Minireview: Timely Ovulation: Circadian Regulation of the Female Hypothalamo-Pituitary-Gonadal Axis

The preovulatory surge in the secretion of LH is timed by a neuroendocrine integrative mechanism that involves ovarian estradiol levels and the endogenous circadian system. Studies in female rats and hamsters have established that the clock in the hypothalamic suprachiasmatic nucleus has a preeminent role in setting the LH surge, and anatomical, physiological, and pharmacological data are revealing the responsible connections between suprachiasmatic nucleus neurons and GnRH and estradiol-receptive areas. Recent investigations show that GnRH and pituitary cells express circadian clock genes that might play a role in the release and reception of the GnRH signal. Analysis of the circadian regulation of the LH surge may provide a model for understanding how multiple neural oscillators function within other neuroendocrine axes.

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The Increase in Signaling by Kisspeptin Neurons in the Preoptic Area and Associated Changes in Clock Gene Expression That Trigger the LH Surge in Female Rats Are Dependent on the Facilitatory Action of a Noradrenaline Input

Endocrinology ◽

10.1210/en.2015-1323 ◽

2016 ◽

Vol 157 (1) ◽

pp. 323-335 ◽

Cited By ~ 7

Author(s):

Bruna Kalil ◽

Aline B. Ribeiro ◽

Cristiane M. Leite ◽

Ernane T. Uchôa ◽

Ruither O. Carolino ◽

...

Keyword(s):

Gene Expression ◽

Median Eminence ◽

Preoptic Area ◽

Clock Genes ◽

Third Ventricle ◽

Female Rats ◽

Ovariectomized Rats ◽

Lh Surge ◽

Clock Gene Expression

Abstract In rodents, kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) of the preoptic area are considered to provide a major stimulatory input to the GnRH neuronal network that is responsible for triggering the preovulatory LH surge. Noradrenaline (NA) is one of the main modulators of GnRH release, and NA fibers are found in close apposition to kisspeptin neurons in the RP3V. Our objective was to interrogate the role of NA signaling in the kisspeptin control of GnRH secretion during the estradiol induced LH surge in ovariectomized rats, using prazosin, an α1-adrenergic receptor antagonist. In control rats, the estradiol-induced LH surge at 17 hours was associated with a significant increase in GnRH and kisspeptin content in the median eminence with the increase in kisspeptin preceding that of GnRH and LH. Prazosin, administered 5 and 3 hours prior to the predicted time of the LH surge truncated the LH surge and abolished the rise in GnRH and kisspeptin in the median eminence. In the preoptic area, prazosin blocked the increases in Kiss1 gene expression and kisspeptin content in association with a disruption in the expression of the clock genes, Per1 and Bmal1. Together these findings demonstrate for the first time that NA modulates kisspeptin synthesis in the RP3V through the activation of α1-adrenergic receptors prior to the initiation of the LH surge and indicate a potential role of α1-adrenergic signaling in the circadian-controlled pathway timing of the preovulatory LH surge.

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Vasopressinergic Activity of the Suprachiasmatic Nucleus and mRNA Expression of Clock Genes in the Hypothalamus-Pituitary-Gonadal Axis in Female Aging

Frontiers in Endocrinology ◽

10.3389/fendo.2021.652733 ◽

2021 ◽

Vol 12 ◽

Author(s):

Angela Cristina Nicola ◽

Larissa Brazoloto Ferreira ◽

Milene Mantovani Mata ◽

Tatiane Vilhena-Franco ◽

Cristiane Mota Leite ◽

...

