Role of Kiss1 neurons in the seasonal and circadian control of reproduction

描述(申请人提供)：Kissl基因编码的多肽称为Kisspeptins，它与一种名为Gpr54的受体结合。Kispeptins刺激促性腺激素释放激素(GnRH)和Kissl表达神经元的分泌-这两个神经元位于调节生殖的下丘脑区域-被认为在性腺类固醇对促性腺激素分泌的反馈调节中发挥关键作用。虽然Kisspeptin-Gpr54信号在激素控制GnRH分泌中的作用已经被很好地研究，但Kissl神经元在生殖环境调节中的作用尚不清楚。本研究的目的是以仓鼠为模型，阐明Kissl系统在GnRH分泌的昼夜节律和光周期控制中的生理作用。第一个主要目标是评估Kissl系统在昼夜节律控制的排卵前黄体生成素高峰中的作用。我将研究Kissl神经元是否经历昼夜节律激活与每日黄体生成素高峰的产生有关。我还将确定视交叉上核(SON)中的昼夜节律振荡器与Kissl神经元之间是否存在直接的神经联系，并确定参与这一回路的神经递质。第二个主要目标是评估Kissl在季节性繁殖控制中的作用。我将评估光周期/褪黑素(MEL)对下丘脑Kissl系统的影响，并确定MEL对Kissl神经元的影响是直接的还是间接的。我还将全面评估SON和其他核团在调节任何间接影响方面的作用。最后，我将研究光周期对Kissl轴突对GnRH神经元的神经支配以及Kissl神经元对性激素反馈效应的敏感性的影响。由于人类在生理和行为(包括生殖的关键方面)以及季节性特征(如季节性情感障碍)中表现出良好的昼夜节律，因此增加对Kissl参与昼夜节律和光周期过程的了解可以提高我们对生育调节的理解，并有助于开发针对人类行为障碍的改进的医学策略。此外，阐明Kispeptins在调节GnRH分泌中的作用可以进一步深入了解特发性性腺激素低促性腺功能减退症的发病机制，并为治疗性早熟或性延迟、月经周期异常和不孕症等潜在的新疗法提供科学依据。

DESCRIPTION (provided by applicant): The Kissl gene encodes peptides called kisspeptins, which bind to a receptor known as GPR54. Kisspeptins stimulate the secretion of gonadotropin-releasing hormone (GnRH) and Kissl-expressing neurons - which are located in hypothalamic regions that regulate reproduction - and are thought to play a crucial role in the feedback regulation of gonadotropin secretion by gonadal steroids. Although the role of kisspeptin-GPR54 signaling in the steroid control of GnRH secretion has been well-studied, the role of Kissl neurons in the environmental regulation of reproduction is unknown. The goal of this research is to elucidate the physiological role of the Kissl system in the circadian and photoperiodic control of GnRH secretion using the hamster as a model. The first main objective is to evaluate the role of the Kissl system in the circadian-controlled pre-ovulatory LH surge. I will investigate whether Kissl neurons undergo circadian activation in association with the generation of daily LH surges. I will also determine if there are direct neural connections between the circadian oscillator in the suprachiasmatic nucleus (SON) and Kissl neurons, and identify the neurotransmitters involved in this circuitry. The second main objective is to evaluate the role of Kissl in the seasonal control of reproduction. I will assess the affects of photoperiod/melatonin (MEL) on the hypothalamic Kissl system and ascertain whether MEL's affects on Kissl neurons are direct or indirect. I will also comprehensively evaluate the roles of the SON and other nuclei in mediating any indirect effects. Lastly, I will investigate the effects of photoperiod on both the innervation of GnRH neurons by Kissl axons and the sensitivity of Kissl neurons to feedback effects of sex steroids. Since humans exhibit well-documented circadian rhythms in physiology and behavior (including critical aspects of reproduction), as well as seasonal traits (such as Seasonal Affective Disorder), increased knowledge of Kissl involvement in circadian and photoperiodic processes could improve our understanding of the regulation of fertility and facilitate the development of improved medical strategies for human behavioral disorders. In addition, elucidating the role of kisspeptins in the regulation of GnRH secretion could offer further insight into the mechanisms responsible for idiopathic hypogonadotropic hypogonadism and provide the scientific rationale for potential new therapies to treat precocious or delayed puberty, menstrual cycle irregularities, and infertility.