BRAIN EFFECTS OF INTERFERON ALPHA

描述（申请人摘要）：暴露于病毒诱导的细胞因子 在艾滋病毒感染可能有助于不适和认知的症状 和神经精神障碍。 由于艾滋病毒感染治疗的最新进展， 因此，长期暴露于升高的细胞因子的可能性 水平提高了。 在本供资期内， 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干扰素α（IFN-α）。 行为 在三种不同的测试中， 通过控制细胞因子水平来控制焦虑行为。 在此期间， 在CNS中IFN控制的基因的上调是通过以下方法建立的： 使用逆转录后聚合酶链检测mRNA 反应扩增（RT-PCR）技术，建立了一种新的 这种用于在组织切片中识别 干扰素作用。 本申请集中于确定神经元的位置。 IFN-α这种作用的底物。 行为研究将扩展 对一种最适合研究的小鼠品系的高度焦虑的发现 神经研究提出并将证实焦虑系统的参与 通过检查苯二氮卓类及其反向激动剂对 IFN的行为效应 最后一项行为研究评估了惊吓和 恐惧增强惊吓将被用来确认解释的 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 将使用立即早期基因c-fos的mRNA的组织化学 为了确定在1时由外周IFN-α治疗激活的脑区域， 注射后2和3小时。 为了确定这些作用点中的哪一个 结果可能直接进入干扰素的大脑，一种新的技术， 原位逆转录聚合酶链反应 IFN控制基因的扩增和原位杂交将被 采用 最后，干扰素上调其自身生产的可能性， 大脑将通过使用同样的极其敏感的技术进行评估 以测定IFN-α的CNS产生。 这些研究的目的是 确定IFN-α影响大脑和行为的部位， 了解其作用机制。 这些研究应加强 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.