Keyword(s):

Mrna Expression ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Feedback Loops ◽

Female Rats ◽

Hpg Axis ◽

Physiological Processes ◽

Reproductive Axis ◽

Reproductive Events ◽

Vasopressinergic Neurons

The important involvement of the suprachiasmatic nucleus (SCN) and the activity of vasopressinergic neurons in maintaining the rhythmicity of the female reproductive system depends on the mRNA transcription-translation feedback loops. Therefore, circadian clock function, like most physiological processes, is involved in the events that determine reproductive aging. This study describes the change of mRNA expression of clock genes, Per2, Bmal1, and Rev-erbα, in the hypothalamus-pituitary-gonadal axis (HPG) of female rats with regular cycle (RC) and irregular cycle (IC), and the vasopressinergic neurons activity in the SCN and kisspeptin neurons in the arcuate nucleus (ARC) of these animals. Results for gonadotropins and the cFos/AVP-ir neurons in the SCN of IC were higher, but kisspeptin-ir was minor. Change in the temporal synchrony of the clock system in the HPG axis, during the period prior to the cessation of ovulatory cycles, was identified. The analysis of mRNA for Per2, Bmal1, and Rev-erbα in the reproductive axis of adult female rodents shows that the regularity of the estrous cycle is guaranteed by alternation in the amount of expression of Bmal1 and Per2, and Rev-erbα and Bmal1 between light and dark phases, which ceases to occur and contributes to determining reproductive senescence. These results showed that the desynchronization between the central and peripheral circadian clocks contributes to the irregularity of reproductive events. We suggest that the feedback loops of clock genes on the HPG axis modulate the spontaneous transition from regular to irregular cycle and to acyclicity in female rodents.

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Vasoactive Intestinal Peptide Modulation of the Steroid-Induced LH Surge Involves Kisspeptin Signaling in Young but Not in Middle-Aged Female Rats

Endocrinology ◽

10.1210/en.2013-1793 ◽

2014 ◽

Vol 155 (6) ◽

pp. 2222-2232 ◽

Cited By ~ 10

Author(s):

Alexander S. Kauffman ◽

Yan Sun ◽

Joshua Kim ◽

Azim R. Khan ◽

Jun Shu ◽

...

Keyword(s):

Vasoactive Intestinal Peptide ◽

Suprachiasmatic Nucleus ◽

Reproductive Age ◽

Female Rats ◽

Mrna Levels ◽

Dependent Manner ◽

Middle Aged ◽

Lh Surge ◽

Young Females ◽

Gnrh Neurons

Age-related LH surge dysfunction in middle-aged rats is characterized, in part, by reduced responsiveness to estradiol (E2)-positive feedback and reduced hypothalamic kisspeptin neurotransmission. Vasoactive intestinal peptide (VIP) neurons in the suprachiasmatic nucleus project to hypothalamic regions that house kisspeptin neurons. Additionally, middle-age females express less VIP mRNA in the suprachiasmatic nucleus on the day of the LH surge and intracerebroventricular (icv) VIP infusion restores LH surges. We tested the hypothesis that icv infusion of VIP modulates the LH surge through effects on the kisspeptin and RFamide-related peptide-3 (RFRP-3; an estradiol-regulated inhibitor of GnRH neurons) neurotransmitter systems. Brains were collected for in situ hybridization analyses from ovariectomized and ovarian hormone-primed young and middle-aged females infused with VIP or saline. The percentage of GnRH and Kiss1 cells coexpressing cfos and total Kiss1 mRNA were reduced in saline-infused middle-aged compared with young females. In young females, VIP reduced the percentage of GnRH and Kiss1 cells coexpressing cfos, suggesting that increased VIP signaling in young females adversely affected the function of Kiss1 and GnRH neurons. In middle-aged females, VIP increased the percentage of GnRH but not Kiss1 neurons coexpressing cfos, suggesting VIP affects LH release in middle-aged females through kisspeptin-independent effects on GnRH neurons. Neither reproductive age nor VIP affected Rfrp cell number, Rfrp mRNA levels per cell, or coexpression of cfos in Rfrp cells. These data suggest that VIP differentially affects activation of GnRH and kisspeptin neurons of female rats in an age-dependent manner.

