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.

抽象的胎盘功能受损与胎儿大脑发育异常密切相关，进而与胎儿大脑发育异常密切相关。神经发育障碍，如自闭症、癫痫和精神分裂症，但其因果机制这些神经发育障碍在新生儿中的患病率是否增加目前仍不清楚。早产或妊娠后出生，有证据显示胎盘功能不良。与许多神经发育障碍有关，但直到最近，检查神经发育障碍的工具才出现胎盘功能障碍、皮质发育改变和 GABA 信号之间的关系在该提案的初始资助期间，我们验证并使用了我们的新型小鼠模型。首次直接证明需要一种关键的胎盘激素——四氢孕酮 (ALLO) ALLO 对正常的大脑发育有重要作用，其缺失会导致长期神经功能障碍。源自黄体酮的强效 GABA 能神经类固醇，主要由胎盘产生啮齿类动物和人类妊娠晚期，导致胎儿脑中胎盘来源的高浓度仅从胎盘中删除编码 ALLO 合成酶的基因会导致 ALLO 减少。妊娠期 ALLO 暴露并产生全球性但与性别相关和区域特定的变化神经解剖学和行为减少胎盘 ALLO 产生受损的产前体感。皮质发生和上层锥体神经元永久性减少，主要发生在女性中人类死后的分子分析也显示出其体感行为受损。脑标本表明小鼠胎盘 ALLO 功能不全与人类早产之间存在相似之处基于这些已发表的发现和显示胎盘的初步数据。 ALLO 丢失与皮质 GABA 能中间神经元密度降低、GABA 系统改变相关基因表达以及小鼠体感皮层自发抑制性突触后电流的变化，我们在小鼠模型中提出了一系列新的实验来测试胎盘 ALLO 的假设损失（1）破坏特定皮质中间神经元亚类的产生和生存，以及（2）永久改变皮质兴奋/抑制（E/I）平衡，然后我们将使用我们最近的分析来扩展我们的分析。建立体外脑类器官系统（3）剂量定义以及 ALLO 暴露和退出的时间这些接下来的研究将跨越人类皮质中间神经元发育的多个阶段。阐明胎盘激素（包括 ALLO）塑造 GABA 能皮质的新机制这项工作开始从根本上改变我们对发育性大脑疾病的理解。以及胎盘在塑造长期神经系统结果中的作用，并使我们更接近于使用新颖的基于胎盘激素的疗法可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）

A new pipeline for clinico-pathological and molecular placental research utilizing FFPE tissues.

利用 FFPE 组织进行临床病理学和分子胎盘研究的新管道。

DOI：
发表时间：
2021-09-01
期刊：
影响因子：
3.8
作者：
O'Reilly, Jiaqi J;Barak, Stephanie;Penn, Anna A
通讯作者：
Penn, Anna A

Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex.

早产会改变人类前额皮质 GABA 能系统的成熟。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Lacaille, Helene;Vacher, Claire;Penn, Anna A
通讯作者：
Penn, Anna A

Placental programming of neuropsychiatric disease.

神经精神疾病的胎盘编程。

DOI：
发表时间：
2019-08
期刊：
影响因子：
3.6
作者：
Kratimenos, Panagiotis;Penn, Anna A
通讯作者：
Penn, Anna A

Lack of placental neurosteroid alters cortical development and female somatosensory function.

缺乏胎盘神经类固醇会改变皮质发育和女性体感功能。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Bakalar, Dana;O'Reilly, Jiaqi J;Lacaille, Helene;Salzbank, Jacquelyn;Ellegood, Jacob;Lerch, Jason P;Sasaki, Toru;Imamura, Yuka;Hashimoto;Vacher, Claire;Penn, Anna A
通讯作者：
Penn, Anna A

Impaired Interneuron Development in a Novel Model of Neonatal Brain Injury.

新生儿脑损伤新模型中中间神经元发育受损。