Postnatal Plasticity in the GnRH System

 描述（由申请人提供）：促性腺激素释放激素（GnRH）神经元驱动所有脊椎动物的生殖激活。成纤维细胞生长因子（Fgf）信号是GnRH神经元早期发育所必需的，但其在GnRH神经元出生后维持中的作用尚不清楚。PI实验室的最新数据显示，FGF信号传导缺陷导致小鼠出生后GnRH神经元的显著损失，但这种损失可以通过异性（OS）住房形式的早期环境干预来逆转。这些新的结果表明，出生后的GnRH系统，像认知大脑一样，是高度可塑的，对改变经验的环境刺激有反应。该提案的总体目标是检查负责Fgf信号缺陷动物中出生后GnRH神经元损失的细胞过程，并确定由OS外壳触发的分子机制和上游线索，以逆转Fgf信号缺陷小鼠中的GnRH神经元损失。这些目标将通过三个具体目标来实现。目的1将使用谱系追踪技术来测试是否Fgf信号转导缺陷导致出生后GnRH神经元的去分化和死亡。Aim 2将首先使用RNA-seq来鉴定由OS外壳差异调节的基因。随后，将通过qPCR验证候选因子，并在小鼠模型允许的情况下，在整个动物中进行检测，以确认其在逆转出生后GnRH神经元丢失中的作用。目标3将确定信息素和升高的雄激素是否是由OS外壳触发的两个上游线索，以重新激活失败的GnRH系统。总的来说，拟议的研究将是重要的，证明出生后的生殖大脑不是一个静态的结构。相反，它的完整性和功能是动态调制的环境线索，也许一个人的生活方式的选择和经验。这些信息可用于通过适当的环境手段操纵高度可塑性的出生后GnRH系统来改善GnRH缺乏者的生殖健康。

 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.