Stress rapidly suppresses in vivo LH pulses and increases activation of RFRP-3 neurons in male mice

Yang, Jennifer; Hughes, Jeffery P.; Parra, Ruby A; Volk, Katrina M.; Kauffman, Alexander S.

doi:10.1530/joe-18-0449

Cited by 30 publications

(22 citation statements)

References 45 publications

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“…We have shown for the first time that TMT increases and maintaines elevated CORT secretion in mice. The TMT-induced rise in CORT was maintained for at least 1-hour after termination of the predator odor stress, indicating prolonged HPA axis activation, which has been observed with prolonged restraint stress in mice (47). This indicates exposure to these psychogenic stressors can lead to prolonged HPA axis activation in mice.…”

Section: Discussionmentioning

confidence: 73%

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Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

Ivanova

McIntyre

et al. 2021

Preprint

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Exposure to psychosocial stress disrupts reproductive function and interferes with pulsatile luteinising hormone (LH) secretion in mammals. The posterodorsal sub-nucleus of the medial amygdala (MePD) is part of the limbic brain and is an upstream modulator of the reproductive axis as well as stress and anxiety states. Corticotropin releasing factor type-2 receptors (CRFR2) are activated in the presence of psychosocial stress together with an increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress exposure on LH pulsatility. Firstly, we administered Ucn3 into the MePD and monitored the effect on pulsatile LH secretion in ovariectomised mice. Next, we delivered Astressin2B, a highly selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-Trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected ovariectomised Ucn3-cre-tdTomato mice with inhibitory DREADDs targeting the MePD Ucn3 neurons while exposing the mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone (CORT) release. Administration of Ucn3 into the MePD dose-dependently inhibited pulsatile LH secretion and intra-MePD administration of Astressin2B blocked the suppressive effect TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses as well as CORT release in the presence of TMT. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and psychosocial stress-induced CORT secretion. Ucn3 signalling in the MePD plays a fundamental role in modulating the hypothalamic-pituitary-ganadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal centre in the crosstalk between the reproductive and stress axes.

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Section: Discussionmentioning

confidence: 73%

“…with prolonged restraint stress in mice (47). This indicates exposure to these psychogenic stressors can lead to prolonged HPA axis activation in mice.…”

Section: Discussionmentioning

confidence: 93%

Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

Ivanova

McIntyre

et al. 2021

Preprint

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“…It remains unclear from this experiment whether RFRP neurons suppress reproductive function in direct response to the stressor or indirectly in response to HPA axis-induced glucocorticoid secretion. It should be noted that the period of restraint was limited to 30 min, and stress-induced glucocorticoid release probably only began to occur toward the end of this brief time period (Yang et al, 2018). Therefore, RFRP neurons may activate in direct response to the stressor and interact with GnRH neurons to suppress pulse frequency independently of glucocorticoid levels, on a time scale of minutes.…”

Section: Discussionmentioning

confidence: 99%

“…RFamiderelated peptide-3 (RFRP-3) is a peptide secreted by RFRP neurons that project from the rodent dorsomedial hypothalamus (DMH), and is mostly (but not exclusively) inhibitory to GnRH activity (Ducret et al, 2009;Rizwan et al, 2009;Wu et al, 2009;Ancel et al, 2017). Interestingly, acute restraint stress was shown to suppress LH pulsatility while concomitantly increasing RFRP neuronal activation in male mice (Yang et al, 2018), and the activity of RFRP neurons was also upregulated by restraint stress in male rats (Kirby et al, 2009), suggesting that RFRP neurons may play a role in mediating the suppressive effects of stress on the HPG axis. Furthermore, approximately half of RFRP neurons express glucocorticoid receptors, and the effect of restraint stress on Rfrp gene expression was blocked by adrenalectomy (Kirby et al, 2009), suggesting that adrenal glucocorticoids activate RFRP neurons in stressful situations.…”

Section: Introductionmentioning

confidence: 99%

RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses

et al. 2020

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RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint-or glucocorticoidinduced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes.

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“…Metabolic challenges, such as short‐term fasting and high‐fat diet, are less effective in decreasing LH secretion in GPR147‐deficient male mice, suggesting that the GnIH‐GPR147 inhibitory pathway mediates gonadotropin suppression by metabolic stress . Stressful stimuli also activate GnIH‐ir neurons or increase GnIH expression in rats and mice . It was further shown that GnIH administration activates hypothalamic‐pituitary‐adrenal (HPA) axis in rats, mice, and rhesus monkeys .…”

Section: Mediation Of Stress Responsesmentioning

confidence: 99%

Reproductive neuroendocrinology of mammalian gonadotropin‐inhibitory hormone

Ubuka

Tsutsui

2019

Reprod Medicine & Biology

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Background Gonadotropin‐inhibitory hormone (GnIH) was discovered in the Japanese quail brain in 2000 as a hypothalamic neuropeptide that suppresses luteinizing hormone release from cultured quail anterior pituitary. Methods The authors investigated the existence of mammalian orthologous peptides to GnIH and their physiological functions in the following 19 years of research. Main findings Mammals have orthologous peptide to GnIH, often described RFamide‐related peptide, expressed in the hypothalamus and gonads. Mammalian GnIH may also suppress gonadotropin synthesis and release by suppressing gonadotropin‐releasing hormone (GnRH) synthesis and release in addition to directly suppressing gonadotropin synthesis and release from the pituitary. Mammalian GnIH may also suppress kisspeptin, a stimulator of GnRH, release. Mammalian GnIH is also expressed in the testis and ovary and suppresses gametogenesis and sex steroid production acting in an autocrine/paracrine manner. Thus, mammalian GnIH may act at all levels of the hypothalamic‐pituitary‐gonadal axis to suppress reproduction. GnIH may be involved in the regulation of puberty, estrous or menstrual cycle, seasonal reproduction, and stress responses. Conclusion Studies suggest that mammalian GnIH is an important neuroendocrine suppressor of reproduction in mammals.

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Stress rapidly suppresses in vivo LH pulses and increases activation of RFRP-3 neurons in male mice

Cited by 30 publications

References 45 publications

Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses

Reproductive neuroendocrinology of mammalian gonadotropin‐inhibitory hormone

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