Postnatal Plasticity in the GnRH System

GnRH 系统的产后可塑性

基本信息

批准号：
9036629
负责人：
Pei-San Tsai
金额：
$ 25.22万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-26 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036629
关键词：
Adopted Adult Androgens Animals Beds Brain Cell physiology Cells Cessation of life Cognitive Cues Data Development Disease Disease model Disputes Environment Environmental Risk Factor Exhibits FGFR1 gene Fertility Fibroblast Growth Factor Gene Mutation Genes Goals Gonadotropin Hormone Releasing Hormone Green Fluorescent Proteins Health Housing Human Implant Individual Intervention Klinefelter&apos s Syndrome Life Style Link Maintenance Mediating Molecular Mus Mutation Nature Neurons Neurosecretory Systems Organism Pharmaceutical Preparations Phenotype Pheromone Reproductive Health Role Signal Transduction Soil Stimulus Structure System Techniques Testing Vertebrates differential expression environmental change environmental intervention experience fertility improvement hormone deficiency improved insight mouse model neuron loss novel postnatal public health relevance reproductive response restoration sensory mechanism sex transcriptome sequencing

项目摘要

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.

描述（由适用提供）：促性腺激素释放的马龙（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神经元的早期发育所必需的，但其在GNRH神经元的产后维持中的作用尚不清楚。 PI实验室的最新数据表明，FGF信号传导缺乏会导致小鼠产后GNRH神经元的显着丧失，但是通过以异性（OS）住房的形式，可以通过早期的环境干预来逆转这种损失。这些新的结果表明，产后GNRH系统像认知大脑一样，对改变体验的环境刺激是高度塑性的。该提案的总体目标是检查导致FGF信号缺陷动物中产后GNRH神经元丧失的细胞过程，并确定OS壳体触发的分子机制和上游提示，从而反向FGF信号传导缺陷小鼠反向GNRH神经元丧失。这些目标将由三个特定目标实现。 AIM 1将使用谱系跟踪技术来测试FGF信号传导缺乏是否依次导致脱氧效果和死亡后GNRH神经元的死亡。 AIM 2将首先使用RNA-Seq识别由OS外壳差异调节的基因。随后，候选因素将通过qPCR验证，并在小鼠模型中允许在整个动物中进行测试，以确认其在逆转产后GNRH神经元损失中的作用。 AIM 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提示，以重新激活失败的GNRH系统。总体而言，拟议的研究对于证明产后生殖大脑不是静态结构至关重要。取而代之的是，其完整性和功能是通过环境线索以及一个人的生活方式选择和经验动态调节的。这些信息可用于通过合适的环境手段来操纵高度塑料的产后GNRH系统，以改善缺乏GnRH缺乏人类的生殖健康。