GABAergic mediation of steroid feedback on GnRH neurons

促性腺激素释放激素（GnRH）神经元是调节生殖的最终共同途径。下丘脑搏动性释放GnRH刺激垂体促性腺激素的合成和分泌，这是生育所必需的。GnRH脉冲模式主要受卵巢类固醇激素雌激素(E)和黄体酮(P)的负反馈调节。有证据表明，类固醇激素反馈的一种机制是通过中间神经元经突触调节GnRH脉搏。解剖学和生理学数据支持γ -氨基丁酸（GABA）产生神经元在这种交流中的作用。本研究的目的是表征GnRH神经元中GABA/ a受体介导的抑制性突触后电流（IPSCs）及其由类固醇和神经类固醇调节。具体来说，全细胞电压钳技术将被用于表征三种类固醇激素反馈小鼠模型中的IPSCs。基于一些下丘脑生育障碍中GnRH神经元对类固醇负反馈的反应降低的报道，IPSCs也将在动物模型中进行表征，该模型概括了对类固醇反馈的反应降低，IPSCs也将在动物模型中进行表征，概括了对类固醇反馈的反应降低。GnRH神经元内GABAA受体亚基表达的分子分析和下丘脑参与神经活性类固醇产生的酶水平的变化将完成这些数据。对生育的GnRH搏动性进行适当调节的绝对要求强调了拟议研究的重要性。

Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway regulating reproduction. Pulsatile GnRH release from the hypothalamus stimulates synthesis and secretion of pituitary gonadotropins and is absolutely required for fertility. GnRH pulse patterns are largely regulated by negative feedback from the ovarian steroids estrogen (E) and progesterone (P). Evidence suggests one mechanism of steroid hormone feedback is via interneurons to modulate GnRH pulsatility transsynaptically. Anatomical and physiological data support a role for gamma-aminobutyric acid (GABA)-producing neurons in this communication. The goal of this study is to characterize GABA/A-receptor-mediated inhibitory post-synaptic currents (IPSCs) within GnRH neurons and their modulation by steroids and neurosteroids. Specifically, whole-cell voltage clamp techniques will be used to characterize IPSCs in three defined mouse models of steroid hormone feedback. Based on reports of decreased GnRH neuron response to steroid negative feedback in some hypothalamic fertility disorders, IPSCs will also be characterized in an animal model that recapitulates reduced responsiveness to steroid feedback, IPSCs will also be characterized in an animal model that recapitulates reduced responsiveness to steroid feedback. Molecular analyses of GABAA receptor subunit expression within GnRH neurons and changes in hypothalamic levels of enzymes involved in the production of neuroactive steroids will complete these data. The absolute requirement for proper regulation of GnRH pulsatility for fertility underscores the importance of the proposed research.