CYTOKINES, BEHAVIOR AND MENTAL HEALTH

许多传染病，包括艾滋病，都伴随着严重的 神经心理和行为改变，即使当致病因素 并不具有神经营养作用。艾滋病患者会出现神经症状，如 如记忆力减退、痴呆症、嗜睡、虚弱和动机缺陷。 最近的证据表明，这些症状是由神经引起的 促炎症细胞因子的作用 白介素1(IL-1)。这些数据导致了这样一种想法，即外围设备 炎症过程中释放的细胞因子导致一种新的 我们称之为疾病行为的动机状态。下一个 这一领域的主要挑战是发展对如何 外周释放的细胞因子将这一信号传递给大脑。 在这里，我们假设感觉神经是由 外周免疫刺激，随后导致合成 中枢神经系统不同结构中的细胞因子。这些中枢细胞因子 通过作用于它们的受体而诱发疾病行为 特定的神经元核团。我们的第一个目标是调查 外周免疫刺激激活感觉的新假说 将这一信息传递给大脑的传入神经。具体来说，我们 将测试是否从腹腔处切断传入神经 废除了外围设备导致的社会探索的减少 激活免疫系统。然后我们将努力确认 外周免疫刺激通过以下方式激活感觉神经 测量传入神经中的速激肽。我们最近已经证明， 外周免疫系统激活引起的疾病的诱发 导致中枢神经系统合成IL-1。在第二个目标中，我们 将通过定量测量IL-1的量来扩展这些发现 1α和IL-1β转录本(竞争性RT-PCR) 特定的大脑结构(海马体、下丘脑、皮质、纹状体、 丘脑)，以响应外周免疫激活。然后我们将评估 切断传入神经对这些基因表达的影响 中枢神经系统内的细胞因子。接下来，我们将确定IL-I的变化是否 中枢神经系统中的表达与致病特性有关 正常小鼠微量注射抗IL-1α和外周IL-1 IL-1β中和抗体进入侧脑室。 根据我们的最新发现，IL-1受体的两种亚型的mRNA 存在于小鼠的大脑中，第三个目标旨在 描述中枢和中枢神经的性质和细胞定位 外周IL-1受体蛋白介导的行为效应 这种细胞因子。这些实验将使用两种基因敲除的小鼠 I型IL-1受体和I.C.V.特定屏蔽的管理 针对每个受体亚型的抗体。一个主要的优势是 这个提议是，我们已经开发了所有的技术，而且 获得IL-1受体基因敲除小鼠成功验证我们的假设 周围神经被用作诱导的传入通路 指由外周免疫系统激活引起的疾病。这些 需要数据来理解，或许还需要防止行为 伴随着广泛的心理健康的改变和障碍 各种传染病。

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.