No 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 ...

The adrenal glucocorticoid, corticosterone, induces changes in gene expression in both neural and non-neural tissues. The rhythmic release of corticosterone has been shown in rats to be necessary for the rhythmic expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain. The mechanisms mediating the effects of glucocorticoids on changes in gene expression have been linked to the transcriptional activity of the low affinity glucocorticoid receptor, GR. We examined the patterns of PER2 expression in the brains of mice containing an inactivation of GR gene restricted to neural tissues (GR(NesCre) mice). We found that central deletion of the GR gene blunts the daily pattern of PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and central nucleus of the amygdala (CEA) both of which make up the central extended amygdala, but not in the suprachiasmatic nucleus (SCN), basolateral amygdala (BLA) or dentate gyrus of the hippocampus (DG). These results implicate brain GR receptors in the regulation of PER2 expression in the BNSTov and CEA and are consistent with our previous findings that the rhythmic expression of PER2 in these areas is selectively sensitive to fluctuations in circulating corticosterone.

Glucocorticoids regulate a wide variety of functions, including synaptic plasticity, hypothalamic-pituitaryadrenal axis activation, conditional fear learning, metabolism, and sensitization to drugs of abuse. The diurnal secretion of glucocorticoids, driven by the mammalian master clock located in the suprachiasmatic nucleus of the hypothalamus, has been shown to induce and entrain clock gene expression in peripheral tissues. However, little attention has been given to the form and function of centrally located subordinate oscillators, and the synchronizing factors that influence them. Here we review findings that implicate glucocorticoids in the circadian regulation of clock genes in select oscillators in the limbic forebrain and propose mechanisms whereby glucocorticoids can feed back on rhythms downstream from the master clock and possibly alter the functional output of these nuclei.

The cyclical expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain is contingent upon the rhythmic secretion of the adrenal glucocorticoid, corticosterone. Daily rhythmic PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the central nucleus of the amygdala (CEA) is abolished with the removal of the adrenal glands but restored with rhythmic hormone replacement via the drinking water at a time corresponding to the endogenous peak of circulating glucocorticoids. Here, we investigated the effects of serial or acute systemic injections of corticosterone on the expression of PER2 in the BNSTov and CEA of both adrenalectomized (ADX) and intact rats. We sought to determine whether there is a temporal window of corticosterone sensitivity by delivering the hormone at a time corresponding to trough levels of circulating glucocorticoids, at lights on. We found that daily morning injections of corticosterone induced PER2 expression in the BNSTov and CEA of ADX rats, with levels peaking 1 h after injection. In intact rats, daily morning injections significantly upregulated the expression of PER2 in the BNSTov and CEA 1 h after injection and dampened the evening peak, while a single injection abolished the rhythm of PER2 expression in the CEA but had no effect on PER2 in the BNSTov. Our findings suggest that despite the potential masking effect of signals from the light-entrained master clock, daytime chronic and acute corticosterone administration can alter the rhythmic expression of PER2 in the BNSTov and CEA, and that the response is region-specific and dependent on the duration of treatment.