BEHAVIORAL AND NEURONAL EFFECTS OF RETROVIRAL INFECTION

人类免疫缺陷病毒I型（HIV-1）的流行蔓延， 艾滋病毒/艾滋病及其引起的后天免疫机能丧失综合症（艾滋病） 认知和情感缺陷（艾滋病痴呆综合征-ADC）已经使 逆转录病毒对行为和神经生物学影响的研究 感染势在必行。以前的研究表明， LP-BM 5逆转录病毒混合物的易感小鼠逐渐诱导 严重的免疫抑制，中枢神经系统（CNS）侵袭， 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， LP-BM5感染人类，LP-BM5感染小鼠， 神经元兴奋性毒素喹啉酸的水平。 此外，LP-BM 5感染导致配体结合至细胞的改变。 N-甲基-D-天冬氨酸（NMDA）受体复合物。由于多巴胺能通路 和NMDA受体与神经元 改变潜在的空间学习，这些数据表明，LP-BM 5可能 通过作用于这些部位而损害空间学习。 这一建议涉及三个主要问题：1.什么神经元 LP-BM5诱导的空间学习障碍的机制是什么？2. LP-BM 5会破坏哪些与学习相关的行为？3.什么 治疗干预阻断或逆转LP-BM 5诱导的学习 赤字？假设：1. LP-BM5感染导致 大脑离散区域内NMDA受体复合物的改变 这与学习缺陷的出现在时间上相对应， 水迷宫; 2. LP-BM5感染不会破坏学习和记忆 在相对简单的任务中， 在相对复杂的学习范式中的影响，例如空间学习 任务和复杂的操作时间表; 3.那些阻止 LP-BM5的增殖，喹啉酸的合成或充当 NMDA受体复合物的拮抗剂将阻断、延迟或逆转 LP-BM 5产生的空间学习缺陷。 小鼠将感染LP-BM 5和非免疫抑制性但CNS 侵入性，亲嗜性病毒，并在一般行为和 范式（旷场探索，高架加迷宫探索）和 难度分级的学习和记忆任务（被动回避， 主动回避、水迷宫和重复获得操作范式） 评估LP-BM 5感染的行为特异性。同样，LP-BM 5 将嗜亲性病毒感染的小鼠在几个时间点处死 在感染过程中的点，并检查死后的影响 在CNS和外周喹啉酸水平上，NMDA受体复合物 以及烟碱和毒蕈碱乙酰胆碱受体。此外，动物 将在死后检查前脑的细胞病理学变化 结构.最后，受感染的小鼠将接受几种潜在的治疗， 治疗剂（喹啉酸合成抑制剂和功能性 NMDA受体拮抗剂），并在水迷宫中测试，以 确定这些药物是否可以阻止或逆转空间学习 LP-BM 5感染引起的缺陷。

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.