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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：
10430104
负责人：
Brenda Cisneros Larios
金额：
$ 2.47万
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/10430104
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)的特征是由于促性腺激素缺乏而导致的不孕不育和嗅觉障碍。释放激素(GnRH)神经元迁移与嗅球发育不全。基因研究揭示了 KS是由包括原激动素受体2基因在内的几个基因的功能丧失突变引起的 (PROKR2)见于10%的KS患者。PROKR2全缺失小鼠复制KS表型表现为嗅球发育不全、GnRH神经元迁移受损和不孕症的患者。鉴于 PROKR2在发育过程中的作用已经确定，但对PROKR2神经元在成年生殖中的作用知之甚少。 PROKR2及其配体的mRNA在成虫生殖控制部位高表达老鼠的大脑。尽管GnRH神经元迁移正常，杂合子小鼠的PROKR2功能缺失突变与野生型窝产仔相比，表现出更长的发情周期。同样，携带PROKR2突变的人类嗅觉系统正常，但生育力下降，表明生殖障碍与正常无关嗅球形态发生与促性腺激素释放激素神经元迁移。然而，PROKR2在脑内的神经基础成虫的繁殖是未知的。我们最近开发了一种PROKR2-CRE小鼠模型，在该模型中，CRE 重组酶由PROKR2启动子驱动。利用这个小鼠模型，我们绘制了PROKR2的分布在两性大脑中都有表达细胞。PROKR2 mRNA和GFP+细胞高表达杏仁内侧核性二型性分裂。雄性小鼠体内PROKR2-Cre水平较高杏仁核-海马区(AHI，也称为杏仁后核)，而女性的杏仁内侧核背后亚区的PROKR2(MeApd)。两者都是MeApd AHI表现为性激素受体的密集表达，在生殖功能中起重要作用以及相关联的行为。我们假设MeApd的PROKR2-Cre神经元是典型的控制女性生殖功能(包括发情周期)，而AHI中的PROKR2-CRE神经元在雄性生殖中起作用。在两个目标中，我们建议映射MeApd PROKR2的神经元投射雌性神经元和雄性AHI PROKR2神经元。我们还将确定PROKR2神经元是否会对异性的气味。最后，我们将使用化学遗传技术，即设计者受体被特制药物(DREADD)激活以激活或抑制女性和男性的AHI。我们将确定这些神经元的激活是否会增加循环生殖激素和IF抑制这些神经元阻止暴露后生殖激素的上升异性的气味。我们的研究将确定PROKR2神经元在内侧脑区细分中的作用杏仁核，啮齿动物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，我们期望我们的研究将有助于了解与PROKR2突变相关的生殖缺陷。