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Biomedical subjects

Shimon Amir

Publications and source records attributed to Shimon Amir.

10 recordsLinked to original sources
PubMed2006

Thyroidectomy alters the daily pattern of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats.

A role for thyroid hormones in the regulation of the rhythmic expression of circadian clock genes is suggested by the finding that surgical removal of the thyroid gland alters circadian behavioral and endocrine rhythms in rodents. Virtually nothing is known about the role of thyroid hormones in the regulation of clock genes responsible for the generation of circadian rhythmicity. To study this issue, we assessed in rats the effect of thyroidectomy/parathyrodectomy (TPX) on the expression of the clock protein, PER2, in the suprachiasmatic nucleus (SCN), the master circadian clock, and in a number of key limbic forebrain structures, the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA) and the dentate gyrus (DG). TPX significantly altered the normal daily pattern of PER2 expression in the BNSTov and CEA, but had no effect on PER2 expression in the SCN, BLA and DG. Thus, although thyroid hormones modulate PER2 expression in the brain, the effect is tissue specific and therefore likely not to be mediated by a direct effect of the hormone on gene expression.

Amygdala↗
PubMed2006

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

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.

Animals↗
PubMed2006

Pinealectomy does not affect diurnal PER2 expression in the rat limbic forebrain.

A role for the pineal hormone, melatonin, in the regulation of the rhythmic expression of circadian clock genes is suggested by the finding that surgical removal of the pineal gland abolishes the rhythm of expression of clock genes such as Per1 in several neural and endocrine tissues in rodents, including the caudate-putamen (CP) and nucleus accumbens, the hypophyseal pars tuberalis and adrenal cortex. Pinealectomy has no effect on clock gene rhythms in the suprachiasmatic nucleus (SCN), the master circadian clock, as well as in the eyes and heart, indicating that the effect of melatonin on clock gene rhythms is tissue specific. To further study the role of melatonin in the regulation of the rhythm of clock genes, we assessed in rats the effect of pinealectomy on the rhythm of expression of the clock protein, PER2, in a number of key limbic forebrain structures, the oval nucleus of the bed nucleus of the stria terminalis (BNST-OV), the central nucleus of the amygdala (CEA) and the hippocampus (HIPP). Despite previous evidence showing that these regions are sensitive to melatonin, pinealectomy had no effect on the daily rhythm of expression of PER2 within these structures, further supporting the view that the role of endogenous melatonin in the regulation of clock gene expression is tissue specific.

Animals↗
PubMed2005

The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2.

There is considerable evidence that circadian rhythms in mammals can be modulated by emotional state, but how emotional state modulates specific circadian outputs is poorly understood. We analyzed the expression of the circadian clock protein Period2 (PER2) in three regions of the limbic forebrain known to play key roles in emotional regulation, the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA), and the dentate gyrus (DG). We report here that cells in all three regions exhibit daily rhythms in expression of PER2 that are under the control of the master clock, the suprachiasmatic nucleus (SCN). The rhythm in the CEA and the rhythms in the BLA and DG are diametrically opposite in phase and are differentially affected by adrenalectomy. Adrenalectomy completely abolished the PER2 rhythm in the CEA but had no effect on the PER2 rhythms in the BLA and DG. We previously reported a rhythm in PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis that is identical in phase and sensitivity to adrenalectomy to that found in the CEA. Together, these findings show that key structures of the limbic forebrain exhibit daily oscillations in clock gene expression that are controlled not only by input from the SCN but, importantly, by hormonal and neurochemical changes that normally accompany motivational and emotional states. Thus, cells within these areas are strategically positioned to integrate the inputs from the SCN and emotional states to modulate circadian rhythms downstream from the SCN clock.

Adrenalectomy↗
PubMed2004

A circadian rhythm in the expression of PERIOD2 protein reveals a novel SCN-controlled oscillator in the oval nucleus of the bed nucleus of the stria terminalis.

Circadian rhythms in mammals are regulated not only globally by the master clock in the suprachiasmatic nucleus (SCN), but also locally by widely distributed populations of clock cells in the brain and periphery that control tissue-specific rhythmic outputs. Here we show that the oval nucleus of the bed nucleus of the stria terminalis (BNST-OV) exhibits a robust circadian rhythm in expression of the Period2 (PER2) clock protein. PER2 expression is rhythmic in the BNST-OV in rats housed under a light/dark cycle or in constant darkness, in blind rats, and in mice, and is in perfect synchrony with the PER2 rhythm of the SCN. Constant light or bilateral SCN lesions abolish the rhythm of PER2 in the BNST-OV. Large abrupt shifts in the light schedule transiently uncouple the BNST-OV rhythm from that of the SCN. Re-entrainment of the PER2 rhythm is faster in the SCN than in the BNST-OV, and it is faster after a delay than an advance shift. Bilateral adrenalectomy blunts the PER2 rhythm in the BNST-OV. Thus, the BNST-OV contains circadian clock cells that normally oscillate in synchrony with the SCN, but these cells appear to require both input from the SCN and circulating glucocorticoids to maintain their circadian oscillation. Taken together with what is known about the functional organization of the connections of the BNST-OV with systems of the brain involved in stress and motivational processes, these findings place BNST-OV oscillators in a position to influence specific physiological and behavioral rhythms downstream from the SCN clock.

Adrenalectomy↗
PubMed2004

Fos expression in the suprachiasmatic nucleus during photic entrainment of circadian rhythms in retinally damaged rats.

