Intranasal immune challenge, brain cytokines and gender differences in depression

描述(申请人提供)：流行病学研究报告，女性比男性更容易受到抑郁症的影响，抑郁症在早春更频繁发生。这些发病率增加的生物学原因引起了激烈的争论。由于许多炎症条件，如某些细菌和病毒呼吸道感染在同一时间段左右达到顶峰，我们假设外周炎症将诱导大脑中细胞因子的表达，这种细胞因子的表达将导致抑郁，并且这种影响在女性中会更高。这项R21应用是开发神经免疫相互作用的动物模型的更广泛目标的一部分，以研究可能导致女性和早春期间抑郁和焦虑发生率较高的机制。本研究的目的是在啮齿动物模型中确定免疫反应的外周激活、脑内炎症基因的表达以及性腺激素在调节抑郁和焦虑行为反应中的作用之间的关系。根据我们的初步研究，我们假设：第一，由于上呼吸道炎症引起的免疫反应的外周激活将在大脑中诱导细胞因子的表达；第二：由于性腺激素的存在，这种细胞因子的表达在雌性比雄性更明显；第三，这种细胞因子的表达将影响大鼠的行为，如在强迫游泳测试中增加不动时间所证明的那样。用性腺激素治疗的动物和未治疗的动物将被鼻腔中的细菌和病毒产物挑战，它们在大脑中的细胞因子谱将通过实时RT-PCR来确定。另一组在相同条件下的动物将在强迫游泳测试和野外活动中进行评估，并将测定它们在大脑中的细胞因子表达。在免疫挑战后，鼻腔注射抗炎药将被用来测试它们是否能阻止细胞因子在大脑中的表达和抑郁症的行为反应。在R21应用中提出的实验结果有望提供有关性别差异和性腺激素对鼻腔免疫攻击后脑内炎症基因表达的调节作用的重要初步数据。此外，它还将提供有关性腺激素和细胞因子在调节对抑郁和焦虑的行为反应方面的相互作用的信息。这一信息目前在文献中还没有，对于启动环境因素与荷尔蒙状态协同影响情绪障碍的机制的研究是至关重要的。这些信息可能对预防和治疗女性抑郁症有用。

DESCRIPTION (provided by applicant): Epidemiological studies report that women are more likely than men to be affected by depression and that depression occurs more frequently in early spring. The biological reasons for these increased incidences are highly debated. Because many inflammatory conditions such as certain bacterial and viral respiratory infections peak around the same period of time, we hypothesize that peripheral inflammation will induce cytokine expression in the brain, that this cytokine expression will induce depression and that this effect will be higher in females. This R21 application is part of a broader goal of developing an animal model of neuroimmune interactions to study the mechanisms that may be promoting the higher incidence of depression and anxiety in women and during early spring. The objective of the proposed studies is to determine in a rodent animal model the relationship between peripheral activation of the immune response, expression of inflammatory genes in the brain and the effects of gonadal hormones in the modulation of behavioral responses of depression and anxiety. Based on our preliminary studies, we hypothesize that first: peripheral activation of the immune response due to inflammation in the upper-respiratory tract will induce cytokine expression in the brain, second: that this cytokine expression will be more pronounced in females as compared to males due to the presence of gonadal hormones, and third that this cytokine expression will affect the behavior of rats as demonstrated by increasing immobility time in the forced swim test. Treated animals with gonadal hormones and untreated animals will be challenged with bacterial and viral products in the nasal cavities and their cytokine profile in the brain will be determined by real-time RT-PCR. Another group of animals under the same conditions will be evaluated in the forced swim test and open field activity and their cytokine expression in the brain will be also determined. Administration of intranasal anti-inflammatory agents after the immune challenge will be used to test if they prevent cytokine expression in the brain and behavioral responses of depression. The results of the experiments proposed in this R21 application are expected to provide important preliminary data about gender differences and regulatory effects of gonadal hormones on inflammatory gene expression in the brain after intranasal immune-challenge. In addition, it will provide information about the interaction between gonadal hormones and cytokines in the modulation of behavioral responses to depression and anxiety. This information is not currently available in the literature and is critical to the initiation of studies on the mechanisms by which environmental factors in coordination with hormonal status may affect mood disorders. This information may be useful to prevent and treat depression in women.