Postnatal Plasticity in the GnRH System

 描述(申请人提供)：促性腺激素释放激素(GnRH)神经元驱动所有脊椎动物的生殖活动。成纤维细胞生长因子信号转导是促性腺激素释放激素神经元早期发育所必需的，但其在促性腺激素释放激素神经元生后维持中的作用尚不清楚。PI实验室的最新数据显示，成纤维细胞生长因子信号缺乏导致小鼠出生后GnRH神经元的显著损失，但这种损失可以通过早期环境干预以异性(OS)住房的形式逆转。这些新的结果表明，出生后的GnRH系统，就像认知大脑一样，是高度可塑性的，对改变经验的环境刺激有反应。该提案的主要目标是研究导致成纤维细胞生长因子信号缺陷动物出生后GnRH神经元丢失的细胞过程，并确定OS住房引发的逆转成纤维细胞生长因子信号缺陷小鼠促性腺激素释放激素神经元丢失的分子机制和上游线索。这些目标将通过三个具体目标来实现。目标1将使用谱系追踪技术来测试成纤维细胞生长因子信号缺乏是否会导致出生后促性腺激素释放激素神经元的去分化和死亡。AIM 2将首先使用RNA-SEQ来识别受OS外壳差异调控的基因。随后，候选因子将通过qPCR进行验证，并在小鼠模型允许的情况下，在整个动物身上进行测试，以确认它们在逆转出生后GnRH神经元丢失方面的作用。目标3将确定信息素和升高的雄激素是否是OS外壳触发的两个上游信号，以重新激活失败的GnRH系统。总而言之，拟议的研究对于证明出生后的生殖大脑不是一个静态结构将是重要的。相反，它的完整性和功能是由环境线索动态调节的，也许还有一个人的生活方式选择和经历。这些信息可以用来通过适当的环境手段操纵出生后高度可塑性的GnRH系统，从而改善GnRH缺乏的人类的生殖健康。

 DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) neurons drive reproductive activation in all vertebrates. Fibroblast growth factor (Fgf) signaling is required for the early development of GnRH neurons, but its role in the postnatal maintenance of GnRH neurons is less clear. Recent data from the PI's lab reveal that Fgf signaling deficiency leads to a significant loss of postnatal GnRH neurons in mice, but this loss can be reversed by early environmental intervention in the form of opposite-sex (OS) housing. These novel results suggest the postnatal GnRH system, like the cognitive brain, is highly plastic and responsive to experience-altering environmental stimuli. The overarching goals of this proposal are to examine the cellular processes responsible for the loss of postnatal GnRH neurons in Fgf signaling-deficient animals, and to identify molecular mechanisms and upstream cues triggered by OS housing to reverse GnRH neuronal loss in Fgf signaling- deficient mice. These goals will be accomplished by three specific aims. Aim 1 will use a lineage tracing technique to test if Fgf signaling deficiency leads sequentially to the de-dedifferentiation and then death of postnatal GnRH neurons. Aim 2 will first use RNA-seq to identify genes differentially regulated by OS housing. Following, the candidate factors will be validated by qPCR and as permitted by mouse models, tested in whole animals to confirm their roles in reversing the postnatal GnRH neuronal loss. Aim 3 will determine if pheromones and elevated androgens are two upstream cues triggered by OS housing to reactivate the failing GnRH system. Collectively, the proposed studies will be important for demonstrating that the postnatal reproductive brain is not a static structure. Instead, its integrity and function are dynamically modulated by environmental cues and perhaps one's lifestyle choices and experience. This information can be used to improve the reproductive health of GnRH-deficient humans by manipulating the highly plastic postnatal GnRH system via suitable environmental means.