KNDy Neurons Modulate the Magnitude of the Steroid-Induced Luteinizing Hormone Surges in Ovariectomized Rats

Helena, Cleyde; Toporikova, Natalia; Kalil, Bruna; Stathopoulos, Andrea; Pogrebna, Veronika V.; Carolino, Ruither Oliveira Gomes; Anselmo-Franci, Janete Aparecida; Bertram, Richard

doi:10.1210/en.2015-1070

Cited by 44 publications

(38 citation statements)

References 82 publications

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“…Our results show that the expression of ARC Kiss1 mRNA co‐varies with circulating LH levels, with RFRP‐3 acting to reduce both Kiss1 mRNA expression and circulating concentrations of LH in the afternoon but not in the morning, consistent with this pathway of control. In support of this possibility, ablation of ARC kisspeptin neurones leads to atypical LH surge amplitude . The present findings are also in agreement with a recent study demonstrating RFRP‐3 suppression of ARC kisspeptin expression in free‐cycling Syrian hamsters maintained in long photoperiods .…”

Section: Discussionsupporting

confidence: 93%

Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

Gotlieb

Baker

Moeller

et al. 2019

J Neuroendocrinology

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In spontaneously ovulating rodent species, the timing of the luteinising hormone (LH) surge is controlled by the master circadian pacemaker in the suprachiasmatic nucleus (SCN). The SCN initiates the LH surge via the coordinated control of two opposing neuropeptidergic systems that lie upstream of the gonadotrophin‐releasing hormone (GnRH) neuronal system: the stimulatory peptide, kisspeptin, and the inhibitory peptide, RFamide‐related peptide‐3 (RFRP‐3; the mammalian orthologue of avian gonadotrophin‐inhibitory hormone [GnIH]). We have previously shown that the GnRH system exhibits time‐dependent sensitivity to kisspeptin stimulation, further contributing to the precise timing of the LH surge. To examine whether this time‐dependent sensitivity of the GnRH system is unique to kisspeptin or a more common mechanism of regulatory control, we explored daily changes in the response of the GnRH system to RFRP‐3 inhibition. Female Syrian hamsters were ovariectomised to eliminate oestradiol (E2)‐negative‐feedback and RFRP‐3 or saline was centrally administered in the morning or late afternoon. LH concentrations and Lhβ mRNA expression did not differ between morning RFRP‐3‐and saline‐treated groups, although they were markedly suppressed by RFRP‐3 administration in the afternoon. However, RFRP‐3 inhibition of circulating LH at the time of the surge does not appear to act via the GnRH system because no differences in medial preoptic area Gnrh or RFRP‐3 receptor Gpr147 mRNA expression were observed. Rather, RFRP‐3 suppressed arcuate nucleus Kiss1 mRNA expression and potentially impacted pituitary gonadotrophs directly. Taken together, these findings reveal time‐dependent responsiveness of the reproductive axis to RFRP‐3 inhibition, possibly via variation in the sensitivity of arcuate nucleus kisspeptin neurones to this neuropeptide.

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Section: Discussionsupporting

confidence: 93%

Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

Gotlieb

Baker

Moeller

et al. 2019

J Neuroendocrinology

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“…Specificity was demonstrated by the preservation of neuropeptide Y, proopiomelanocortin, and GnRH neuronal elements in the arcuate nucleus and adjacent median eminence (31). Dopamine neurons are also preserved after injections of NK 3 -SAP (32), consistent with the lack of NK 3 R receptor on arcuate neurons that project to the fenestrated capillaries in the median eminence (33).…”

mentioning

confidence: 75%

“…In the ewe, dynorphin neurons in the arcuate nucleus mediate the inhibition of GnRH pulses by P (72,73). Interestingly, a recent study showed that injection of a -opioid receptor agonist into the preoptic area increases the E 2 -induced LH surge, similar to their amplification of the LH surge after NK 3 -SAP injections into the arcuate nucleus (32). Finally, central infusion of a -opioid receptor agonist on proestrous afternoon markedly amplifies the LH surge, suggesting that endogenous -opioid tone limits the size of the preovulatory LH surge in intact rats (74).…”

mentioning

confidence: 98%

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

et al. 2016

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In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function, we recently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17β-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17β-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

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“…Yet, AVPV Kiss1 gene expression is decreased after prolonged (48 hours) fasting [Kalamatianos et al, 2008], which suggests that ARH and AVPV kisspeptin neurons may impose effects of acute versus persistent metabolic imbalance on GnRH. Recent studies show that ARH kisspeptin/neurokinin B/dynorphin (KNDy) neurons may regulate the LH surge via dynorphin signaling to the AVPV [Helena et al, 2015]. The present work introduces the novel premise that these cells may mediate rapid hypoglycemic repression of the LH surge.…”

Section: Discussionmentioning

confidence: 91%

Hindbrain estrogen receptor-beta antagonism normalizes reproductive and counter-regulatory hormone secretion in hypoglycemic steroid-primed ovariectomized female rats

Briski

Shrestha

2016

Neuroscience

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Hindbrain dorsal vagal complex A2 noradrenergic signaling represses the pre-ovulatory luteinizing hormone (LH) surge in response to energy deficiency. Insulin-induced hypoglycemia augments A2 neuron adenosine 5′-monophosphate-activated protein kinase (AMPK) activity and estrogen receptor-beta (ERβ) expression, coincident with LH surge suppression. We hypothesized that ERβ is critical for hypoglycemia-associated patterns of LH secretion and norepinephrine (NE) activity in key reproduction-relevant forebrain structures. The neural mechanisms responsible for tight coupling of systemic energy balance and procreation remain unclear; here, we investigated whether ERβ-dependent hindbrain signals also control glucose counter-regulatory responses to hypoglycemia. Gonadal steroid-primed ovariectomized female rats were pretreated by caudal fourth ventricular administration of the ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) or vehicle at LH surge onset before insulin injection. Western blot analysis of laser-microdissected A2 neurons revealed hypoglycemic augmentation of 5′-monophosphate-activated protein kinase activity and dopamine-β-hydroxylase protein expression; the latter response was attenuated by PHTPP pretreatment. PHTPP regularized LH release, but not preoptic GnRH-I precursor protein expression in insulin-injected rats, and reversed hypoglycemic stimulation of glucagon and corticosterone secretion. Hypoglycemia caused PHTPP-reversible changes in NE and prepro-kisspeptin protein content in the hypothalamic arcuate (ARH), but not anteroventral periventricular nucleus. Results provide novel evidence for ERβ-dependent caudal hindbrain regulation of LH and counter-regulatory hormone secretion during hypoglycemia. That inhibition of LH likely involves mechanisms at the axon terminal that impede GnRH neurotransmission. Data also show that caudal hindbrain ERβ exerts site-specific control of NE activity in forebrain projection sites during hypoglycemia, including the ARH where prepro-kisspeptin may be a target of this signaling.

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KNDy Neurons Modulate the Magnitude of the Steroid-Induced Luteinizing Hormone Surges in Ovariectomized Rats

Cited by 44 publications

References 82 publications

Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

Hindbrain estrogen receptor-beta antagonism normalizes reproductive and counter-regulatory hormone secretion in hypoglycemic steroid-primed ovariectomized female rats

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