Neuroendocrine regulation of puberty and reproductive development

项目总结 大脑通过促性腺激素释放激素(GnRH)神经元调节生殖轴。GnRH 神经元本身受到“上游”神经回路的调节，但其背后的机制仍然是 不为人所知的，尤其是在成年之前。特别是，对激活和进展进行计时的过程 对于青春期发育的性别，人们知之甚少。青春期是如何触发的，为什么会发生？ 当它发生的时候？为什么女孩比男孩先进入青春期？这些根本问题仍未得到解答。 最近，神经肽Kispeptin被认为与青春期和生育有关。然而，确切的角色和监管 青春期不同的Kispeptin神经群体中，人们仍然知之甚少，其时机或必要性也是如此 Kispeptin信号在青春期的独特阶段。此外，青春期接吻的潜在性别差异 时机和行动，可能与正常青春期和青春期障碍中已知的性别差异有关，是 完全没有被开发过。该方案使用小鼠模型来研究功能角色和潜力 Kispeptin和抑制性神经信号因子强啡肽和GABA在青春期控制中的相互作用 性别。目的I阐明内源性Kispeptin信号在时间和神经解剖学上的精确作用 男性和女性在青春期关键阶段之前和期间。目标I决定1)短期内 在关键发育时期阻断或增强Kispeptin神经元放电改变青春期开始或 完成性，如果性别不同，2)离散神经解剖学接吻的必要性 男女青春期开始和发展的人群，以及3)青春期周围的分子图谱 Kispeptin神经元确定已知生殖基因和新基因如何识别Kiss1中的特定基因 神经元群体的表达随着青春期的变化而变化，以及这是否在性别之间有所不同。AIM II 研究神经抑制因子强啡肽和GABA在两者青春期发生和发展中的作用 性别。这些因素与抑制成人促性腺激素释放激素/促黄体生成素的分泌有关，但尚不清楚是什么 强啡肽或GABA参与了青春期的发育，无论男女，或者它们是否直接相互作用 Kispeptin神经元来协调青春期。AIM II测试1)如果阻断内源性强啡肽或GABA 信号促进男性或女性青春期的开始或完成，2)无论是内源性强啡肽还是 直接出现在kispeptin神经元中的GABA信号对于正常的青春期开始和/或 性别之间的进展，以及3)内源性强啡肽或GABA信号是否构成关键 青春期前Kispeptin神经元的神经抑制成分以性别特异性的方式帮助时间 青春期开始。总体而言，这项提案使用了尖端的转基因、化学、药理学和 分子图谱技术在两性中提供了对神经机制的新见解-包括 刺激和抑制因素--正常青春期和青春期的触发和时机 障碍，这两种疾病都是性二态的，原因尚不清楚。

PROJECT SUMMARY The brain regulates the reproductive axis via gonadotropin-releasing hormone (GnRH) neurons. GnRH neurons are themselves regulated by “upstream” neural circuits, but the mechanisms underlying this are still not well known, especially before adulthood. In particular, the processes timing the activation and progression of pubertal development in either sex are poorly understood. How is puberty triggered, and why does it occur when it does? Why do girls enter puberty before boys? These fundamental questions remain unanswered. Recently, the neuropeptide kisspeptin was linked to puberty and fertility. Yet, the precise roles and regulation of the various kisspeptin neural populations in puberty are still poorly understood, as is the timing or necessity of kisspeptin signaling at unique pubertal stages. Moreover, potential sex differences in pubertal kisspeptin timing and action, which may relate to known sex differences in normal puberty and pubertal disorders, are completely unexplored. This proposal uses mouse models to study the functional roles and potential interplays of kisspeptin and inhibitory neural signaling factors, dynorphin and GABA, in puberty control in both sexes. Aim I illuminates the precise temporal and neuroanatomical roles of endogenous kisspeptin signaling before and during key stages of puberty in males and females. Aim I determines 1) whether short-term blockade or enhancement of kisspeptin neuronal firing during key developmental times alters puberty onset or completion and if this differs between the sexes, 2) the necessity of discrete neuroanatomical kisspeptin populations for pubertal onset and progression in each sex, and 3) the molecular profile of peripubertal kisspeptin neurons to ascertain how known reproductive genes and novel identified genes specifically in Kiss1 neuronal populations change their expression with puberty, and whether this differs between sexes. Aim II studies the role of the inhibitory neural factors, dynorphin and GABA, in puberty onset and progression in both sexes. These factors have been implicated in suppressing adult GnRH/LH secretion, but it is unknown to what degree dynorphin or GABA are involved in pubertal timing in either sex or whether they interact directly with kisspeptin neurons to coordinate puberty. Aim II tests 1) if blockade of endogenous dynorphin or GABA signaling advances pubertal onset or completion in males or females, 2) whether endogenous dynorphin or GABA signaling occurring directly in kisspeptin neurons is necessary for normal puberty onset and/or progression in either sex, and 3) whether endogenous dynorphin or GABA signaling comprise a key component of the neural suppression of prepubertal kisspeptin neurons in a sex specific manner to help time puberty onset. Overall, this proposal using cutting-edge transgenic, chemogenic, pharmacologic, and molecular profiling techniques in both sexes to provide new insight into the neural mechanisms—including both stimulatory and inhibitory factors—underlying the triggering and timing of normal puberty and pubertal disorders, which are both sexually dimorphic for reasons not yet known.