ELECTROPHYSIOLOGICAL AND BEHAVIORAL STUDIES IN THE FELINE MODEL OF NEUROAIDS

人类获得性免疫缺陷痴呆综合征已经 最近重新分类为两类：1。HIV-1相关性痴呆 复杂的或HIV-1相关的脊髓病，和; 2. HIV-1相关未成年人 认知/运动障碍（HMCD）。 这两类，以前称为艾滋病 痴呆综合症（ADC）的特征是进行性损害 受影响的人的心理能力，包括一个复杂的集合 不同严重程度的神经心理和认知体征， HIV-1 CNS病毒感染。 神经心理学的持续衰退 性能仍然是迄今为止最具破坏性的方面之一 无法治愈的疾病，但传统治疗仍然难以治愈 战略布局 该中心应用程序的这一研究组件建议 继续电生理学，并启动体内行为研究， 开始分析特定神经过程的潜在作用， 导致注意力、动机和记忆功能的早期丧失， 神经艾滋病的猫科动物模型FIV 脑干和皮层感觉神经 将在对照猫中分析认知诱发电位， 用FIV的分子克隆株FIV-PPR接种。 此外，本发明还提供了一种方法， 我们将继续全面评估睡眠/觉醒参数， 植入皮质电极导线的动物，以补充目前的研究 人类睡眠研究的一部分。 使用这些方法更多 将获得关于持续性病毒感染的影响的精确知识， 感染对细胞反应性改变的影响 我们认为突触回路是直接和 CNS中的间接和间接病毒作用。 猫免疫缺陷 病毒（FIV）感染将作为间接病毒的一个例子进行研究 影响神经元功能（类似于HIV-1）。 假设陈述 病毒感染对神经元活动和功能的影响 可以通过神经生理学和神经药理学来评估回路 方法将在以下具体目标进行评估：1. 我们将 表征神经系统的时间模式和顺序， 生理和行为变化的猫感染的分子 FIV的克隆分离株，通过采用一系列措施， 与认知表现相关的生物学终点; 2. 我们将 研究几类有前途的治疗剂的效果 （喷替福林、沙利度胺和美金刚）对上述措施的影响。 试图恢复或防止这些进一步下降 功能终点; 3. 我们将在体内评估 各种神经活性剂（例如， 细胞因子、病毒包膜糖蛋白（即gp 120、喹啉酸盐等） 假设是参与认知能力下降的关键因素， 神经艾滋病 这些研究将提供全面的 神经生理学方法研究的关键细胞 人慢病毒小动物模型中的底物和电路 感染的中枢神经系统，并将提供线索的机制，导致 神经艾滋病的神经心理学衰退。

The human acquired immunodeficiency dementia complex syndrome has been recently reclassified into two categories: 1. HIV-1-associated dementia complex or HIV-1-associated myelopathy, and; 2. HIV-1-associated minor cognitive/motor disorder (HMCD). Both classes, previously termed Aids Dementia Complex (ADC) are characterized by progressively compromised mental capacities in affected people including a complex collection of neuropsychological and cognitive signs of varying severity, pathognomonc of HIV-1 CNS viral infection. The relentless decline in neuropsychological performance remains as one of the most devastating aspects of this as yet incurable disease and it yet remains refractory to conventional treatment strategies. This research component of the Center application proposes to continue electrophysiological, and initiate behavioral studies in vivo that begin to analyze the potential role of specific neural processes that may underlie the early loss of attention, motivation, and memory functions in the feline model of neuroAIDS, FIV. Brainstem and cortical sensory- and cognitive evoked potentials will be analyzed in control cats and those inoculated with a molecularly cloned strain of FIV, FIV-PPR. In addition, we will continue comprehensive evaluation of sleep/wake parameters in animals implanted with cortical leads to complement the studies currently being undertaken by the human sleep studies. Using these approaches more precise knowledge will be gained regarding the effects of persistent viral infection on the alteration in cellular responsiveness and actions on synaptic circuitry that we believe is the major consequence of direct and indirect and indirect viral action in the CNS. The feline immunodeficiency virus (FIV) infection will be studied as an example of an indirect virus affecting neuronal function (similar to HIV-1). The hypothesis stating that effects of viral infection on neuronal activity and functional circuitry can be assessed by neurophysiological and neuropharmacological methods will be evaluated in the following Specific Aim: 1. We will characterize the temporal pattern and sequence of neurological, physiological, and behavioral changes in cats infected with molecularly cloned isolates of FIV, by employing a battery of measures providing biological endpoints relevant for cognitive performance; 2. We will investigate the effects of several classes of promising treatment agents (Pentoxifylline, Thalidomide, and Memantine) on the above measures in an attempt to restore to restore or prevent further decline in these functional endpoints; 3. We will evaluate, in vivo, the neuropharmacological actions of a variety of neuroactive agents (e.g. cytokines, viral envelope glycoproteins i.e. gp120, quinolinate etc.) hypothesized to be critical factors involved in cognitive decline in neuroAIDS. Taken together these studies will provide a comprehensive neurophysiological approach to the investigation of the critical cellular substrates and circuits in a small animal model of human lentivirus infection of the CNS and will provide clues as to the mechanisms leading to the neuropsychological decline in neuroAIDS.