An Inhibitory Circuit From Brainstem to GnRH Neurons in Male Mice: A New Role for the RFRP Receptor
An Inhibitory Circuit From Brainstem to GnRH Neurons in Male Mice: A New Role for the RFRP Receptor
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DOI：
10.1210/endocr/bqab030
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发表时间：
2021-02-10
期刊：
影响因子：
4.8
通讯作者：
Wray, Susan
中科院分区：
文献类型：
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作者：
Constantin, Stephanie;Pizano, Katherine;Wray, Susan
rfamily相关肽（RFRPs，促性腺激素抑制激素的哺乳动物同源物）向生殖系统传递昼夜、季节和社会线索。它们通过RFRP受体调节促性腺激素释放激素（GnRH）神经元来调节促性腺激素的分泌。缺乏这种受体的小鼠是可生育的，但在代谢挑战中表现出异常的促性腺激素反应，如急性禁食，当促性腺激素水平的正常下降被延迟。虽然已知这些传递给生殖回路的食物摄入信号起源于脑干的孤束核（NTS），但传递信号的神经元的表型仍然未知。鉴于神经肽FF （NPFF）是另一种RFamide肽，存在于NTS中并可与RFRP受体结合，我们假设NPFF可能调节GnRH神经元。为了解决这个问题，我们使用了一系列技术：在急性脑切片中对gnrh驱动的绿色荧光蛋白标记的神经元进行细胞附着电生理学；培养GnRH神经元的钙显像；对成人脑组织进行免疫染色。我们发现(1)NPFF通过RFRP受体及其典型信号通路（Gi/o蛋白和G蛋白偶联的向内纠正钾通道）抑制GnRH神经元的兴奋性，(2)GnRH神经元附近的NPFF样纤维共表达神经肽Y， (3) NTS中大多数NPFF样细胞体也共表达神经肽，(4)急性禁食增加NPFF样免疫反应性。综上所述，这些数据表明NTS内的NPFF神经元在禁食期间但在能量不足之前抑制GnRH神经元，从而抑制其繁殖。
RFamide-related peptides (RFRPs, mammalian orthologs of gonadotropin-inhibitory hormone) convey circadian, seasonal, and social cues to the reproductive system.They regulate gonadotropin secretion by modulating gonadotropin-releasing hormone (GnRH) neurons via the RFRP receptor. Mice lacking this receptor are fertile but exhibit abnormal gonadotropin responses during metabolic challenges, such as acute fasting, when the normal drop in gonadotropin levels is delayed. Although it is known that these food intake signals to the reproductive circuit originate in the nucleus tractus solitarius (NTS) in the brainstem, the phenotype of the neurons conveying the signal remains unknown. Given that neuropeptide FF (NPFF), another RFamide peptide, resides in the NTS and can bind to the RFRP receptor, we hypothesized that NPFF may regulate GnRH neurons. To address this question, we used a combination of techniques: cell-attached electrophysiology on GnRH-driven green fluorescent protein-tagged neurons in acute brain slices; calcium imaging on cultured GnRH neurons; and immunostaining on adult brain tissue. We found (1) NPFF inhibits GnRH neuron excitability via the RFRP receptor and its canonical signaling pathway (Gi/o protein and G protein-coupled inwardly rectifying potassium channels), (2) NPFF-like fibers in the vicinity of GnRH neurons coexpress neuropeptide Y, (3) the majority of NPFF-like cell bodies in the NTS also coexpress neuropeptideY, and (4) acute fasting increased NPFF-like immunoreactivity in the NTS. Together these data indicate that NPFF neurons within the NTS inhibit GnRH neurons, and thus reproduction, during fasting but prior to the energy deficit.