BEHAVIORAL AND NEURONAL EFFECTS OF RETROVIRAL INFECTION

人类免疫缺陷病毒I型(HIV-1)的流行传播 由此产生的获得性免疫缺陷综合征(艾滋病)及其伴随而来的 认知和情感缺陷(艾滋病痴呆复合体-ADC) 逆转录病毒的行为和神经生物学效应研究 感染势在必行。以前的研究已经证明，感染 易感小鼠与LP-BM5逆转录病毒混合物渐进性诱导 严重的免疫抑制，中枢神经系统(CNS)的入侵， 老年人的神经功能障碍和空间学习记忆障碍 莫里斯水迷宫。最近的研究表明，像HIV-1一样 人感染，小鼠Lp-BM5感染使中枢神经系统深度增加 谷氨酸能神经元兴奋性毒素、喹啉酸水平。 此外，Lp-BM5感染会导致配体结合的改变 N-甲基-D-天冬氨酸(NMDA)受体复合体。因为谷氨酸能通路 而NMDA受体被认为与神经细胞的 改变--潜在的空间学习，这些数据表明Lp-BM5可能 通过作用于这些网站来损害空间学习。 这一建议解决了三个主要问题：1.什么神经元 结论：1.Lp-BM5诱导的空间学习障碍可能与其发病机制有关。 Lp-BM5干扰了哪些与学习相关的行为？3.什么 治疗性干预阻断或逆转LP-BM5诱导的学习 赤字？推测：1.Lp-BM5感染可导致 大脑不同区域内NMDA受体复合体的变化 在时间上与学习障碍的出现相对应 水迷宫；2.Lp-BM5感染不会破坏学习记忆 在相对简单的任务中，但会表现出越来越具破坏性 对相对复杂的学习范式的影响，如空间学习 任务和复杂的操作时间表；3.阻止 LP-BM5的增殖、喹啉酸的合成或作为 NMDA受体复合体的拮抗剂将阻断、延迟或逆转 Lp-BM5所致的空间学习障碍。 小鼠将感染LP-BM5和非免疫抑制，但中枢神经系统 侵袭性、环保性病毒，并在两种一般行为 范例(露天探险、高架+迷宫探险)和 难度递增的学习记忆任务(被动回避， 主动回避、水迷宫和重复获取操作范式) 目的探讨LP-BM5感染的行为特异性。同样，LP-BM5 而感染了生态病毒的小鼠将被分几次处死 在感染过程中进行积分，并在死后检查影响 在中枢和外周喹啉酸水平上，NMDA受体复合体 烟碱型和毒酪碱型乙酰胆碱受体。此外，动物 将在尸检中检查前脑的细胞病理变化 结构。最后，受感染的小鼠将接受几种潜在的治疗 治疗药物(喹啉酸合成抑制剂和功能性药物 NMDA受体拮抗剂)，并在水迷宫中测试，以便 确定这些药物是否能阻断或逆转空间学习 Lp-BM5感染所致的缺陷。

The epidemic spread of human immunodeficiency virus, type I (HIV-1) with its resulting acquired immunodeficiency syndrome (AIDS) and attendant cognitive and affective deficits (AIDS dementia complex - ADC) have made studies of the behavioral and neurobiological effects of retroviral infection imperative. Previous studies have demonstrated that infection of susceptible mice with the LP-BM5 retrovirus mixture progressively induces profound immunosuppression, central nervous system (CNS) invasion, neurological impairment and spatial learning and memory deficits in the Morris water maze. More recent studies have shown that, like HIV-1 infection of humans, LP-BM5 infection of mice profoundly increases CNS levels of the glutamatergic neuronal excitotoxin, quinolinic acid. Moreover, LP-BM5 infection results in alterations in ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. Since glutamatergic pathways and the NMDA receptor have been critically implicated in the neuronal changes-underlying spatial learning, these data suggest that LP-BM5 may impair spatial learning by acting on these sites. This proposal addresses three primary questions: 1. What neuronal mechanisms are involved in LP-BM5-induced spatial learning deficits? 2. Which behaviors relevant to learning does LP-BM5 disrupt? 3. What therapeutic interventions block or reverse LP-BM5 induced learning deficits? It is hypothesized that: 1. LP-BM5 infection results in alterations in the NMDA receptor complex within discrete regions of brain which correspond temporally with the appearance of learning deficits in the water maze; 2. LP-BM5 infection does not disrupt learning and memory in relatively simple tasks but will display increasingly disruptive effects in relatively complex learning paradigms, such as spatial learning tasks and complex operant schedules and; 3. that agents which block the proliferation of LP-BM5, the synthesis of quinolinic acid or act as antagonists at the NMDA receptor complex will block, delay or reverse the spatial learning deficits produced by LP-BM5. Mice will be infected with LP-BM5 and the non-immunosuppressive, but CNS invasive, ecotropic virus and examined in both general behavioral paradigms (open field exploration, elevated plus maze exploration) and learning and memory tasks of graduated difficulty (passive avoidance, active avoidance, water maze and repeated acquisition operant paradigms) to assess the behavioral specificity of LP-BM5 infection. Likewise, LP-BM5 and ecotropic virus infected mice will be sacrificed at several time points over the course of infection and examined post-mortem for effects on CNS and peripheral quinolinic acid levels, the NMDA receptor complex and nicotinic and muscarinic acetylcholine receptors. In addition, animals will be examined post-mortem for cytopathological changes in forebrain structures. Finally, infected mice will be treated with several potential therapeutic agents (quinolinic acid synthesis inhibitors and functional NMDA receptor antagonists) and tested in the water maze in order to determine whether these drugs can block or reverse the spatial learning deficits induced by LP-BM5 infection.