Developmental Origins of Decreased Resilience

描述（由申请方提供）：妊娠期间母体病毒感染是神经精神疾病和神经发育障碍的风险因素。越来越多的证据表明，母体或胎儿免疫系统在感染期间产生的炎症介质会影响大脑发育，降低成功适应急性压力或逆境的能力。弹性较低的受试者对温和或无害的压力源会产生夸张或延长的生理和心理反应。因此，在弹性较低的受试者中，过度的压力反应增加了非稳态负荷，对身体造成磨损 和大脑，以及健康问题。然而，在人类中，这可能导致神经心理问题，在农业动物中，它对动物健康产生负面影响，降低生产效率，并导致屠宰前和屠宰后的损失。由于母亲在怀孕期间感染而丧失弹性的发育起源知之甚少，但最近在啮齿动物模型中的研究表明，在大脑快速生长的早期敏感期感染会使小胶质细胞敏感，使它们在以后的生活中对侮辱反应过度。然而，由于大脑发育的深刻差异（例如，时间表）和结构。事实上，许多人认为，在脑回动物中进行研究，以了解神经发育障碍的病因，是该领域研究的重中之重。因此，拟议研究的目标是调查猪怀孕期间由于母体感染而丧失弹性的发育起源-猪是一种农业上重要的动物，其大脑在大体解剖特征，整体生长模式和成熟方面与人类非常相似。我们的具体假设是，怀孕期间的母体感染会影响大脑的发育轨迹，特别是小胶质细胞环境，降低以后的恢复力。由于应激恢复力对人类健康和畜牧业非常重要，因此了解恢复力下降的发育起源具有双重目的和双重利益。提出了三个具体目标来解决我们的假设，其中将在妊娠的最后三分之一（即，相当于人类的第三个三个月），此时大脑正在快速发育。将对7- 42日龄仔猪进行研究，以模拟6个月至3岁的人类，并代表从分娩环境到断奶后托儿所的压力过渡。在目标1中，我们将通过评估ACTH和皮质醇对压力反应的幅度和持续时间，并使用旨在探索几个行为领域（包括学习和记忆、焦虑、挫折和社交）的测试，来描述母体病毒感染对出生后（a）小胶质细胞活化、（B）促炎基因和神经营养基因在离散脑区的表达以及（c）恢复力的影响。在目标2中，由于胎脑在妊娠母猪感染期间和之后经历快速生长和发育，因此我们将确定母体感染如何影响结构性脑发育，首先通过纵向研究设计中的定量MRI;第二，使用Golgi-Cox染色程序和Neurolucida产生三个-用于确定与所研究的行为域相对应的大脑区域中的神经元结构的维度描记。最后，在目标3中，我们将确定减少病毒感染妊娠仔猪中的小胶质细胞活性是否可以保护大脑发育和恢复力。我们提出了一个临床相关的计划，使用米诺环素，第二代四环素，通过阻断小胶质细胞的激活抑制神经炎症。 公共卫生相关性：这项研究的目的是调查猪在怀孕期间由于母体感染而丧失弹性的发育起源，猪是一种农业上重要的动物，其大脑在大体解剖特征，整体生长模式和成熟方面与人类非常相似。我们的假设是，怀孕期间的母体感染会影响大脑的发育轨迹，特别是小胶质细胞环境，降低以后的恢复力。压力恢复力对人类健康很重要，因为恢复力较低的个体患神经精神疾病的风险增加，并且对畜牧业很重要，因为过度或长期的压力反应会对动物的健康产生负面影响，降低生产效率，并导致屠宰前和屠宰后的损失。因此，理解心理弹性下降的发展根源具有双重目的和双重益处。

DESCRIPTION (provided by applicant): Maternal viral infection during pregnancy is a risk factor for neuropsychiatric disease and neurodevelopmental disorders. Mounting evidence indicates that inflammatory mediators produced by the maternal or fetal immune system during infection affect brain development, reducing the ability to adapt successfully to acute stress or adversity later in life. Less resilient subjects experience exaggerated or prolonged physiological and psychological responses to mild or innocuous stressors. Thus, the exaggerated stress response in less resilient subjects adds to the allostatic load, creating wear-and-tear to the body and brain, and ill health. Whereas in humans, this may lead to neuropsychatric problems, in agricultural animals it negatively impacts animal well- being, reduces production efficiency, and leads to pre- and post-slaughter losses. The developmental origins of the loss of resilience owing to maternal infection during pregnancy are poorly understood but recent studies in rodent models suggest infection during an early sensitive period when the brain is experiencing rapid growth sensitizes microglial cells, making them hyper responsive to insults later in life. Extrapolating findings of immune effects on neurodevelopment from rodents to gyrencephalic species is complicated, however, due to profound differences in brain development (e.g., chronology) and structure. Indeed, studies in gyrencephalic animals to gain insight on the pathogenic origins of neurodevelopmental disorders are considered by many, a top priority for research in this field. Thus, the goal of the proposed research is to investigate the developmental origins of the loss of resilience due to maternal infection during pregnancy in pigs- an agriculturally important animal whose brain is remarkably similar to that of humans with respect to gross anatomical features, overall growth pattern, and maturation. Our specific hypothesis is that maternal infection during pregnancy affects the developmental trajectory of the brain and particularly the microglial cell environment, reducing resilience later. As stress resilience is important to human health and animal agriculture, understanding the developmental origins of decreased resilience has dual purpose with dual benefit. Three specific aims are proposed to address our hypothesis wherein postnatal brain structure and resilience will be studied in piglets born by dams inoculated with PRRSV in the final one-third of pregnancy (i.e., equivalent to the third trimester in humans) when the brain is undergoing rapid growth. Piglets will be studied from 7- to 42-d of age to model humans aged 6-months to 3-years and to represent the stressful transition from the farrowing environment to the post weaning nursery. In Aim 1, we will characterize the effects of maternal viral infection on postnatal (a) microglial cell activation, (b) expression of pro-inflammatory and neurotrophic genes in discrete brain regions, and (c) resilience by assessing the magnitude and duration of the ACTH and cortisol responses to stress and using tests designed to probe several behavioral domains including learning and memory, anxiety, frustration, and sociability. In Aim 2, because the fetal brain experiences rapid growth and development during and after the time pregnant gilts will be infected, here we will determine how maternal infection affects structural brain development, first by quantitative MRI in a longitudinal study design; and second using Golgi-Cox staining procedures and Neurolucida to generate three-dimensional tracings for determining the structure of neurons in brain regions corresponding to the behavioral domains under investigation. Finally, in Aim 3, we will determine if reducing microglial cell activity in piglets from virally-infected pregnancies protects brain development and resilience. We propose a clinically relevant scheme using minocycline, a second-generation tetracycline that inhibits neuroinflammation by blocking activation of microglia. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to investigate the developmental origins of the loss of resilience due to maternal infection during pregnancy in pigs-an agriculturally important animal whose brain is remarkably similar to that of humans with respect to gross anatomical features, overall growth pattern, and maturation. Our hypothesis is that maternal infection during pregnancy affects the developmental trajectory of the brain and particularly the microglial cell environment, reducing resilience later. Stress resilience is important to human health since less resilient individuals are at increased risk for neuropsychiatric disease, and it is important to animal agriculture because an exaggerated or prolonged stress response negatively impacts animal well-being, reduces production efficiency, and leads to pre- and post-slaughter losses. Thus, understanding the developmental origins of decreased resilience has dual purpose with dual benefit.