Viral Pathogenesis of Neural and Behavior Injury

描述（由申请人提供）：1型人类免疫缺陷病毒（HIV-1）感染中枢神经系统可导致认知、运动和感觉障碍，表现为皮层下痴呆。现有数据表明，激活的常驻免疫系统分泌的病毒因子和可溶性神经毒素会损害脆弱的神经元群，导致神经化学（即多巴胺能）改变和行为缺陷，使人联想到帕金森病。尽管基底神经节是HIV感染的主要靶点，但对继发于HIV感染的行为障碍的病理生理机制仍知之甚少。经济的啮齿动物系统的缺乏严重延缓了这一领域的进展。因此，在这个竞争性的持续应用中，我们建议使用我们的病毒神经发病机制的小动物模型，新生儿博尔纳病病毒感染（BDV），来研究可溶性神经毒素（如谷氨酸和促炎细胞因子）诱导基底神经节中gaba能神经元的持续损失的机制，导致多巴胺（DA）神经传递的改变和相关的行为缺陷。特异性目标1将通过定量测量gaba -能神经元和DA神经元随时间的持续损失来评估bdv相关的基底神经节损伤。特异性目标2将通过体内和体外神经化学和行为方法评估基底节区GABA和DA神经传递的改变。特异性目的3将利用分子生物学和细胞培养技术研究谷氨酸毒性和病毒感染在神经元损伤中的直接作用。这个多学科项目的结果将促进我们对病毒诱导的基底神经节疾病的病理生理学，神经元损伤的直接和间接机制的理解，并将刺激对hiv感染相关和其他神经退行性疾病中观察到的神经行为改变的新治疗方法的探索。

DESCRIPTION (provided by applicant): Infection of the central nervous system with the human immunodeficiency virus, type 1 (HIV-1) can lead to cognitive, motor and sensory disorders that manifest as subcortical dementia. Available data suggest that viral factors and soluble neurotoxins secreted by activated resident immune system damage vulnerable neuronal populations, resulting in neurochemical (i.e., dopaminergic) alterations and behavioral deficits reminiscent of parkinsonism. Although the basal ganglia represent the major target of HIV infection, the pathophysiology of behavioral disorders secondary to HIV infection remains poorly understood. The paucity of economical rodent animal systems significantly delays the progress in this field. Thus, in this competing continuation application, we propose to use our small animal model of viral neuropathogenesis, neonatal Borna disease virus infection (BDV), to study the mechanisms by which soluble neurotoxins (e.g., glutamate and pro-inflammatory cytokines) induce a continuing loss of GABA-ergic neurons in the basal ganglia, leading to alterations in dopamine (DA) neurotransmission and associated behavioral deficits. Specific Aim 1 will evaluate BDV-associated injury to the basal ganglia by quantitatively measuring a continuing loss of GABA-ergic and DA neurons over time. Specific Aim 2 will assess alterations in GABA and DA neurotransmissions in the basal ganglia by using in vivo and in vitro neurochemical and behavioral methods. Specific Aim 3 will investigate a role of glutamate toxicity and direct effects of virus infection in neuronal injury employing molecular biology and cell culture techniques. The results of this multidisciplinary project will advance our understanding of the pathophysiology of virus-induced basal ganglia disorders, the direct and indirect mechanisms of neuronal damage and will stimulate a search for new treatments of the neurobehavioral alterations observed in HIV-infection-related and other neurodegenerative diseases.