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.
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