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Prenatal Virally Induced Brain Disorder in Mouse

产前病毒引起的小鼠脑部疾病

基本信息

批准号：
7933161
负责人：
seyyed HOSSEIN FATEMI
金额：
$ 8.77万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7933161
关键词：
Adult Affect Animal Model Animals Anxiety Apoptosis Behavior Behavioral Biochemical Birth Brain Brain Diseases Cerebellum Data Development Diffusion Diffusion Magnetic Resonance Imaging Dose Embryo Embryonic Development Environment Environmental Risk Factor Epidemiology Etiology Exposure to Funding Gene Expression Genes Genetic Glutamates Goals Hippocampus (Brain)Human Image Incidence Infection Influenza Knowledge Laboratories Lead Lesion Life Link Magnetic Resonance Measures Medicine Membrane Proteins Messenger RNA Molecular Profiling Morphology Motor Mus Nature Neocortex Neurodevelopmental Disorder Neurosciences Outcome Pathogenesis Patients Perinatal Exposure Pilot Projects Polymerase Chain Reaction Population Pregnancy Prevention Preventive Proteins Reflex action Regulation Reporting Research Research Personnel Resource Sharing Resources Schizophrenia Second Pregnancy Trimester Sensory Serological Signal Transduction Structure Synapses Techniques Testing Thick Time Ventricular Viral Viral Pathogenesis Virus Diseases Western Blotting Work animal data base behavior measurement critical period expectation influenzavirus innovation mature animal mouse model myelination offspring postnatal prenatal prenatal exposure prepulse inhibition presynaptic prevent response virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia, which affects 1% of the world's population, has been linked epidemiologically to prenatal exposure to human influenza virus. Experimental animal data supporting this linkage are lacking. Our long-range goal is to understand how prenatal human influenza viral infection affects brain development adversely, leading to the genesis of schizophrenia. The objective of this application is to determine how prenatal infection of mice with human influenza virus causes subsequent brain structural and behavioral abnormalities in adult animals. The central hypothesis of the application is that prenatal viral infection at critical periods during embryogenesis causes permanent changes in brain structure and function, leading to the development of postnatal behavioral abnormalities. The rationale for the proposed research is that, once the pathogenesis of influenza virus-induced behavioral abnormalities is understood in mice, similar pathogenic mechanisms can be selectively sought for schizophrenia. We are uniquely prepared to undertake the proposed research, because we have succeeded in performing pilot studies, indicating that infection of mice on day 9 of pregnancy with a sublethal dose of human influenza virus causes abnormal corticogenesis and changes in levels of several important brain markers in postnatal life. Additionally, infection on day 9 of pregnancy leads to development of abnormal behavioral responses on prepulse inhibition in the affected adult mice. The central hypothesis will be tested and the objective of the application accomplished by pursuing three specific aims: 1) identify neuroanatomical molecular profiles for postnatal brain development that result from the effects of prenatal human influenza viral infection in mice using DMA microarray, 2) characterize morphometric abnormalities that are produced in the offspring following prenatal human influenza viral infection in mice by diffusion tensor microimaging and magnetic resonance volumetric studies, and 3) characterize behavioral abnormalities that are produced in mice by brain lesions that are comparable to those in patients with schizophrenia. The proposed work is innovative, because it capitalizes on our new animal model, which links a viral insult to abnormal brain development. It is our expectation that we will link the onset of post-viral structural changes in the brains of mice with the subsequent development of specific biochemical, behavioral and structural changes in affected animals. Such outcomes will be significant, because they are expected to provide a rational explanation for the epidemiological data supporting the link between human influenza viral infection, and the subsequent rise in births that lead to schizophrenia. In addition, it is expected that the results will provide clues that will lead to fundamental advances in our knowledge of the pathogenesis of schizophrenia and, therefore, of how it can be prevented and treated.

描述（由申请方提供）：精神分裂症影响世界人口的1%，在流行病学上与产前暴露于人流感病毒有关。缺乏支持这种联系的实验动物数据。我们的长期目标是了解产前人类流感病毒感染如何对大脑发育产生不利影响，从而导致精神分裂症的发生。本申请的目的是确定小鼠产前感染人流感病毒如何导致成年动物随后的脑结构和行为异常。该申请的中心假设是，在胚胎发育的关键时期，产前病毒感染导致大脑结构和功能的永久性变化，导致出生后行为异常的发展。这项研究的基本原理是，一旦在小鼠中了解了流感病毒诱导的行为异常的发病机制，就可以选择性地寻找精神分裂症的类似致病机制。我们为开展拟议的研究做好了独特的准备，因为我们已经成功地进行了试点研究，表明在妊娠第9天用亚致死剂量的人流感病毒感染小鼠会导致出生后皮质生成异常和几种重要脑标志物水平的变化。此外，妊娠第9天的感染导致受影响的成年小鼠出现前脉冲抑制的异常行为反应。将通过追求三个具体目标来检验中心假设，并实现申请的目标：1）使用DMA微阵列鉴定出生后脑发育的神经解剖学分子谱，所述神经解剖学分子谱是由小鼠中产前人流感病毒感染的影响引起的，（二）通过扩散张量显微成像表征小鼠产前人流感病毒感染后后代中产生的形态学异常和磁共振体积研究，以及3）表征由脑损伤在小鼠中产生的行为异常，所述脑损伤与精神分裂症患者中的脑损伤相当。这项工作是创新性的，因为它利用了我们新的动物模型，将病毒感染与异常的大脑发育联系起来。我们期望将小鼠大脑中病毒感染后结构变化的发生与受影响动物随后发生的特定生化、行为和结构变化联系起来。这些结果将是重要的，因为它们有望为流行病学数据提供合理的解释，这些数据支持人类流感病毒感染与随后导致精神分裂症的出生率上升之间的联系。此外，预计这些结果将提供线索，导致我们对精神分裂症发病机制的认识取得根本性进展，从而了解如何预防和治疗。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The effects of prenatal H1N1 infection at E16 on FMRP, glutamate, GABA, and reelin signaling systems in developing murine cerebellum.

DOI：
10.1002/jnr.23949
发表时间：
2017-05
期刊：
Journal of neuroscience research
影响因子：
4.2
作者：
Fatemi SH;Folsom TD;Liesch SB;Kneeland RE;Karkhane Yousefi M;Thuras PD
通讯作者：
Thuras PD

Dopamine and serotonin levels following prenatal viral infection in mouse--implications for psychiatric disorders such as schizophrenia and autism.

DOI：
10.1016/j.euroneuro.2008.06.001
发表时间：
2008-10
期刊：
EUROPEAN NEUROPSYCHOPHARMACOLOGY
影响因子：
5.6
作者：
Winter, Christine;Reutiman, Teri J.;Folsom, Timothy D.;Sohr, Reinhard;Wolf, Rainer J.;Juckel, Georg;Fatemi, S. Hossein
通讯作者：
Fatemi, S. Hossein

Viral infection, inflammation and schizophrenia.