Neurodevelopment after postnatal Zika virus infection in infant macaques

幼年猕猴出生后感染寨卡病毒后的神经发育

基本信息

批准号：
10864259
负责人：
Ann M Chahroudi
金额：
$ 17.19万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10864259
关键词：
2 year old Address Adult Affect Age Age Months Amygdaloid structure Animals Area Attention Basal Ganglia Behavior Behavioral Birth Blood Brain Brain imaging Cells Child Childhood Cognition Cognitive Communicable Diseases Compensation Congenital Abnormality Data Defect Development Disease Disease Outbreaks Emotional Epidemic Euthanasia Event Exposure to Flavivirus Future Goals Growth Hippocampus Histologic Histology Human Immune response Infant Infection Knowledge Lead Learning Life Longitudinal Studies Macaca Macaca mulatta Measures Memory Microcephaly Modeling Motor Neurodevelopmental Deficit Neurodevelopmental Disorder Neurodevelopmental Problem Neuroglia Neurologic Dysfunctions Neurologic Effect Neurons Neurosciences Outcome Parietal Pathway interactions Pilot Projects Pregnancy Public Health Recovery of Function Reporting Research Research Personnel Rest Series Short-Term Memory Social Functioning Social Interaction Structure Symptoms Testing Time Viral Virus Visual Work ZIKV infection Zika Virus acute stress behavioral response brain abnormalities cell type congenital zika syndrome early childhood emotional functioning executive function functional MRI scan gray matter in utero in vivo infancy infant infection insight longitudinal analysis memory recognition neurobehavioral neurodevelopment neuroimaging nonhuman primate novel postnatal postnatal development postnatal period prenatal prenatal exposure skills transcriptomics virology virus host interaction white matter

项目摘要

PROJECT SUMMARY / ABSTRACT Intense research has focused on the neurologic effects of prenatal Zika virus (ZIKV) infection; however, the consequences of postnatal infection early in life are understudied. Infants exposed to ZIKV in utero but born without microcephaly can develop postnatal microcephaly, neurologic dysfunction, and neurodevelopmental ab- normalities, highlighting the potential of ZIKV to cause ongoing damage after birth. This damage is likely related to the exponential maturation of the brain that occurs during the first 2 years of life, particularly in temporal, prefrontal and parietal regions important for emotional, social and executive functions, including learning, atten- tion and memory. Our group has previously reported that postnatal ZIKV infection causes abnormalities in brain structure, function, and behavior in a pilot study of infant rhesus macaques (RMs) infected postnatally. Here, we propose to extend the scope and duration our prior pilot study and generate novel data regarding the impact of postnatal ZIKV infection on the developing brain. The Objective of this application is to bring new mechanistic insights into postnatal ZIKV infection to address the existing knowledge gap regarding outcomes and host-virus interactions. We will use our postnatal ZIKV-RM model to interrogate the neurobehavioral impact of ZIKV infection at different stages of postnatal brain develop- ment, with approaches that span from single cells to whole animal. This model of postnatal ZIKV exposure allows us to generate key data on the mechanisms by which ZIKV and/or the immune response to infection leads to cellular changes that ultimately result in aberrant postnatal development of limbic structures and behavioral def- icits later in life. We hypothesize that 1) ZIKV and/or the immune response to infection disproportionately affects limbic structures in the postnatally developing brain; 2) cellular changes in these limbic structures lead to aberrant neurodevelopment and abnormal behaviors; and 3) there may be a period of vulnerability to ZIKV during post- natal brain development. We will test our hypotheses in these Specific Aims: 1) Determine the spectrum of abnormal behavior and cognition following ZIKV infection of infant RMs at different stages of brain development; 2) Identify developmental trajectories of brain structure and function following postnatal ZIKV infection of infant RMs at different stages of brain development; and 3) Define the neurodevelopmental pathways and cell types impacted by postnatal ZIKV infection. This work will include RM infants infected with ZIKV at 1 or 6 months of age (equivalent to 4 and 24 month old humans) as well as age- and rearing-matched and viral mimic controls, that over their first 2 years of life will undergo a series of detailed assessments including validated tests of soci- oemotional behavior and cognition, structural and functional brain imaging, brain histology, stereology and single cell and bulk cell transcriptomics. Our results may have important public health implications for children living in ZIKV-endemic/epidemic areas as well as for travelers to these regions.

项目摘要 /摘要激烈的研究集中在产前寨卡病毒（ZIKV）感染的神经系统作用上。但是，生命早期产后感染的后果被研究了。婴儿在子宫内暴露于Zikv，但出生没有小头畸形可以发展产后小头畸形，神经功能障碍和神经发育正常水平，突出了ZIKV在出生后造成持续破坏的潜力。这种损害可能相关在生命的头两年中，尤其是在时间上，大脑的指数成熟对情感，社会和执行功能至关重要的前额叶和顶叶区域，包括学习， tion和记忆。我们的小组以前报道说，产后ZIKV感染会导致大脑异常婴儿猕猴（RMS）感染的初步研究中的结构，功能和行为。在这里，我们建议扩大我们先前的试点研究的范围和持续时间，并生成有关有关影响的新数据发育中大脑的产后ZIKV感染。该应用程序的目的是将新的机械洞察力带入产后ZIKV感染中以解决现有有关结果和主机病毒相互作用的知识差距。我们将使用我们的产后zikv-rm 询问ZIKV感染在产后大脑不同阶段的神经行为影响的模型用从单细胞到整个动物的方法。这种产后ZIKV暴露模型允许我们生成有关ZIKV和/或感染免疫反应的机制的关键数据细胞变化最终导致边缘结构的异常发生和行为辩护以后生活的ICIT。我们假设1）ZIKV和/或对感染的免疫反应不成比例地影响产后发育的大脑中的边缘结构； 2）这些边缘结构的细胞变化导致异常神经发育和异常行为； 3）在后期，可能会有一段时期的ZIKV。出生脑发育。我们将在这些特定目的中测试我们的假设：1）确定在大脑发育的不同阶段，婴儿RMS ZIKV感染后的异常行为和认知； 2）确定婴儿产后ZIKV感染后大脑结构和功能的发育轨迹 RMS处于大脑发育的不同阶段； 3）定义神经发育途径和细胞类型受产后ZIKV感染的影响。这项工作将包括在1或6个月后感染ZIKV的RM婴儿年龄（相当于4个月和24个月大的人）以及年龄和饲养匹配和病毒模仿对照，在他们的头两年中，将经过一系列详细的评估作战行为和认知，结构和功能性脑成像，大脑组织学，立体学和单一细胞和散装细胞转录组学。我们的结果可能对居住在的儿童有重要的公共卫生影响 ZIKV流行/流行病区以及这些地区的旅行者。