Vasoactive intestinal peptide exerts an excitatory effect on hypothalamic kisspeptin neurons during estrogen negative feedback

Mansano, Naira da Silva; Paradela, Regina Silva; Bohlen, Tabata Mariz; Zanardi, Izabela M.; Chaves, Fernanda Machado; Silveira, Marina A.; Tavares, Mariana; Donato, José; Frazão, Renata

doi:10.1016/j.mce.2021.111532

Cited by 11 publications

(5 citation statements)

References 78 publications

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“…However, other neurons involved may express VPIR1 and its involvement cannot be ruled out. Moreover, electrophysiology recent evidence suggests that VIP may directly communicate with RP3V KISS cells in an excitatory manner during diestrus ( Mansano et al, 2022 ); what the relevance of such diestrus VIP signaling is for the LH surge process and whether this also occurs on proestrus is not yet known.…”

Section: Possible Suprachiasmatic Nucleus Circuits Regulating Gonadot...mentioning

confidence: 99%

Neuroendocrine mechanisms underlying estrogen positive feedback and the LH surge

Kauffman

2022

Front. Neurosci.

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A fundamental principle in reproductive neuroendocrinology is sex steroid feedback: steroid hormones secreted by the gonads circulate back to the brain to regulate the neural circuits governing the reproductive neuroendocrine axis. These regulatory feedback loops ultimately act to modulate gonadotropin-releasing hormone (GnRH) secretion, thereby affecting gonadotropin secretion from the anterior pituitary. In females, rising estradiol (E2) during the middle of the menstrual (or estrous) cycle paradoxically “switch” from being inhibitory on GnRH secretion (“negative feedback”) to stimulating GnRH release (“positive feedback”), resulting in a surge in GnRH secretion and a downstream LH surge that triggers ovulation. While upstream neural afferents of GnRH neurons, including kisspeptin neurons in the rostral hypothalamus, are proposed as critical loci of E2 feedback action, the underlying mechanisms governing the shift between E2 negative and positive feedback are still poorly understood. Indeed, the precise cell targets, neural signaling factors and receptors, hormonal pathways, and molecular mechanisms by which ovarian-derived E2 indirectly stimulates GnRH surge secretion remain incompletely known. In many species, there is also a circadian component to the LH surge, restricting its occurrence to specific times of day, but how the circadian clock interacts with endocrine signals to ultimately time LH surge generation also remains a major gap in knowledge. Here, we focus on classic and recent data from rodent models and discuss the consensus knowledge of the neural players, including kisspeptin, the suprachiasmatic nucleus, and glia, as well as endocrine players, including estradiol and progesterone, in the complex regulation and generation of E2-induced LH surges in females.

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Section: Possible Suprachiasmatic Nucleus Circuits Regulating Gonadot...mentioning

confidence: 99%

Neuroendocrine mechanisms underlying estrogen positive feedback and the LH surge

Kauffman

2022

Front. Neurosci.

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“…The estrous cycle is regulated by hormonal feedback throughout the reproductive axis. Within the hypothalamus, VIP neurons directly project onto GnRH neurons to regulate the frequency of GnRH release to the pituitary ( 31 ) and indirectly through projections onto AVP neurons in the anteroventral paraventricular nucleus to regulate kisspeptin neurons that modulate the surge release of GnRH needed for ovulation ( 102 , 103 ). Although only a single dose of kisspeptin was tested, we found that Vax1 Vip females had a greater release of LH in response to a kisspeptin challenge than Ctrls, a difference we did not observe in the males.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice

Van Loh,

Yaw,

Breuer

et al. 2023

Front. Endocrinol.

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BackgroundThe suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function. MethodsTo specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1Vip; Vax1fl/fl:VipCre).ResultsWe found that Vax1Vip females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1Vip males and females presented with a shortened circadian period in locomotor activity and ex vivo SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes Bmal1 and Per2. Interestingly, Vax1Vip females presented with increased expression of arginine vasopressin (Avp) in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1Vip mice, we assessed GnRH sensitivity to a kisspeptin challenge in vivo. We found that GnRH neurons in Vax1Vip females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1Vip males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1Vip mice were fertile and generated litters comparable in size and frequency to controls.ConclusionTogether, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.

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“…In fact, Vip was shown to rescue the observed GnRH depletion only in aged female rats [ 65 ]. In addition to the direct innervation of GnRH neurons by Vip neurons in the suprachiasmatic nucleus, it was recently demonstrated that Vip neurons innervate kisspeptin neurons in the anteroventral periventricular and rostral periventricular nuclei, and the arcuate nucleus of the hypothalamus of mice, to modulate the negative steroid feedback [ 66 ]. Therefore, the depletion in GnRH3 neurons in zebrafish females may be mitigated by the induction of LH directly by Vip [ 49 ], through kisspeptin neurons or via other unknown factors.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic Depletion of Hypophysiotropic GnRH Neurons Does Not Affect Fertility in Mature Female Zebrafish

Tanaka

Zmora

Levavi‐Sivan

et al. 2022

IJMS

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The hypophysiotropic gonadotropin-releasing hormone (GnRH) and its neurons are crucial for vertebrate reproduction, primarily in regulating luteinizing hormone (LH) secretion and ovulation. However, in zebrafish, which lack GnRH1, and instead possess GnRH3 as the hypophysiotropic form, GnRH3 gene knockout did not affect reproduction. However, early-stage ablation of all GnRH3 neurons causes infertility in females, implicating GnRH3 neurons, rather than GnRH3 peptides in female reproduction. To determine the role of GnRH3 neurons in the reproduction of adult females, a Tg(gnrh3:Gal4ff; UAS:nfsb-mCherry) line was generated to facilitate a chemogenetic conditional ablation of GnRH3 neurons. Following ablation, there was a reduction of preoptic area GnRH3 neurons by an average of 85.3%, which was associated with reduced pituitary projections and gnrh3 mRNA levels. However, plasma LH levels were unaffected, and the ablated females displayed normal reproductive capacity. There was no correlation between the number of remaining GnRH3 neurons and reproductive performance. Though it is possible that the few remaining GnRH3 neurons can still induce an LH surge, our findings are consistent with the idea that GnRH and its neurons are likely dispensable for LH surge in zebrafish. Altogether, our results resurrected questions regarding the functional homology of the hypophysiotropic GnRH1 and GnRH3 in controlling ovulation.

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Vasoactive intestinal peptide exerts an excitatory effect on hypothalamic kisspeptin neurons during estrogen negative feedback

Cited by 11 publications

References 78 publications

Neuroendocrine mechanisms underlying estrogen positive feedback and the LH surge

Neuroendocrine mechanisms underlying estrogen positive feedback and the LH surge

The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice

Chemogenetic Depletion of Hypophysiotropic GnRH Neurons Does Not Affect Fertility in Mature Female Zebrafish

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