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：
10190983
负责人：
Brenda Cisneros Larios
金额：
$ 3.9万
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/10190983
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.

项目摘要 Kallmann综合征（KS）的特征是不育和厌食，这是由于促性腺激素缺乏释放激素（GNRH）神经元迁移和嗅球失调。遗传研究表明 KS是由多种基因的功能丧失突变引起的（PROKR2）在10％的KS患者中观察到。 pROKR2全球缺失的小鼠复制了KS的表型表现出嗅球失调，GNRH神经元迁移和不育的患者。而 prokr2在开发过程中的作用是定义的，对于成人繁殖中的prokr2神经元知之甚少。 PROKR2 mRNA和mRNA的配体在成人的生殖控制位点高度表达小鼠大脑。尽管GNRH神经元迁移正常，但用于PROKR2功能突变的杂合小鼠与野生型同窝仔相比，显示更长的发情周期。同样，具有ProKR2突变的人类具有正常的嗅觉系统，但生育力降低，表明与正常无关的生殖缺陷嗅球的形态发生和GNRH神经元迁移。但是，prokr2在成人繁殖尚不清楚。我们最近开发了一种prokr2-cre小鼠模型，其中CRE 重组酶由PROKR2启动子驱动。使用此鼠标模型，我们映射了Prokr2的分布在男女的大脑中表达细胞。 PROKR2 mRNA和GFP+细胞在内侧杏仁核的细分以性差异模式。雄性小鼠在杏仁核公寓区域（AHI，也称为杏仁核的后核），而女性的雌性则具有较高的 PROKR2在杏仁核（MEAPD）的内侧核的后部细分中。两个人 AHI显示性类固醇受体的密集表达，并在生殖功能中起重要作用和相关的行为。我们假设MEAPD的prokr2-cre神经元对于典型控制女性生殖功能（包括发情环境），而AHI中的Prokr2-Cre神经元在男性繁殖中起作用。在两个目标中，我们建议绘制MEAPD PROKR2的神经元预测雌性的神经元和雄性AHI PROKR2神经元。我们还将确定prokr2神经元是否反应到异性气味。最后，我们将使用化学发生技术，即设计器受体专门被设计师药物（Dreadds）激活以激活或抑制女性Meapd的Prokr2神经元男性的Ahi。我们将确定这些神经元的激活是否增加了循环的生殖激素和如果这些神经元的抑制会阻止暴露后观察到的生殖激素的增加到异性气味。我们的研究将定义prokr2神经元在内侧细分中的作用杏仁核，啮齿动物和灵长类动物，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。