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Phase Differences in Expression of Circadian Clock Genes in the Central Nucleus of the Amygdala, Dentate Gyrus, and Suprachiasmatic Nucleus in the Rat

PLoS ONE ◽

10.1371/journal.pone.0103309 ◽

2014 ◽

Vol 9 (7) ◽

pp. e103309 ◽

Cited By ~ 29

Author(s):

Valerie L. Harbour ◽

Yuval Weigl ◽

Barry Robinson ◽

Shimon Amir

Keyword(s):

Circadian Clock ◽

Dentate Gyrus ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Central Nucleus ◽

Circadian Clock Genes ◽

Phase Differences

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Circadian Clock Genes and Photoperiodism: Comprehensive Analysis of Clock Gene Expression in the Mediobasal Hypothalamus, the Suprachiasmatic Nucleus, and the Pineal Gland of Japanese Quail under Various Light Schedules

Endocrinology ◽

10.1210/en.2003-0435 ◽

2003 ◽

Vol 144 (9) ◽

pp. 3742-3748 ◽

Cited By ~ 129

Author(s):

Shinobu Yasuo ◽

Miwa Watanabe ◽

Naritoshi Okabayashi ◽

Shizufumi Ebihara ◽

Takashi Yoshimura

Keyword(s):

Pineal Gland ◽

Circadian Clock ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Expression Patterns ◽

Hypothalamic Nucleus ◽

Mediobasal Hypothalamus ◽

Clock Gene Expression ◽

Circadian Clock Genes ◽

Important Center

Abstract In birds, the mediobasal hypothalamus (MBH) including the infundibular nucleus, inferior hypothalamic nucleus, and median eminence is considered to be an important center that controls the photoperiodic time measurement. Here we show expression patterns of circadian clock genes in the MBH, putative suprachiasmatic nucleus (SCN), and pineal gland, which constitute the circadian pacemaker under various light schedules. Although expression patterns of clock genes were different between long and short photoperiod in the SCN and pineal gland, the results were not consistent with those under night interruption schedule, which causes testicular growth. These results indicate that different expression patterns of the circadian clock genes in the SCN and pineal gland are not an absolute requirement for encoding and decoding of seasonal information. In contrast, expression patterns of clock genes in the MBH were stable under various light conditions, which enables animals to keep a steady-state photoinducible phase.

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Knockdown of clock genes in the suprachiasmatic nucleus blocks prolactin surges and alters FRA expression in the locus coeruleus of female rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00341.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. E1325-E1334 ◽

Cited By ~ 7

Author(s):

Maristela O. Poletini ◽

De'Nise T. McKee ◽

Jessica E. Kennett ◽

Jamie Doster ◽

Marc E. Freeman

Keyword(s):

Circadian Rhythm ◽

Locus Coeruleus ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Random Sequence ◽

Female Rats ◽

Ovariectomized Rats ◽

Gene Expressions ◽

Circadian Time

The nature of the circadian signal from the suprachiasmatic nucleus (SCN) required for prolactin (PRL) surges is unknown. Because the SCN neuronal circadian rhythm is determined by a feedback loop of Period (Per) 1, Per2, and circadian locomotor output cycles kaput ( Clock) gene expressions, we investigated the effect of SCN rhythmicity on PRL surges by disrupting this loop. Because lesion of the locus coeruleus (LC) abolishes PRL surges and these neurons receive SCN projections, we investigated the role of SCN rhythmicity in the LC neuronal circadian rhythm as a possible component of the circadian mechanism regulating PRL surges. Cycling rats on proestrous day and estradiol-treated ovariectomized rats received injections of antisense or random-sequence deoxyoligonucleotide cocktails for clock genes ( Per1, Per2, and Clock) in the SCN, and blood samples were taken for PRL measurements. The percentage of tyrosine hydroxylase-positive neurons immunoreactive to Fos-related antigen (FRA) was determined in ovariectomized rats submitted to the cocktail injections and in a 12:12-h light:dark (LD) or constant dark (DD) environment. The antisense cocktail abolished both the proestrous and the estradiol-induced PRL surges observed in the afternoon and the increase of FRA expression in the LC neurons at Zeitgeber time 14 in LD and at circadian time 14 in DD. Because SCN afferents and efferents were probably preserved, the SCN rhythmicity is essential for the magnitude of daily PRL surges in female rats as well as for LC neuronal circadian rhythm. SCN neurons therefore determine PRL secretory surges, possibly by modulating LC circadian neuronal activity.

