Maternal Viral Infection and Fetal Brain Development

母体病毒感染与胎儿大脑发育

基本信息

批准号：
6731285
负责人：
PAUL H PATTERSON
金额：
$ 36.45万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-09 至 2008-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Maternal viral infection can increase the incidence of mental illness and cerebral palsy in the offspring. Such infections can also lead to miscarriage, premature and stillbirth and early neonatal mortality. We are utilizing a mouse model to examine the effects of maternal respiratory infection with influenza virus on fetal brain development. We find that the adult offspring of these mothers exhibit interesting behavioral abnormalities and striking responses to psychoactive drugs, as well as a neuropathological finding that is remarkably similar to that found in autism. (i) We have preliminary evidence that adult mice born to infected mothers exhibit a highly localized loss of Purkinje cells, similar to that observed in autistic brain. We will quantitate Purkinje cell density, as well as the width of the molecular layer in this and other parts of the cerebellum, in both adults and during development. (ii) It is possible that the infected mothers have altered maternal behavior, which could have lasting effects on the offspring. To investigate this, we will carry out cross-fostering experiments, in which the offspring of infected mothers are raised from birth by control mothers. These offspring will be tested behaviorally with the assays we have employed previously, and their brains will be examined by histology. (iii) As we have not detected viral infection of the fetus, it is possible that these morphological and behavioral abnormalities found in the offspring are due to the anti-viral inflammatory response mounted by the mother. Supporting this hypothesis are results of injecting pregnant mice with poly I:C, a double stranded RNA that causes an inflammatory response resembling that induced by viral infection. At least one of the behavioral abnormalities in the offspring can be elicited by this procedure, so further analysis of such offspring is merited. We also plan to test the effects of viral vaccination of pregnant mice on the behavior and neuropathology of the offspring. (iv) In parallel studies using cytokine knockout mice and cytokine adenoviral vectors, we are able to manipulate the inflammatory response in the brain and periphery. These and other strategies will be used to test whether manipulation of the mother's response to viral infection can prevent the development of brain abnormalities. Importantly, anti-cytokine strategies in influenza-infected mice have already proven effective in treating fever and lung inflammation. We will also use cytokine injections of non-infected mothers to help identify cytokines that may mediate the effects of maternal viral infection.

描述（由申请人提供）：母体病毒感染可以增加后代精神疾病和脑瘫的发生率。这种感染也会导致流产，早产和早期新生儿死亡率。我们利用小鼠模型来检查孕产妇病毒感染对胎儿脑发育的影响。我们发现，这些母亲的成年后代表现出有趣的行为异常和对精神活性药物的惊人反应，以及与自闭症中发现的神经病理学发现非常相似。（i）我们有初步的证据表明，受感染母亲出生的成年小鼠表现出高度高度的浦肯野细胞丧失，类似于自闭症大脑中观察到的细胞。在成年人和发育过程中，我们将定量Purkinje细胞密度以及小脑和其他部分的分子层的宽度。（ii）受感染的母亲可能改变了产妇行为，这可能会对后代产生持久影响。为了调查这一点，我们将进行交叉促进实验，其中控制母亲从出生中养育了受感染母亲的后代。这些后代将通过我们先前使用的测定法进行行为测试，并将通过组织学检查它们的大脑。（iii）由于我们尚未检测到胎儿的病毒感染，因此后代中发现的这些形态和行为异常可能是由于母亲安装的抗病毒炎症反应引起的。支持这一假设的是将孕妇小鼠注射Poly I：C，这是一种双链RNA，会导致类似于病毒感染引起的炎症反应。该程序可以引起后代中至少一种行为异常，因此应进一步分析这种后代。我们还计划测试怀孕小鼠病毒疫苗接种对后代行为和神经病理学的影响。（iv）在使用细胞因子敲除小鼠和细胞因子腺病毒载体的平行研究中，我们能够操纵大脑和周围的炎症反应。这些策略和其他策略将用于测试母亲对病毒感染反应的操纵是否可以防止脑异常的发展。重要的是，感染了流感的小鼠的抗周期策略已经证明有效治疗发烧和肺部炎症。我们还将使用未感染母亲的细胞因子注射来帮助鉴定可能介导孕产妇病毒感染作用的细胞因子。