BORNA VIRUS ALTERS PERINATAL BEHAVIOR DEVELOPMENT

博尔纳病毒改变围产期行为发育

基本信息

批准号：
2248497
负责人：
KATHRYN M. CARBONE
金额：
$ 21.67万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-30 至 1998-08-31
项目状态：
已结题

项目摘要

Damage to the CNS by exogenous insults during critical periods in intrauterine, perinatal or early postnatal CNS development may lead to subtle or severe behavioral abnormalities. Viral pathogens constitute a significant portion of the defined teratogens to the nervous system; among the most devastating of human viral infections, HIV causes significant perinatal nervous system morbidity in children. Many congenital neurological or behavioral diseases of the CNS may have an as yet unidentified viral etiology. In this application we will enhance our understanding of the effects of perinatal virus infections on neuroanatomical development and behavior by studying an animal model of a virus infection of the developing nervous system: Lewis rats infected with Boma disease virus (BDV) as neonates. BDV infection in the perinatal period (up to the second postnatal day of life) is associated with persistent virus replication without encephalitis, and produces behavioral abnormalities (e.g. hyperactivity, hyper-reactivity and learning and memory disorders) neuroanatomical abnormalities in the hippocampus and cerebellum, and stunted growth. This model allows a unique opportunity to test the effects of virus replication in the developing nervous system in the absence of generalized nervous system destruction due to encephalitis. In this application we will evaluate the effects of neonatal BDV infection on morphological development of brain regions which undergo postnatal neurogenesis, the hippocampus and cerebellum, and determine BDV's effects on neuroblast division and neuronal migration in these areas. Behaviors specific to the cerebellum (e.g. motor) and hippocampus (e.g. memory and learning) will be tested in neonatally BDV-infected rats. We will discern the relative contributions of neonatal BDV infection upon abnormal brain development and abnormal neural function of persistently infected neurons by utilizing a model developed in our laboratory. Using the immunosuppressive drug, Cyclosporine A, to suppress encephalitic response to the virus, we can infect rats at or beyond critical points in brain and behavior development. We will also determine mechanisms for the pathogenesis of the anatomical and behavioral abnormalities in these rats, including viral tropism for the hippocampus on neonatal cerebellum. Finally, we will present evidence for BDV infection in humans and propose a new approach for the recovery of BDV from BDV-seropositive humans. Based on our work in the immunocompromised animal, bone marrow from HIV- infected BDV seropositive humans is a likely source from which to recover a human BDV-like agent. Finding a human BDV-like pathogen would make the study of BDV infection of direct medical relevance, in addition to its value as a model system.

关键时期外源性损伤对中枢神经系统的损害宫内、围产期或产后早期中枢神经系统发育可能导致微妙或严重的行为异常。病毒病原体构成确定的致畸物的很大一部分对神经系统有影响；之中艾滋病毒是人类最具破坏性的病毒感染，它会导致严重的儿童围产期神经系统发病率。很多是先天性的中枢神经系统的神经或行为疾病可能尚未病毒病因不明。在此应用程序中，我们将增强我们的了解围产期病毒感染对胎儿的影响通过研究动物模型来了解神经解剖学的发育和行为发育中的神经系统的病毒感染：Lewis大鼠感染新生儿感染博马病病毒 (BDV)。围产期（直至产后第二天）BDV 感染生命）与持续的病毒复制有关，而无需脑炎，并产生行为异常（例如多动，反应过度以及学习和记忆障碍）神经解剖学海马体和小脑异常，生长发育迟缓。这模型提供了测试病毒复制效果的独特机会在发育中的神经系统中，缺乏广泛的神经系统脑炎引起的系统破坏。在此应用中，我们将评估新生儿 BDV 感染的影响出生后大脑区域的形态发育神经发生、海马和小脑，并确定 BDV 的影响关于这些区域的神经母细胞分裂和神经元迁移。行为特定于小脑（例如运动）和海马体（例如记忆和学习）将在感染 BDV 的新生大鼠中进行测试。我们会辨别新生儿 BDV 感染对大脑异常的相对影响持续感染神经元的发育和神经功能异常通过利用我们实验室开发的模型。使用免疫抑制剂，环孢菌素 A，抑制脑炎反应对于病毒，我们可以在大脑的临界点或临界点之外感染老鼠行为发展。我们还将确定机制这些大鼠解剖和行为异常的发病机制，包括新生儿小脑海马体的病毒趋向性。最后，我们将提供人类 BDV 感染的证据并提出一种从 BDV 血清阳性人类中恢复 BDV 的新方法。根据我们对免疫功能低下动物的研究，来自艾滋病毒的骨髓- 感染 BDV 血清阳性的人类可能是恢复的来源人类 BDV 样制剂。找到人类 BDV 样病原体将使 BDV 感染的研究除了其直接医学意义外作为模型系统的价值。