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Identification of the suprachiasmatic nucleus in birds

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.4.r1185 ◽

2001 ◽

Vol 280 (4) ◽

pp. R1185-R1189 ◽

Cited By ~ 43

Author(s):

Takashi Yoshimura ◽

Shinobu Yasuo ◽

Yoshikazu Suzuki ◽

Eri Makino ◽

Yuki Yokota ◽

...

Keyword(s):

Locomotor Activity ◽

Circadian Rhythms ◽

Circadian Clock ◽

Suprachiasmatic Nucleus ◽

Japanese Quail ◽

Clock Genes ◽

Biological Clock ◽

Circadian Oscillators ◽

Circadian Clock Genes ◽

Dim Light

Circadian rhythms are generated by an internal biological clock. The suprachiasmatic nucleus (SCN) in the hypothalamus is known to be the dominant biological clock regulating circadian rhythms in mammals. In birds, two nuclei, the so-called medial SCN (mSCN) and the visual SCN (vSCN), have both been proposed to be the avian SCN. However, it remains an unsettled question which nuclei are homologous to the mammalian SCN. We have identified circadian clock genes in Japanese quail and demonstrated that these genes are expressed in known circadian oscillators, the pineal and the retina. Here, we report that these clock genes are expressed in the mSCN but not in the vSCN in Japanese quail, Java sparrow, chicken, and pigeon. In addition, mSCN lesions eliminated or disorganized circadian rhythms of locomotor activity under constant dim light, but did not eliminate entrainment under light-dark (LD) cycles in pigeon. However, the lesioned birds became completely arrhythmic even under LD after the pineal and the eye were removed. These results indicate that the mSCN is a circadian oscillator in birds.

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Global But Not Gonadotrope-Specific Disruption of Bmal1 Abolishes the Luteinizing Hormone Surge Without Affecting Ovulation

Endocrinology ◽

10.1210/en.2013-1080 ◽

2013 ◽

Vol 154 (8) ◽

pp. 2924-2935 ◽

Cited By ~ 35

Author(s):

Adrienne Chu ◽

Lei Zhu ◽

Ian D. Blum ◽

Oliver Mai ◽

Alexei Leliavski ◽

...

Keyword(s):

Luteinizing Hormone ◽

Circadian Clock ◽

Estrous Cycle ◽

Suprachiasmatic Nucleus ◽

Cycle Length ◽

Constant Darkness ◽

Circadian Regulation ◽

Lh Surge ◽

Luteinizing Hormone Surge

Abstract Although there is evidence for a circadian regulation of the preovulatory LH surge, the contributions of individual tissue clocks to this process remain unclear. We studied female mice deficient in the Bmal1 gene (Bmal1−/−), which is essential for circadian clock function, and found that they lack the proestrous LH surge. However, spontaneous ovulation on the day of estrus was unaffected in these animals. Bmal1−/− females were also deficient in the proestrous FSH surge, which, like the LH surge, is GnRH-dependent. In the absence of circadian or external timing cues, Bmal1−/− females continued to cycle in constant darkness albeit with increased cycle length and time spent in estrus. Because pituitary gonadotropes are the source of circulating LH and FSH, we assessed hypophyseal circadian clock function and found that female pituitaries rhythmically express clock components throughout all cycle stages. To determine the role of the gonadotrope clock in the preovulatory LH and FSH surge process, we generated mice that specifically lack BMAL1 in gonadotropes (GBmal1KO). GBmal1KO females exhibited a modest elevation in both proestrous and baseline LH levels across all estrous stages. BMAL1 elimination from gonadotropes also led to increased variability in estrous cycle length, yet GBmal1KO animals were otherwise reproductively normal. Together our data suggest that the intrinsic clock in gonadotropes is dispensable for LH surge regulation but contributes to estrous cycle robustness. Thus, clocks in the suprachiasmatic nucleus or elsewhere must be involved in the generation of the LH surge, which, surprisingly, is not required for spontaneous ovulation.

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