Developmental Origins of Decreased Resilience

描述(申请人提供)：孕妇在怀孕期间感染病毒是神经精神疾病和神经发育障碍的危险因素。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影响大脑发育，降低了在以后的生活中成功适应急性压力或逆境的能力。韧性较差的受试者对温和或无害的压力源会经历夸张或延长的生理和心理反应。因此，在弹性较差的受试者中，夸大的应激反应增加了不平衡负荷，对身体造成磨损 和大脑，还有健康问题。在人类中，这可能会导致神经心理问题，而在农业动物中，它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。孕期母体感染导致韧性丧失的发育起源尚不清楚，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变得敏感，使它们在以后的生活中对侮辱反应强烈。然而，由于大脑发育(例如，年表)和结构的巨大差异，推断从啮齿类动物到轮脑物种的免疫对神经发育的影响的发现是复杂的。事实上，对轮脑动物进行研究以了解神经发育障碍的致病原因被许多人认为是该领域研究的重中之重。因此，这项拟议研究的目标是调查怀孕期间由于母体感染而导致弹性丧失的发育起源。猪是一种农业上重要的动物，其大脑在大体解剖特征、总体生长模式和成熟度方面与人类非常相似。我们的具体假设是，孕妇在怀孕期间感染会影响大脑的发育轨迹，特别是小胶质细胞环境，从而降低后来的弹性。由于压力复原力对人类健康和畜牧业非常重要，了解复原力下降的发育根源具有双重目的和双重好处。提出了三个具体的目标来解决我们的假设，其中将研究出生后的小猪的大脑结构和韧性将在怀孕最后三分之一(即相当于人类的第三个月)大脑快速发育时由接种PRRSV的母猪所生。将对7至42天的仔猪进行研究，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紧张过渡。在目标1中，我们将通过评估ACTH和皮质醇对应激反应的幅度和持续时间，并使用旨在探索包括学习和记忆、焦虑、挫折和社交在内的几个行为领域的测试，来表征母亲病毒感染对出生后(A)小胶质细胞激活，(B)促炎症和神经营养基因在离散脑区的表达，以及(C)韧性的影响。在目标2中，由于胎儿大脑在妊娠母猪感染期间和之后经历了快速的生长和发育，在这里我们将首先通过纵向研究设计中的定量磁共振成像来确定母体感染如何影响结构脑发育；其次使用高尔基-考克斯染色程序和NeuroLucida来生成三维跟踪图，以确定与所研究的行为域相对应的大脑区域的神经元结构。最后，在目标3中，我们将确定减少感染病毒的怀孕仔猪的小胶质细胞活性是否可以保护大脑发育和弹性。我们提出了一个使用米诺环素的临床相关方案，米诺环素是第二代四环素，通过阻断小胶质细胞的激活来抑制神经炎症。 公共卫生相关性：拟议研究的目标是调查怀孕期间因母亲感染而丧失韧性的发育起源-猪是一种农业上重要的动物，其大脑在大体解剖特征、总体生长模式和成熟度方面与人类非常相似。我们的假设是，孕妇在怀孕期间感染会影响大脑的发育轨迹，特别是小胶质细胞环境，从而降低后来的弹性。应激恢复能力对人类健康很重要，因为恢复能力较差的个体患神经精神疾病的风险增加，对畜牧业也很重要，因为夸大或持续的应激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，理解韧性降低的发育根源具有双重目的和双重好处。

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.