Many infectious diseases, including AIDS, are accompanied by profound neuropsychological and behavioral alterations, even when the causal agent is not neurotrophic. AIDS patients experience neurological symptoms such as memory loss, dementia, drowsiness, weakness and motivational defects. Recent evidence indicates that these symptoms are caused by the neural effects of proinflammatory cytokines of which the predominant one is interleukin- 1 (IL-1). These data have led to the idea that peripheral cytokines released during inflammation lead to development of a new motivational state which we have designated as sickness behavior. The next major challenge in this field is to develop an understanding of how cytokines released in the periphery communicate this signal to the brain. Here we hypothesize that sensory afferent nerves are activated by peripheral immune stimuli which subsequently lead to synthesis of cytokines in distinct structures of the CNS. These central cytokines induce sickness behavior by acting on their receptors which are located on specific neuronal nuclei. Our first objective is designed to investigate the novel hypothesis that peripheral immune stimuli activate sensory afferent nerves which relay this message to the brain. Specifically, we will test whether transection of afferent nerves from the abdominal cavity abrogates the reduction in social exploration caused by peripheral activation of the immune system. We will then try to confirm that peripheral immune stimulation activates sensory afferent nerves by measuring tachykinins in the afferent nerves. We have recently shown that induction of sickness caused by activation of the peripheral immune system leads to the synthesis of IL-1 in the CNS. In the second objective, we will extend these findings by quantitatively measuring the amount of IL- 1alpha and IL-1beta transcripts (competitive RT-PCR) that are expressed in specific brain structures (hippocampus, hypothalamus, cortex, striatum, thalamus) in response to peripheral immune activation. We will then assess the consequences of transection of afferent nerves on expression of these cytokines within the CNS. Next, we will determine whether changes in IL-I expression in the CNS are responsible for the sickness-inducing properties of peripheral IL-1 by microinjecting intact mice with anti-IL-1alpha and IL-1beta neutralizing antibodies into the lateral ventricle of the brain. Based on our newest findings that mRNA for both isoforms of IL-1 receptors are present in mouse brain, the third objective is designed to characterize the nature and cellular localization of both central and peripheral IL-1 receptor proteins that mediate the behavioral effects of this cytokine. These experiments will employ both knock-out mice for the type I IL-1 receptor and i.c.v. administration of specific blocking antibodies directed against each receptor subtype. A major strength of this proposal is that we have developed all of the techniques and also obtained IL-1 receptor knock out mice to successfully test our hypothesis that peripheral nerves are used as an afferent pathway for the induction of sickness caused by activation of the peripheral immune system. These data are needed to understand and perhaps prevent the behavioral alterations and disturbances in mental health that accompany a wide variety of infectious diseases.
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