The protein product of the immediate-early gene c-fos is expressed rhythmically in the shell region of the suprachiasmatic nucleus (SCN), the mammalian circadian clock. Recently, we found that exposure to an entraining light pulse caused a suppression of Fos expression in the SCN shell in rats. To study the hypothesis that suppression of Fos in the shell is a correlate of photic entrainment, we used rats that were treated with the retinal neurotoxin monosodium glutamate (MSG) during the neonatal period. In spite of retinal degeneration, MSG-treated rats entrained normally and displayed light-induced suppression of Fos within the SCN shell. These results support the view that light-induced suppression of Fos within the SCN shell is a cellular correlate of photic entrainment.

Animals↗
PubMed2003

Melanopsin in the circadian timing system.

In mammals, circadian rhythms are generated by a light-entrainable oscillator located in the hypothalamic suprachiasmatic nucleus (SCN). Light signals reach the SCN via a dedicated retinal pathway, the retinohypothalamic tract (RHT). One question that continues to elude scientists is whether the circadian system has its own dedicated photoreceptor or photoreceptors. It is well established that conventional photoreceptors, rods and cones, are not required for circadian photoreception, suggesting that the inner retinal layer might contribute to circadian photoreception. Melanopsin, a novel photo pigment expressed in retinal ganglion cells (RGCs), has been proposed recently as a candidate circadian photoreceptor. Melanopsin-containing RGCs are intrinsically photosensitive, form part of the RHT, and contain neurotransmitters known to play a critical role in the circadian response to light. Furthermore, melanopsin-containing RGCs do not depend on inputs from rods and cones to transmit light signals to the SCN. However, based on a review of the available information about melanopsin and on new data from our laboratory, we propose that melanopsin, in itself, is not necessary for circadian photoreception. In fact, it appears that of the known photoreceptor systems, none, in and of itself, is necessary for circadian photoreception. Instead, it appears that within the photoreceptive systems there is some degree of redundancy, each contributing in some way to photic entrainment.

Animals↗
PubMed2003

Expression profiles of PER2 immunoreactivity within the shell and core regions of the rat suprachiasmatic nucleus: lack of effect of photic entrainment and disruption by constant light.

The circadian clock cells of the mammalian suprachiasmatic nucleus (SCN) generate oscillations in physiology and behavior that are synchronized (entrained) by the external light/dark (LD) cycle. The mechanisms that mediate the effect of light on the core molecular mechanism of the clock are not well understood, but evidence suggests that the Period2 gene, which encodes a key clock regulator (PER2), might be involved. We assessed the expression of PER2 immunoreactivity in the retinorecipient core and shell compartments of the SCN of rats entrained to cycles of discrete light pulses presented at the early subjective day (dawn) or night (dusk), or housed in constant light. We found that in animals entrained to a 0.5 h:23.5-h LD cycle (light falls near dawn), PER2 expression is rhythmic both in the shell and in the core regions of the SCN and indistinguishable from that seen in the SCN of control rats housed in complete darkness. Similarly, the pattern of PER2 expression in the SCN of rats entrained to a 0.5-h:25.5-h LD cycle (light falls near dusk) resembled that in dark-housed controls. We also found that presentation of a discrete light pulse in the early subjective night did not induce PER2 protein expression in the SCN, even 6 h after photic stimulation. Finally, in constant light-housed, behaviorally arrhythmic rats, PER2 expression in the SCN was low and nonrhythmic. These results show that rhythmic PER2 expression occurs both in the shell and core regions of the rat SCN. Furthermore, they show that the expression of PER2 in the SCN is not regulated by entraining light. Finally, constant light-induced behavioral arrhythmicity is associated with a disruption of rhythmic PER2 expression in the whole SCN. Together, the results are consistent with a proposed role for PER2 in the core mechanism of the circadian clock but argue against an important role for PER2 in the mechanism mediating photic entrainment.

Animals↗
PubMed2002

Effect of 192 IgG-saporin on circadian activity rhythms, expression of P75 neurotrophin receptors, calbindin-D28K, and light-induced Fos in the suprachiasmatic nucleus in rats.

Photic entrainment of circadian rhythms in mammals is mediated through a direct retinal projection to the core region of the suprachiasmatic nucleus (SCN), the circadian clock. A proportion of this projection contains the low-affinity p75 neurotrophic receptor (p75NTR). Neonatal monosodium glutamate (MSG) treatment, which dramatically reduces p75NTR immunoreactivity in the SCN has no impact on photic entrainment. In order to clarify the contribution of p75NTR fibers in photic entrainment, targeted lesions of the p75NTR-immunoreactive SCN plexus were performed using intracerebroventricular (ICV) or intrahypothalamic injections of the immunotoxin 192 IgG-saporin (SAP) in rats. SAP treatment effectively abolished p75NTR immunoreactivity within the SCN core. ICV SAP treatment produced three different behavioral activity patterns: Animals became arrhythmic, displayed a shorter free-running period, or remained rhythmic following the lesion. Arrhythmic animals had large hypothalamic lesion which encompassed the entire SCN. In rhythmic rats, ICV-SAP significantly reduced immunostaining for calbindin-D28k (CaBP) in the SCN, and rats with shortened free-running periods had the lowest number of CaBP immunoreactive cells. ICV SAP also attenuated light-induced Fos expression in the SCN core. Despite lack of p75NTR and reduced CaBP and Fos expression in the SCN, SAP-treated rhythmic rats displayed normal photic entrainment. Intrahypothalamic SAP treatment reduced CaBP expression in the SCN but had no effect on light-induced Fos expression, free-running rhythms, or photic entrainment. The data show that p75NTR-immunoreactive elements in the SCN are not required for photic entrainment.

Activity Cycles↗