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RFamide-related peptide neurons modulate reproductive function and stress responses

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J Neurosci. 2020 Nov 20;JN-RM-1062-20. doi: 10.1523/JNEUROSCI.1062-20.2020. Online ahead of print.

RFamide-related peptide neurons modulate reproductive function and stress responses

A Mamgain;IL Sawyer;DAM Timajo;MZ Rizwan;MC Evans;CM Ancel;MA Inglis;GM Anderson

Centre for Neuroendocrinology and Department of Anatomy, University of Otago School of Biomedical Sciences, Dunedin, New Zealand.

Service type: Knock-in mice


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 in order 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 glucocorticoid-induced 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 of the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes.SIGNIFICANCE STATEMENTThe neuronal pathways whereby psychosocial stress leads to suppression of reproduction remain poorly understood, however the neurons that drive the reproductive axis are thought to be indirectly influenced by stress steroids and neuropeptides in a sex-specific manner. We used in vivo testing in combination with Cre-dependent neuronal ablation and DREADD technology to demonstrate a physiological necessity of hypothalamic RFRP neurons as mediators of stress-induced suppression of pulsatile reproductive hormone secretion. This effect was specific to females. We also reveal a causative link between RFRP neuronal function and the hormonal stress axis. Our findings suggest that pharmacological blockade of the receptors acted on by RFRP neuronal secretions could be used to overcome clinical infertility associated with stress or affective disorders.

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