Alterations in primate brain development following prenatal immune challenge

产前免疫挑战后灵长类动物大脑发育的变化

• 批准号: 10793198
• 负责人: Melissa Dawn Bauman
• 金额: $ 78.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793198
• 关键词: Adolescent; Affect; Age; Amygdaloid structure; Anatomy; Anterior; Array tomography; Bacterial Infections; Behavioral; Biological Markers; Biological Response Modifier Therapy; Birth; Brain; Brain region; Cell Nucleus; Cells; Child; Cognition; Complex; Data; Development; Disease; Emotional; Environment; Equilibrium; Event; Exhibits; Exposure to; Female; Fluorescent in Situ Hybridization; Functional disorder; Gene Expression Profile; Genes; Glutamates; Goals; Human; Human Development; Immune; Immune response; Individual; Infection; Intervention; Knowledge; Label; Laboratories; Lateral; Link; Maps; Maternal-Fetal Exchange; Mediating; Mental Health; Mental disorders; Modeling; Molecular; Neuroanatomy; Neurobiology; Neurodevelopmental Disorder; Neuropil; Pathway interactions; Physiology; Population; Pre-Clinical Model; Prefrontal Cortex; Pregnancy; Prevention strategy; Primates; Proteins; Research; Risk; Risk Factors; Rodent Model; Schizophrenia; Signal Pathway; Social Behavior; Spatial Distribution; Structure; Synapses; Synaptic Transmission; Testing; Time; Tissue Banks; Tissues; Transcript; Translating; Viral; Virus Diseases; autism spectrum disorder; biobank; brain circuitry; brain tissue; cell type; cohort; critical period; density; differential expression; emotional behavior; experience; fetal; glutamatergic signaling; immune activation; male; neural circuit; neurobiological mechanism; neurodevelopment; neurotransmission; nonhuman primate; novel; novel therapeutic intervention; offspring; postnatal; postsynaptic; pre-clinical; prenatal; prenatal exposure; presynaptic; programs; receptor; response; segregation; single molecule; single nucleus RNA-sequencing; social cognition; timeline; tissue resource; transcriptomics; ultra high resolution

ABSTRACT Prenatal exposure to viral or bacterial infections during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders, including autism and schizophrenia. Gestational biomarkers indicate that the maternal immune response is the critical link between maternal infection and altered offspring neurodevelopment. However, our ability to mitigate the deleterious impact of maternal infection on offspring brain development is severely restricted by our limited mechanistic understanding of the underlying neurobiological changes. Although preclinical rodent models have provided foundational evidence of alterations in brain and behavioral development resulting from MIA exposure that mirror some changes in human disorders, translational limitations provide a need to extend this program of research into a species more closely related to humans. Nonhuman primates (NHPs) provide the closest model to human development, sharing similarities in placental structure and pregnancy physiology, maternal-fetal interface, gestational timeline, fetal and postnatal brain development, and complex social behavior and cognition. Our laboratory has developed the first viral-mimic based NHP MIA model and demonstrated that MIA-exposed NHPs exhibit alterations in brain and behavioral development implicating selective vulnerability to socioemotional amygdala-prefrontal circuitry. Here we propose to leverage the entire biorepository of brain tissue from previous NHP MIA models to determine, at the single cell level, the transcriptomic, cellular, and connectomic alterations triggered by prenatal immune challenge. We have developed a novel pipeline for a genes-to-circuitry approach that maximizes the yield of information from this precious tissue resource. Here, we will target key brain regions in the amygdala-prefrontal network mediating socioemotional behaviors implicated in human neurodevelopmental and mental health disorders at two critical age time points for the pathophysiology of mental illness: juvenile (18 month) and adolescent (4 year). We will generate single-nuclei transcriptomic profiles and quantify differentially expressed genes (DEGs) in specific cell types (Aim 1), spatially map and quantify high-priority transcripts in specific cell types and within-cell transcriptomic colocalization (Aim 2), and map spatial distribution of synaptic composition, receptors, and direct inputs onto specific cell types (Aim 3). These data, in combination with the extensive, longitudinal characterization of offspring brain and behavioral development, build a comprehensive picture of MIA-induced changes in NHP brain circuitry, toward the ultimate goal of identifying pathways of vulnerability and critical periods for novel, targeted interventions and biotherapeutics to reduce the number of children adversely affected by prenatal exposure to maternal infection.

摘要 妊娠期间产前暴露于病毒或细菌感染与以下风险增加有关： 后代神经发育障碍，包括自闭症和精神分裂症。生物标志物显示 母亲的免疫反应是母亲感染和改变后代之间的关键联系 神经发育然而，我们减轻母体感染对后代有害影响的能力 大脑的发育受到我们对潜在的机械理解的限制， 神经生物学变化尽管临床前啮齿动物模型提供了 MIA暴露导致的大脑和行为发育的改变，反映了一些变化， 人类疾病，翻译的限制提供了需要扩展到一个物种的研究计划 与人类关系更密切。非人灵长类动物（NHP）提供了最接近人类的模型 发育，胎盘结构和妊娠生理学的相似性，母胎界面， 妊娠期时间轴、胎儿和出生后的大脑发育以及复杂的社会行为和认知。我们 一个实验室已经开发出第一个基于病毒模拟的NHP MIA模型，并证明MIA暴露 NHPs表现出大脑和行为发育的改变，暗示着选择性的脆弱性， 社会情绪杏仁核-前额叶回路在这里，我们建议利用整个大脑生物库， 组织从以前的NHP MIA模型，以确定，在单细胞水平，转录组，细胞， 由产前免疫挑战引发的连接组学改变。我们开发了一种新颖的管道， 基因到电路的方法，最大限度地从这个宝贵的组织资源的信息产量。在这里， 我们将瞄准杏仁核-前额网络中调节社会情绪行为的关键大脑区域， 在两个关键年龄点， 精神疾病的病理生理学：少年（18个月）和青少年（4岁）。我们将产生单核 转录组学谱和定量特定细胞类型中的差异表达基因（DEG）（Aim 1）， 在特定细胞类型和细胞内转录组中空间定位和定量高优先级转录物 共定位（目标2），并映射空间分布的突触组成，受体，并直接输入到 特定细胞类型（目标3）。这些数据，结合广泛的，纵向的特点， 后代的大脑和行为发育，建立一个全面的图片MIA诱导的变化，NHP 大脑回路，朝着识别脆弱性途径和新的关键时期的最终目标， 有针对性的干预措施和生物治疗，以减少产前 暴露于母体感染。