BRAIN EFFECTS OF INTERFERON ALPHA

描述(申请人摘要)：接触病毒诱导的细胞因子 在感染HIV期间可能会导致身体不适和认知障碍的症状 以及在感染的某些阶段出现的神经精神障碍。 由于最近在治疗艾滋病毒感染方面的进展，存活率 长期接触升高的细胞因子的可能性 级别是增加的。在本供资期间，在 研究人员的实验室已经确定了 暴露于病毒特异性细胞因子α干扰素(干扰素-a)。行为 在三种不同的测试中，小鼠的焦虑指标都增加了 通过操纵细胞因子水平而产生的焦虑行为。在此期间， 中枢神经系统中干扰素控制基因的上调是通过 逆转录-聚合酶链法检测基因的表达 反应扩增(RT-PCR)技术，并在建立 这项用于组织切片以识别肿瘤部位的困难技术 干扰素的作用。本申请的重点是确定神经 干扰素-α这种作用的底物。行为研究将延长 发现对一种品系的小鼠的高度焦虑是对 神经研究建议并将证实焦虑症系统的参与 通过检测苯二氮卓类及其反向激动剂对 干扰素的行为效应。一项最终的行为研究评估了惊吓和 恐惧强化的惊吓将被用来确认对 行为变化，并将提供有关可能的 杏仁核参与干扰素的作用。原位杂交 即刻早期基因c-fos的信使核糖核酸将采用组织化学方法。 为了确定外周干扰素-a治疗在1激活的脑区， 注射后2、3小时。为了确定这些行动地点中的哪些 可能是由于干扰素可能直接进入大脑，这是一项新技术，在 原位逆转录聚合酶链式反应 干扰素控制基因的扩增和原位杂交将被 使用。最后，干扰素上调自身生产的可能性 我们将使用同样极其敏感的技术对大脑进行评估 测定中枢神经系统产生的干扰素-α。这些研究的目标是 依次确定干扰素-a影响大脑和行为的部位 了解其作用机制。这些研究应该加强 我们对病毒性痴呆的病因和治疗的认识 感染，如艾滋病毒。

DESCRIPTION (Applicant's abstract): Exposure to virus-induced cytokines during HIV infection may contribute to the symptoms of malaise and cognitive and neuropsychiatric disturbance seen during some phases of this infection. Because of recent advances in the treatment of HIV infection, survival is prolonged and thus the potential for long-term exposure to elevated cytokine levels is increased. In the current funding period, work in the investigators' laboratory has established neuropsychiatric effects of exposure to the virus-specific cytokine interferon alpha (IFN-a). Behaviors indicative of anxiety in mice were increased in three different tests of anxiety behavior by manipulation of cytokine levels. During this period, up-regulation of IFN-controlled genes in the CNS was established by detection of mRNA using reverse-transcription followed by polymerase chain reaction amplification (RT-PCR) and much progress was made in establishing this difficult technique for use in tissue sections to identify the sites of IFN action. The present application focuses on determining the neural substrate for this effect of IFN-a. Behavioral studies will extend the finding of heightened anxiety to a strain of mouse that is optimal for the neural studies proposed and will confirm the involvement of anxiety systems by examining the effects of benzodiazepine and their inverse agonists on the behavioral effects of IFN. A final behavioral study assessing startle and fear-potentiated startle will be used to confirm the interpretation of the behavioral change and will provide additional information about the probable involvement of the amygdala in the actions of IFN. In situ hybridization histochemistry for the mRNA for the immediate early gene c-fos will be used to determine the brain areas activated by peripheral IFN-a treatment at 1, 2, and 3 hrs postinjection. To determine which of these sites of action result from possible direct access of IFN to the brain, a new technique, in situ reverse transcription followed by polymerase chain reaction amplification and in situ hybridization for an IFN controlled gene will be used. Finally, the possibility that IFN up regulates its own production in the brain will be assessed by using this same extremely sensitive technique to determine CNS production of IFN-a. The goal of these studies is to determine the sites at which IFN-a affects the brain and behavior in order to understand the mechanisms of its effects. These studies should enhance our understanding of the cause and treatment of the dementia caused by viral infections such as HIV.