CYTOKINES, BEHAVIOR AND MENTAL HEALTH

包括艾滋病在内的许多传染病都伴随着深刻的 神经心理学和行为改变，即使当致病因素 不是神经营养性的艾滋病患者会出现神经系统症状， 如记忆丧失、痴呆、嗜睡、虚弱和动机缺陷。 最近的证据表明，这些症状是由神经系统引起的。 促炎细胞因子的作用，其中主要的一种是 白细胞介素-1（IL-1）。这些数据让我们想到 炎症过程中释放的细胞因子导致新的 我们称之为病态行为。下一 这一领域的一个主要挑战是了解如何 在外周中释放的细胞因子将该信号传递到大脑。 在这里，我们假设感觉传入神经被激活， 外周免疫刺激，随后导致合成 在CNS的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来诱导疾病行为，所述受体位于 特定的神经细胞核。我们的第一个目标是调查 外周免疫刺激激活感觉神经元新假说 将信息传递给大脑的传入神经。我们特别 将测试从腹腔切断传入神经 消除了由外围设备引起的社会探索减少 激活免疫系统。我们会尽力确认 外周免疫刺激激活感觉传入神经， 测量传入神经中的速激肽我们最近的研究表明 诱导由外周免疫系统激活引起的疾病 导致CNS中IL-1的合成。第二个目标，我们 将通过定量测量IL-1的量来扩展这些发现， 1 α和IL-1 β转录本（竞争性RT-PCR）， 特定的脑结构（海马体，下丘脑，皮层，纹状体， 丘脑）响应于外周免疫激活。我们将评估 切断传入神经对这些表达的影响 CNS内的细胞因子。接下来，我们将确定IL-1的变化是否 在中枢神经系统中的表达负责疾病诱导特性 通过显微注射抗-IL-1 α的完整小鼠外周IL-1， IL-1 β中和抗体进入侧脑室。 基于我们的最新发现，IL-1受体两种亚型的mRNA 存在于小鼠大脑中，第三个目标旨在 表征中央和中央神经元的性质和细胞定位， 外周IL-1受体蛋白介导的行为效应 这个细胞因子。这些实验将使用两种基因敲除小鼠进行研究。 I型IL-1受体和特异性阻断剂的i.c.v.给药 针对每种受体亚型的抗体。的一个主要优势 这个提议是，我们已经开发了所有的技术， 获得了IL-1受体敲除小鼠，成功地验证了我们的假设 外周神经被用作诱导的传入通路 由外周免疫系统激活引起的疾病。这些 我们需要数据来了解，也许还能防止 心理健康的改变和干扰，伴随着广泛的 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.