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Role of PROKR2 Neurons of the Amygdala in Reproductive Function

杏仁核 PROKR2 神经元在生殖功能中的作用

基本信息

批准号：
9759333
负责人：
Brenda Cisneros Larios
金额：
$ 3.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759333
关键词：
Adult Agonistic Behavior Amygdaloid structure Anosmia Area Behavior Brain Cell Nucleus Cells Cues Dependovirus Development Dorsal Endocrine Enterobacteria phage P1 Cre recombinase Estrous Cycle Estrus Exposure to Female Fertility Gene Mutation Genes Genetic study Gonadal Steroid Hormones Gonadotropin Hormone Releasing Hormone Human Hypothalamic structure Impairment Infertility Kallmann Syndrome Lesion Ligands Luteinizing Hormone Maps Medial Messenger RNA Modeling Morphogenesis Mus Neurons Neurosecretory Systems Odors Olfactory Pathways Operative Surgical Procedures Output Patients Pattern Periodicity Phenotype Play Primates Rattus Reporter Reproduction Rodent Role Site Soil Steroid Receptors Surrogate Markers Synaptophysin Technology Testing designer receptors exclusively activated by designer drugs differential expression hypothalamic pituitary gonadal axis immunoreactivity loss of function mutation male mating behavior migration mind control mouse model olfactory bulb prevent promoter receptor relating to nervous system reproductive reproductive function reproductive hormone response sex sexual dimorphism

项目摘要

Project Summary Kallmann Syndrome (KS) is characterized by infertility and anosmia due to deficiency in gonadotropin- releasing hormone (GnRH) neuronal migration and olfactory bulb dysgenesis. Genetic studies have revealed that KS is caused by loss-of-function mutations in several genes including the prokineticin receptor 2 gene (PROKR2) observed in 10% of KS patients. Mice with global deletion of Prokr2 replicate the phenotype of KS patients displaying olfactory bulb dysgenesis, impaired GnRH neuronal migration and infertility. Whereas the role of PROKR2 during development is defined, little is known about PROKR2 neurons in adult reproduction. PROKR2 mRNA and the mRNA for its ligand are highly expressed in reproductive control sites of the adult mouse brain. Despite normal GnRH neuronal migration, heterozygous mice for Prokr2 loss of function mutation display longer estrous cycles compared to wild type littermates. Similarly, humans with PROKR2 mutations have a normal olfactory system but decreased fertility suggesting reproductive deficits independent of normal olfactory bulb morphogenesis and GnRH neuronal migration. However, the neural basis for PROKR2 role in adult reproduction is unknown. We recently developed a PROKR2-Cre mouse model in which Cre recombinase is driven by the Prokr2 promoter. With this mouse model, we mapped the distribution of PROKR2 expressing cells in the brain of both sexes. PROKR2 mRNA and GFP+ cells were highly expressed in subdivision of the medial amygdala in a sexually-dimorphic pattern. Male mice have higher PROKR2-Cre in the amygdalohippocampal area (AHi, also called posterior nucleus of the amygdala) whereas females have higher PROKR2 in the posterodorsal subdivision of the medial nucleus of the amygdala (MeApd). Both the MeApd and the AHi show dense expression of sex steroid receptors and play important role in reproductive function and associated behaviors. We hypothesize PROKR2-Cre neurons of the MeApd are necessary for typical control of female reproductive function (including estrous cyclicity), whereas PROKR2-Cre neurons in the AHi have a role in male reproduction. In two aims, we propose to map the neuronal projections of MeApd PROKR2 neurons in females and AHi PROKR2 neurons in males. We will also determine if PROKR2 neurons respond to opposite sex odors. Lastly, we will use chemogenetic technology, i.e. the designer receptors exclusively activated by designer drugs (DREADDs) to activate or inhibit PROKR2 neurons of the MeApd in females and of the AHi in males. We will determine if activation of these neurons increases circulating reproductive hormones and if inhibition of these neurons blocks the rise in reproductive hormones observed after exposure to opposite sex odors. Our studies will define a role for PROKR2 neurons in subdivisions of the medial amygdala, an important site of socio-sexual inputs and reproductive neuroendocrine responses in rodents and primates, including humans. Upon completion, we expect our studies will contribute to the understanding of the reproductive deficits associated with PROKR2 mutations.

项目概要卡尔曼综合症（KS）的特点是由于促性腺激素缺乏而导致不孕和嗅觉丧失。释放激素（GnRH）神经元迁移和嗅球发育不全。遗传学研究表明 KS 是由包括前动力蛋白受体 2 基因在内的多个基因的功能丧失突变引起的 (PROKR2) 在 10% 的 KS 患者中观察到。 Prokr2 整体缺失的小鼠复制了 KS 表型患者表现出嗅球发育不良、GnRH 神经元迁移受损和不育。鉴于 PROKR2 在发育过程中的作用已被定义，但人们对 PROKR2 神经元在成年生殖中的作用知之甚少。 PROKR2 mRNA 及其配体 mRNA 在成虫的生殖控制位点高表达老鼠的大脑。尽管 GnRH 神经元迁移正常，但 Prokr2 功能缺失突变杂合小鼠与野生型同窝小鼠相比，显示出更长的发情周期。同样，携带 PROKR2 突变的人类有正常的嗅觉系统，但生育能力下降，表明生殖缺陷与正常情况无关嗅球形态发生和 GnRH 神经元迁移。然而，PROKR2 作用的神经基础成虫繁殖情况未知。我们最近开发了 PROKR2-Cre 小鼠模型，其中 Cre 重组酶由 Prokr2 启动子驱动。通过该小鼠模型，我们绘制了 PROKR2 的分布图两性大脑中的表达细胞。 PROKR2 mRNA 和 GFP+ 细胞在内侧杏仁核以性别二态性模式细分。雄性小鼠的 PROKR2-Cre 较高杏仁核海马区（AHi，也称为杏仁核后核），而女性则具有更高的 PROKR2 位于杏仁核内侧核的后背细分 (MeApd)。 MeApd 均 AHi显示性类固醇受体的密集表达并在生殖功能中发挥重要作用以及相关的行为。我们假设 MeApd 的 PROKR2-Cre 神经元对于典型的控制女性生殖功能（包括动情周期），而 AHi 中的 PROKR2-Cre 神经元对男性生殖有一定作用。为了实现两个目标，我们建议绘制 MeApd PROKR2 的神经元投影图女性神经元和男性 AHi PROKR2 神经元。我们还将确定 PROKR2 神经元是否做出反应对异性气味。最后，我们将使用化学遗传学技术，即专门设计的受体由设计药物（DREADD）激活，以激活或抑制女性 MeApd 的 PROKR2 神经元和男性的 AHi 值。我们将确定这些神经元的激活是否会增加循环生殖激素以及这些神经元的抑制是否会阻止暴露后观察到的生殖激素的上升对异性气味。我们的研究将确定 PROKR2 神经元在内侧神经元细分中的作用杏仁核，啮齿动物和动物中社会性输入和生殖神经内分泌反应的重要部位灵长类动物，包括人类。完成后，我们希望我们的研究将有助于理解与 PROKR2 突变相关的生殖缺陷。