Intranasal immune challenge, brain cytokines and gender differences in depression

描述（由申请人提供）：流行病学研究报告表明，女性比男性更容易受到抑郁症的影响，并且抑郁症在早春更频繁发生。这些发病率增加的生物学原因备受争议。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期达到高峰，我们假设外周炎症会诱导大脑中细胞因子的表达，这种细胞因子的表达会导致抑郁，并且这种影响在女性中会更高。该R21应用程序是开发神经免疫相互作用动物模型的更广泛目标的一部分，以研究可能促进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、大脑中炎症基因的表达和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：上呼吸道炎症引起的外周免疫反应激活会诱导大脑中细胞因子的表达；第二：由于性腺激素的存在，这种细胞因子的表达在雌性中比雄性更明显；第三，这种细胞因子的表达会影响大鼠的行为，这一点在强迫游泳测试中通过增加静止时间来证明。使用性腺激素治疗的动物和未使用性腺激素治疗的动物将在鼻腔中受到细菌和病毒产物的挑战，它们在大脑中的细胞因子谱将通过实时RT-PCR测定。另一组动物在相同条件下进行强迫游泳试验和野外活动评估，并测定其脑内细胞因子的表达。在免疫攻击后，将使用鼻内抗炎药来测试它们是否能阻止大脑细胞因子的表达和抑郁症的行为反应。本R21申请中提出的实验结果有望为鼻内免疫攻击后性别差异和性激素对脑内炎症基因表达的调节作用提供重要的初步数据。此外，它将提供关于性腺激素和细胞因子在调节抑郁和焦虑行为反应中的相互作用的信息。这一信息目前还没有在文献中得到，这对于启动环境因素与激素状态协调可能影响情绪障碍的机制的研究至关重要。这些信息可能有助于预防和治疗女性抑郁症。

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.