The gonadotropin-releasing hormone (GnRH) pulse is fundamental for mammalian reproduction: GnRH pulse regimens are needed as therapies for infertile women as continuous GnRH treatment paradoxically inhibits gonadotropin release. Circumstantial evidence suggests that the hypothalamic arcuate KNDy neurons expressing kisspeptin (encoded by Kiss1), neurokinin B (encoded by Tac3), and dynorphin A serve as a GnRH pulse generator; however, no direct evidence is currently available. Here, we show that rescuing >20% KNDy neurons by transfecting Kiss1 inside arcuate Tac3 neurons, but not outside of these neurons, recovered folliculogenesis and luteinizing hormone (LH) pulses, an indicator of GnRH pulses, in female global Kiss1 knockout (KO) rats and that >90% conditional arcuate Kiss1 KO in newly generated Kiss1-floxed rats completely suppressed LH pulses. These results first provide direct evidence that KNDy neurons are the GnRH pulse generator, and at least 20% of KNDy neurons are sufficient to maintain folliculogenesis via generating GnRH/gonadotropin pulses.

促性腺激素释放激素（GnRH）脉冲是哺乳动物繁殖的基础：由于持续的GnRH治疗自相矛盾地抑制了促性腺激素的释放，因此需要GnRH脉冲疗法作为不育妇女的疗法。间接证据表明，下丘脑弓形弓形神经元表达k isspeptin（由Kiss1编码），n eurokinin B（由Tac3编码）和d y诺啡A充当GnRH脉冲发生器。但是，目前尚无直接证据。在这里，我们显示了通过在弓形Tac3内转染Kiss1来拯救> 20％的KNDy神经元雌性整体Kiss1基因敲除（KO）大鼠中，以及新生成的Kiss1- floxed大鼠中> 90％的条件弓形Kiss1 KO中，神经元（但不在这些神经元外部）恢复了毛囊生成和促黄体生成素（LH）脉冲（GnRH脉冲的指标）完全抑制了LH脉冲。这些结果首先提供了直接证据，表明KNDy神经元是GnRH脉冲发生器，并且至少20％的KNDy神经元足以通过产生GnRH /促性腺激素脉冲来维持卵泡生成。