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Novel Roles of Placental Allopregnanolone in Brain Development and Injury

胎盘四氢孕酮在大脑发育和损伤中的新作用

基本信息

批准号：
10735940
负责人：
ANNA A PENN
金额：
$ 50.22万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-08 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735940
关键词：
3-Dimensional Acute Agonist Allopregnanolone Apoptosis Autopsy Behavior Brain Brain Diseases Brain Injuries Cell Cycle Cognitive deficits Data Defect Development Dorsal Dose Electrophysiology (science)Enzymes Epilepsy Equilibrium Exposure to Female Functional disorder Funding Gene Deletion Gene Expression Gene Proteins Genes Genetic Transcription Goals Grant Hormonal Hormones Human Hydroxysteroid Dehydrogenases Immunohistochemistry Impairment In Vitro Infant Infection Injury Interneurons Investigation Link LoxP-flanked allele Measures Mediating Modeling Molecular Analysis Molecular Target Mus Neuroanatomy Neurodevelopmental Disorder Neurodevelopmental Impairment Neurologic Dysfunctions Neurological outcome Neurons Organoids Perinatal Placenta Placental Hormones Placental Insufficiency Pre-Eclampsia Pregnancy Premature Birth Prevalence Production Progesterone Publishing Risk Rodent Role Schizophrenia Series Shapes Signal Transduction Somatosensory Cortex Specificity Specimen System Testing Time Withdrawal Work autism spectrum disorder cell type cellular targeting defined contribution density design dosage experimental study fetal functional improvement gamma-Aminobutyric Acid hippocampal pyramidal neuron indexing induced pluripotent stem cell male migration mouse model nervous system disorder neural circuit neurodevelopment neurogenesis neuron loss neurosteroids novel novel therapeutics offspring post pregnancy postnatal postsynaptic prenatal prevent protein expression public health relevance receptor sex somatosensory tool

项目摘要

ABSTRACT Compromised placental function is highly associated with abnormal fetal brain development, and later with neurodevelopmental disorders such as autism, epilepsy, and schizophrenia, but the causal mechanisms remain largely unknown. The prevalence of these neurodevelopmental disorders is increased in those born preterm or born after pregnancies with evidence of poor placental function. Altered cortical GABAergic signaling has been implicated in many neurodevelopmental disorders, but until recently the tools to examine the relationship between placental dysfunction, altered cortical development and GABAergic signaling did not exist. In the initial funding period of this proposal, we validated and used our novel mouse model to directly demonstrate for the first time that a key placental hormone-- allopregnanolone (ALLO)-- is needed for normal brain development and that its loss contributes to long-term neurological dysfunction. ALLO is a potent GABAergic neurosteroid derived from progesterone that is made predominantly by the placenta in both rodent and human late gestation, resulting in high fetal brain concentrations of placentally-derived ALLO. Deleting the gene encoding the ALLO synthesis enzyme only from the placenta resulted in decrease in gestational ALLO exposure and produced global, yet sex-linked and regionally-specific, changes neuroanatomy and behavior. Reduced placental ALLO production impaired prenatal somatosensory corticogenesis and upper layer pyramidal neurons were permanently decreased, predominantly in female offspring, who also showed impaired somatosensory behavior. Molecular analyses of human postmortem brain specimens suggested similarities between mouse placental ALLO insufficiency and human preterm cortical development. Building on these published findings and on preliminary data showing that placental ALLO loss is associated with decreased cortical GABAergic interneuron density, altered GABA system-related gene expression, and changes in spontaneous inhibitory post-synaptic currents in mouse somatosensory cortex, we propose a new series of experiments in our mouse model to test the hypotheses that placental ALLO loss (1) disrupts the production and survival of specific cortical interneuron subclasses and (2) permanently alters the cortical excitation/inhibition (E/I) balance. We will then extend our analysis using our recently established in vitro brain organoid system to (3) define dosage and timing of ALLO exposure and withdrawal across multiple stages of human cortical interneuron development. Together, these next studies will elucidate new mechanisms by which placental hormones, including ALLO, can shape GABAergic cortical development. This work is starting to fundamentally change our understanding of developmental brain disorders and the placenta’s role in shaping long-term neurological outcomes and moves us closer to use of novel therapies based on placental hormones to prevent or ameliorate neurodevelopmental impairments.

摘要胎盘功能受损与胎儿大脑发育异常高度相关，自闭症、癫痫和精神分裂症等神经发育障碍，但因果机制但基本上仍不为人所知。这些神经发育障碍的患病率在那些出生于早产或妊娠后出生，有证据表明胎盘功能差。皮质GABA能信号改变与许多神经发育障碍有关，但直到最近，胎盘功能障碍、皮质发育改变和GABA能信号之间的关系不存在.在该提案的最初资助期间，我们验证并使用了我们的新型小鼠模型，首次直接证明了一种关键的胎盘激素--别孕烯醇酮（ALLO）--是必需的正常的大脑发育，它的损失有助于长期的神经功能障碍。ALLO是一种强效GABA能神经类固醇，来源于孕酮，主要由胎盘产生，啮齿动物和人类妊娠晚期，导致胎儿脑中胎盘来源的高浓度喂。仅从胎盘中删除编码ALLO合成酶的基因，妊娠期ALLO暴露，并产生全球性，但与性别相关和区域特异性的变化神经解剖学和行为学胎盘ALLO产生减少损害产前体感皮质生成和上层锥体神经元永久性减少，主要在女性后代，他们也表现出受损的躯体感觉行为。人类死后组织的分子生物学分析大脑标本表明小鼠胎盘ALLO功能不全和人类早产之间的相似性皮质发育基于这些已发表的发现和初步数据， ALLO丢失与皮质GABA能中间神经元密度降低、GABA系统相关改变有关。基因表达，以及小鼠躯体感觉皮层中自发抑制性突触后电流的变化，我们提出了一系列新的实验，在我们的小鼠模型，以测试假设，胎盘ALLO 缺失（1）破坏特定皮质中间神经元亚类的产生和存活，以及（2）永久性改变皮质兴奋/抑制（E/I）平衡。然后，我们将使用最近的建立体外脑类器官系统，以（3）确定ALLO暴露和停药的剂量和时间人类皮层中间神经元发育的多个阶段。总之，接下来的研究将阐明了胎盘激素（包括ALLO）可以塑造GABA能皮质的新机制，发展这项工作开始从根本上改变我们对大脑发育障碍的理解以及胎盘在塑造长期神经学结果中的作用，并使我们更接近于使用新的基于胎盘激素的治疗，以预防或改善神经发育障碍。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Controversies in preterm brain injury.

DOI：
10.1016/j.nbd.2015.10.012
发表时间：
2016-08
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Penn AA;Gressens P;Fleiss B;Back SA;Gallo V
通讯作者：
Gallo V

Proceedings of the 13th International Newborn Brain Conference: Fetal and/or neonatal brain development, both normal and abnormal

第十三届国际新生儿大脑会议论文集：胎儿和/或新生儿大脑发育，正常和异常

DOI：
10.3233/npm-229002
发表时间：
2022
期刊：
Journal of Neonatal-Perinatal Medicine
影响因子：
0
作者：
Abdi Khadar;Kawaguchi Mas Lind;Hermans Tim;Hershkovitz Reli;Holgersenmad;Kidokoro Hiroyuki
通讯作者：
Kidokoro Hiroyuki

Correlation of preterm infant illness severity with placental histology.