Kriegsfeld Lance J, Mei Dan Feng, Bentley George E, Ubuka Takayoshi, Mason Alex O, Inoue Kazuhiko, Ukena Kazuyoshi, Tsutsui Kazuyoshi, Silver Rae
Department of Psychology and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2410-5. doi: 10.1073/pnas.0511003103. Epub 2006 Feb 7.
Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-alpha and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.
成功的繁殖需要通过性类固醇的负反馈作用将生殖轴维持在精细的运作范围内。尽管这一稳态过程很重要，但我们对负责的神经位点、通路和神经化学物质的理解仍不完整。在这里，我们揭示了一条神经肽能通路，它直接将性腺类固醇作用与生殖系统的调节联系起来。最近鉴定出一种抑制鹌鹑垂体促性腺激素释放的RFamide（精氨酸 - 苯丙氨酸 - 酰胺）肽，并将其命名为促性腺激素抑制激素（GnIH）。已知鸟类具有与促性腺激素释放激素（GnRH）调节相关的特殊适应性以优化繁殖（例如，脑内光感受器），而下丘脑肽抑制促性腺激素的存在可能是也可能不是另一种这样的特殊适应性。为了确定GnIH是否作为生殖轴性类固醇调节的信号通路，我们使用免疫组织化学和原位杂交来表征该肽在仓鼠、大鼠和小鼠中的分布和功能作用。GnIH免疫反应性（GnIH-ir）细胞体聚集在中基底下丘脑，在整个中枢神经系统中有明显的投射和终末。体内给予GnIH可迅速抑制促黄体生成素分泌。此外，GnIH-ir神经元与GnRH细胞紧密相邻，提示存在一种直接调节GnRH的方式。最后，GnIH-ir细胞表达雌激素受体α，并在性腺激素刺激后表现出强烈的即刻早期基因表达。综上所述，GnIH向调节生殖行为和神经内分泌分泌的神经位点的传出分布、GnIH-ir核中类固醇受体的表达以及GnIH对促黄体生成素分泌的抑制表明发现了一个调节哺乳动物生殖轴的系统。
