Neuroendocrine regulation of puberty and reproductive development

项目摘要 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“上游”神经回路的调节，但其背后的机制仍然是 不为人所知，尤其是在成年之前。特别是，激活和进展的时间过程 对青春期发育的影响知之甚少。青春期是如何引发的，为什么会发生 当它发生的时候？为什么女孩比男孩早进入青春期？这些根本问题仍然没有答案。 最近，神经肽kisspeptin与青春期和生育能力有关。然而，准确的角色和监管 在青春期的各种kisspeptin神经群体仍然知之甚少，因为是时间或必要性 kisspeptin信号在独特的青春期阶段。此外，青春期kisspeptin的潜在性别差异 可能与正常青春期和青春期障碍中已知的性别差异有关的时间和作用， 完全未被探索过该建议使用小鼠模型来研究功能角色和潜力 kisspeptin和抑制性神经信号传导因子，强啡肽和GABA在青春期控制中的相互作用， 性别目的阐明内源性kisspeptin信号在时间和神经解剖学上的作用 在男性和女性青春期的关键阶段之前和期间。目标1：确定是否短期 在关键发育时期阻断或增强kisspeptin神经元放电可改变青春期的开始， 完成，如果这在两性之间有所不同，2）离散神经解剖学kisspeptin的必要性 每个性别的青春期开始和进展的人群，和3）青春期周围的分子谱 kisspeptin神经元，以确定如何已知的生殖基因和新的识别基因，特别是在Kiss 1 神经元群体随着青春期的到来而改变其表达，以及这在性别之间是否存在差异。Aim II 研究了抑制性神经因子强啡肽和GABA在青春期开始和发展中的作用， 性别这些因素与抑制成人GnRH/LH分泌有关，但尚不清楚是什么原因。 强啡肽或GABA参与青春期的时间，无论是在性别或他们是否直接相互作用， kisspeptin神经元协调青春期。目的II测试1）如果阻断内源性强啡肽或GABA 在男性或女性中，信号传导促进青春期的开始或完成，2）内源性强啡肽或 直接发生在kisspeptin神经元中的GABA信号传导是正常青春期开始和/或发育所必需的。 进展，以及3）内源性强啡肽或GABA信号传导是否包括一个关键 组成部分的神经抑制青春期前kisspeptin神经元在性别特异性的方式，以帮助时间 青春期开始总的来说，这项建议使用尖端的转基因，化学，药理学， 在两种性别的分子分析技术，以提供新的洞察神经机制，包括 刺激和抑制因素-- 疾病，这两个性别的原因尚不清楚。

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.