ELECTROPHYSIOLOGICAL AND BEHAVIORAL STUDIES IN THE FELINE MODEL OF NEUROAIDS

人类获得性免疫缺陷痴呆综合征 最近被重新归类为两类：1.艾滋病毒-1相关性痴呆 复杂性或HIV-1相关的脊髓病，以及2.HIV-1相关的未成年人 认知/运动障碍(HMCD)。这两个类别，以前被称为艾滋病 痴呆症复合体(ADC)的特征是逐渐妥协 受影响人群的精神能力，包括一组复杂的 不同严重程度的神经心理和认知体征，病因 HIV-1中枢神经系统病毒感染。神经心理学的无情衰退 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，但对常规治疗仍难以治愈 战略。中心应用程序的这一研究部分建议 继续电生理，并在体内启动行为研究 开始分析特定神经过程的潜在作用，这些过程可能 早期注意力、动力和记忆功能的丧失是由 猫的神经艾滋病模型，FIV。脑干和皮质感官--以及 认知诱发电位的分析将在对照猫和 接种FIV分子克隆株FIV-PPR。此外, 我们将继续对睡眠/觉醒参数进行全面评估 植入皮质铅的动物是对目前研究的补充 是由人类睡眠研究承担的。更多地使用这些方法 将获得有关持续病毒的影响的准确知识 感染对细胞反应性改变的影响及其作用 突触回路，我们认为这是直接和 病毒在中枢神经系统的间接和间接作用。猫科动物的免疫缺陷 病毒(FIV)感染将作为间接病毒的一个例子进行研究 影响神经功能(类似于HIV-1)。假说表明 病毒感染对神经元活动和功能的影响 电路可以通过神经生理学和神经药理学来评估 方法将在以下具体目标中进行评估：1.我们将 描述神经系统的时间模式和序列， 猫感染分子疫苗后的生理和行为变化 FIV的克隆分离株，通过采用一系列措施提供 与认知表现相关的生物端点；2.我们将 研究几类有前景的治疗药物的效果 (己酮可可碱、沙利度胺和美金刚) 尝试恢复以恢复或防止这些项目的进一步下降 功能终点；3.我们将在体内评估 多种神经活性物质的神经药理作用 细胞因子、病毒包膜糖蛋白，如gp120、喹啉酸盐等) 被认为是与认知能力下降有关的关键因素 神经艾滋病。综上所述，这些研究将提供一个全面的 关键细胞研究的神经生理学方法 人类慢病毒小动物模型中的底物和环路 并将提供导致中枢神经系统感染的机制的线索 神经艾滋病患者的神经心理衰退。

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.