Depression and Immunity: Behavioral and CNS Mechanisms

描述（由申请人提供）：大多数研究者假设，在抑郁症患者中发现的免疫异常是继发于脑功能的改变，特别是与免疫功能调节有关的区域和系统。然而，尽管有证据表明抗抑郁药物治疗在临床人群中使免疫功能正常化，但这一假设尚未得到广泛的验证。拟议的研究将使用弗林德斯敏感系（FSL）抑郁症遗传大鼠模型来测试大脑单胺能系统的改变导致抑郁症相关免疫功能异常的假设。该项目建立在最近令人兴奋的数据上，数据显示FSL大鼠体内1型免疫反应显着降低。拟议的研究包括两个具体目标。第一个源于先前的研究，表明用三环或血清素特异性抗抑郁药进行慢性抗抑郁治疗可以使FSL大鼠的行为和神经化学异常正常化。在拟议的研究中，FSL和对照大鼠将接受抗抑郁药地西帕明和舍曲林的慢性治疗。这些治疗有望使FSL动物的行为和免疫异常正常化。第二个目的是验证慢性脑室内输注去甲肾上腺素或血清素（分别是地西帕明和舍曲林的药理靶点）将使FSL和FRL菌株之间的行为和免疫差异正常化的假设。这些实验将同时评估(a)抗抑郁药对行为的作用部位和对免疫功能的假设影响（即中枢或外周），(b)特定单胺能系统在调节1型免疫反应中可能发挥更大作用的程度，以及(c)脑单胺类物质慢性升高的免疫调节作用。总的来说，这些研究建立在令人兴奋的新数据之上，它们被设计为描述源自大脑并最终改变特定免疫细胞功能的无缝影响链过程的第一步。由于FSL大鼠已经被确立为抑郁症的有效模型，从这些研究中产生的数据有望阐明临床抑郁症患者对身体疾病的脆弱性增加的综合生物学过程

DESCRIPTION (provided by applicant): Most investigators hypothesize that immunological abnormalities that have been identified in depressed individuals are secondary to alterations in brain function, particularly in regions and systems that are implicated in the regulation of immune function. Nonetheless, this hypothesis has not been broadly tested despite evidence that immune function is normalized by antidepressant treatment in clinical populations. The proposed research will use the Flinders Sensitive Line (FSL) genetic rat model of depression to test the hypothesis that alterations in brain monoaminergic systems contribute to depression-related abnormalities of immune function. This project builds on exciting recent data showing markedly reduced in vivo type 1 immune responses in FSL rats. Two specific aims comprise the proposed research. The first stems from previous work showing that chronic antidepressant treatment with tricyclic or serotonin-specific antidepressants normalizes behavioral and neurochemical abnormalities in the FSL rats. In the proposed studies, FSL and control rats will receive chronic treatment with the antidepressants desipramine and sertraline. These treatments are expected to normalize behavioral and immunological abnormalities in the FSL animals. The second aim will test the hypothesis that chronic intracerebroventricular infusion of norepinephrine or serotonin, the pharmacological targets of desipramine and sertraline, respectively, will normalize behavioral and immunological differences between the FSL and FRL strains. These experiments will simultaneously evaluate (a) the site of action for antidepressant effects on behavior and hypothesized effects on immune function (i.e. central or peripheral), (b) the extent to which a specific monoaminergic system may play a greater role in regulating type 1 immune responses, and (c) the immunomodulatory effects of chronic elevations in brain monoamines. Collectively, these studies build on exciting new data, and they are designed as initial steps in the process of describing a seamless chain of influence originating in the brain and culminating in altered function of specific immunological cells. Because the FSL rat has already been established as a valid model for depression, the data generated from these studies promise to illuminate the integrated biological processes that produce increased vulnerability to physical illness in the clinically depressed