STRESSOR INDUCED IMMUNE ALTERATION

所提出的研究来自于这样的假设，即压力- 诱导性免疫抑制（SIIS）是由离散的神经元介导的， CNS中的通路。 拟议研究的重点是 确定某些大脑区域在调解 应激诱导脾神经依赖性免疫功能的变化 老鼠的反应 具体目标是：（1）识别和 大脑中支配脾脏的神经元回路：（2） 确定抑制离散的脑核团是否可以消除 使用体外有丝分裂原试验评估脾脏中的SIIS;以及 (3)确定对离散脑核团的抑制是否可以 消除应激诱导的抗体反应抑制 注射绵羊红细胞。为了确定哪些神经元 大脑中的细胞群支配脾交感神经 节前神经元，一种跨神经元的逆行转运 将进行定位研究;伪狂犬病毒将 注射到脾脏，随后通过这个 通过突触连接的神经回路的亲神经病毒将是 采用光镜免疫组织化学技术进行检查。 为了研究SIIS中特定脑区的重要性， 基于神经回路的方法将用于确定是否 急性抑制离散脑部位的神经元功能， 足震应激改变脾脏中的SIIS。 这将被评估 使用体外非特异性有丝分裂原测定（Aim 2），和 抗原特异性淋巴细胞反应测定（AIM 3）。 平行 使用免疫组织化学检测Fos表达的研究 方法将被执行，以评估我们的有效性 抑制神经元功能的方法。 此外，这些研究将 提供了关于大脑特定部位在压力中的重要性的数据- 诱导Fos表达的神经元群体在整个 个脑袋拟议研究的结果将有助于描述 神经回路介导SIIS，并提供框架 研究合理的治疗方法，以减少 应激对免疫系统功能和疾病的影响 易感性

The proposed studies are derived from the hypothesis that stress- induced immunosuppression (SIIS) is mediated by discrete neuronal pathways in the CNS. The focus of the proposed studies is to determine the importance of certain brain regions in mediating stress-induced changes in splenic nerve-dependent immune responses in rats. The specific aims are to: (1) identify and neuronal circuits in the brain that innervate the spleen: (2) determine whether inhibition of discrete brain nuclei can eliminate SIIS in the spleen as assessed using an in vitro mitogen assay; and (3) determine whether inhibition of discrete brain nuclei can eliminate stress-induced suppression of the antibody response injection of sheep red blood cells. To determine which neuronal populations in the brain innervate the splenic sympathetic preganglionic neurons, a transneuronal retrograde transport mapping study will be performed; pseudorabies virus will be injected into the spleen, and the subsequent passage of this neurotropic virus through synaptically-linked neural circuits will be examined using light microscopy immunohistochemical techniques. To examine the importance of specific brain regions in SIIS, a neural-circuit based approach will be used to determine whether acute inhibition of neuronal function in discrete brain sites during footshock stress alters SIIS in the spleen. This will be assessed using both an in vitro non-specific mitogen assay (Aim 2), and an antigen-specific lymphocyte response assay (aim 3). Parallel studies examining Fos expression using immunohistochemical methods will be performed to evaluate the effectiveness of our methods to inhibit neuronal function. In addition, these studies will provide data on the importance of specific brain sites in stress- induced Fos expression in neuronal populations throughout the brain. Results from the proposed studies will help delineate the neural circuits that mediate SIIS, and provide the framework for examining rational therapeutic approaches to reduce the impact of stress-related effects on immune system function and disease susceptibility.