Intranasal immune challenge, brain cytokines and gender differences in depression

鼻内免疫挑战、脑细胞因子和抑郁症的性别差异

• 批准号: 7142457
• 负责人: Leonardo H Tonelli
• 金额: $ 20.05万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142457
• 关键词: anxiety; behavior test; behavioral medicine; brain; cytokine; depression; disease /disorder model; environmental stressor; gender difference; gene expression; immune response; inflammation; inhalation drug administration; laboratory rat; model design /development; neuroendocrine system; neuroimmunomodulation; paranasal sinus; polymerase chain reaction; psychoneuroimmunology; respiratory infections; sex hormones

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.

描述（由申请人提供）：流行病学研究报告称，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常见。发病率增加的生物学原因存在高度争议。由于许多炎症性疾病，如某些细菌和病毒性呼吸道感染的高峰在同一时间段左右，我们假设外周炎症将诱导细胞因子在大脑中的表达，这种细胞因子的表达将诱导抑郁症，这种影响将在女性中更高。这项R21应用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抑郁和焦虑发病率较高的机制。提出的研究的目的是在啮齿动物模型中确定外周激活的免疫反应，大脑中的炎症基因的表达和性腺激素在抑郁症和焦虑症的行为反应的调制的影响之间的关系。基于我们的初步研究，我们假设第一：由于上呼吸道炎症引起的免疫应答的外周激活将诱导脑中的细胞因子表达，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在雄性中更显著，第三，这种细胞因子表达将影响大鼠的行为，如通过增加强迫游泳试验中的不动时间所证明的。用性腺激素处理的动物和未处理的动物将用鼻腔中的细菌和病毒产物进行攻毒，并通过实时RT-PCR测定其脑中的细胞因子谱。将在强迫游泳试验中评价相同条件下的另一组动物，还将测定旷场活动及其脑中的细胞因子表达。在免疫激发后给予鼻内抗炎剂将用于测试它们是否阻止脑中的细胞因子表达和抑郁症的行为反应。R21申请中提出的实验结果有望提供关于性别差异和性腺激素对鼻内免疫激发后大脑中炎症基因表达的调节作用的重要初步数据。此外，它将提供有关性腺激素和细胞因子在抑郁和焦虑的行为反应的调制之间的相互作用的信息。这一信息是目前在文献中不可用的，是至关重要的启动研究的机制，环境因素与激素状态的协调可能会影响情绪障碍。这些信息可能有助于预防和治疗女性抑郁症。