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）：流行病学研究报告说，女性比男性更有可能受到抑郁症的影响，并且抑郁症在早春更频繁。这些增加的发病率的生物学原因是高度争议的。由于许多炎症状况（例如某些细菌和病毒呼吸道感染）在同一时期左右达到峰值，因此我们假设外周炎症会诱导大脑中的细胞因子表达，这种细胞因子的表达将诱导抑郁症，并且这种作用在女性中会较高。这种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，以研究可能促进女性和早春期间抑郁症和焦虑症发生率更高的机制。拟议的研究的目的是在啮齿动物模型中确定免疫反应的周围激活，大脑中炎症基因的表达与性腺激素在调节抑郁症和焦虑行为反应调节中的影响。根据我们的初步研究，我们假设首先：由于上呼吸呼吸道的炎症在炎症中引起的免疫反应的周围激活会引起大脑中的细胞因子表达，其次：由于这种细胞因子的表达将更加明显，因为女性在女性中的表现会因这种症状而导致的表达而导致男性的表达，并且由于刺激性的表达而导致刺激性的行为，而刺激了刺激性的刺激性，而行为会导致刺激性的行为，而行为却是行为的，而行为会导致女性的表现，而这种行为会导致女性的表达。强制游泳测试。用性腺激素和未经治疗的动物处理的动物将在鼻腔中受到细菌和病毒产物的挑战，其在大脑中的细胞因子特征将由实时RT-PCR确定。在相同条件下的另一组动物将在强制游泳测试和开放田活动中进行评估，并且还将确定它们在大脑中的细胞因子表达。免疫攻击后鼻内抗炎药的给药将用于测试它们是否防止大脑中的细胞因子表达和抑郁症的行为反应。预计在此R21应用中提出的实验结果有望提供有关性别差异和性别差异和调节性效应在鼻腔内免疫挑战后大脑炎症基因表达的重要初步数据。此外，它将提供有关性腺激素与细胞因子之间对抑郁和焦虑的行为反应的相互作用的信息。该信息目前在文献中尚不可用，对于启动有关与荷尔蒙地位协调可能影响情绪障碍的机制的研究至关重要。此信息可能有助于预防和治疗女性抑郁症。