2005, Perrin et al 2006. We also find that P 4 efficiently activates the expression of Per1 gene in the uterus, which indicates that P 4 might also have profound effects on circadian clockwork.…”

“…It has been demonstrated that estrogen administration alters the circadian rhythms in behavior and endocrine physiology in rodents (Morin et al 1977, Thomas & Armstrong 1989. Recently, it was found that the phase of estrous cycle has a profound effect on the oscillation of PER2 protein within the brain (Perrin et al 2006). It was further reported that chronic treatment with E 2 drastically alters the circadian rhythms of Per1 and Per2 expression in the liver, kidney, and uterus (Nakamura et al 2005).…”

The clock gene Per2 links the circadian system to the estrogen receptor

“…Together, these Per2 links the circadian system to ER S Gery et al studies suggest that control of protein turnover is an important feature of circadian regulation. Recent studies in rats showed Per2 is differentially regulated by E2 in specific tissues (Nakamura et al, 2005;Perrin et al, 2006). We found that Per2 mRNA levels were induced by E2 in ERa-positive breast cancer cell lines (Figure 3a), showing that the human Per2 gene is E2-inducible in mammary epithelial cells.…”

The Role of Circadian Regulation in Cancer

“…Interestingly, Per2 was also suggested to have a role in normal mammary cell differentiation (Metz et al 2006). Studies in rats have shown that estrogen differentially regulates the expression of per1 and per2 in specific brain regions as well as in some peripheral tissues (i.e., liver, kidney, and uterus) (Nakamura et al 2005;Perrin et al 2006). A circadian clock was reported to function in rat ovarian cells, further implicating circadian regulation in local endocrine tissues, as well as its role in the hypothalamopituitary-ovarian axis (Fahrenkrug et al 2006).…”