Sex Differences in Stress-Induced Genome-Wide Transcriptional Profiles

描述(申请人提供)：抑郁症和焦虑症是我们社会的巨大健康负担，据报道，普通人群的年患病率为9%-18%。尽管女性患抑郁症或焦虑症的可能性是男性的两倍，并且表现出更严重的症状，但绝大多数基础科学水平的研究只使用雄性啮齿动物来确定潜在的生物学机制。因此，人们对女性抑郁的机制知之甚少。在这里，我们使用慢性可变应激(CVS)范式，这是一个在小鼠中诱导强烈的抑郁和焦虑样行为的模型。我们的发现表明，在5个已建立的抑郁和焦虑行为和神经化学领域，女性比男性对CVS更敏感。例如，雌性在强迫游泳试验(FST)上表现出更大的不动能力，在蔗糖偏好试验(SPT)上表现出非享乐反应，在飞溅试验中减少了梳理时间，延长了进食新奇抑制进食(NSF)的潜伏期，并增加了血清皮质酮水平。尽管导致这些性别差异的直接机制尚不清楚，但我们使用RNA测序技术发现，在男性和女性中，大约有800个基因受到CVS的调控，其中只有不到3%的基因重叠。有趣的是，CVS对男性比女性调节更多的基因，这表明男性缺乏行为反应可能并不是被动的。相反，雄性可能会参与提供一种应对机制的替代转录途径。在这项应用中，我们将使用高分辨率的配对末端RNA测序和先进的生物信息学分析来确定剪接事件、替代启动子的使用和microRNA的加工，从而在整个转录组中测量应激诱导变化中的详细性别差异。所有数据集将被进一步分析为功能生物学簇，以确定性别差异 在受压力调节的主要途径中。我们相信，这项工作将为未来的应激研究提供一个非常重要的信息来源，并启动一个程序来测试这些转录组差异的功能相关性。后者将帮助开发新的个性化抗焦虑和抗抑郁治疗策略。

DESCRIPTION (provided by applicant): Depression and anxiety disorders are large health burdens to our society with reported yearly prevalence rates of 9-18% in the general population. Although women are twice as likely to suffer from depression or anxiety, and exhibit more severe symptoms, the great majority of studies at the basic science level have used only male rodents to determine the underlying biological mechanisms. As a consequence, there is far less known about the mechanisms of depression in females. Here we use the chronic variable stress (CVS) paradigm, a model that induces robust depression- and anxiety-like behavior in mice. Our findings show that females are more sensitive to CVS than males on 5 established depression and anxiety behavioral and neurochemical domains. For example, females exhibit greater immobility on the forced swim test (FST), anhedonic responses on sucrose preference tests (SPT), decreased time grooming on the splash test, increased latency to feed on novelty suppressed feeding (NSF), and increased serum corticosterone levels. Although the direct mechanisms driving these sex differences are unclear, we used RNA sequencing and found that there are approximately 800 genes regulated by CVS in males and females and less than 3% of them overlap. Interestingly, CVS regulates more genes in males than females, suggesting that the lack of behavioral response in males may not be a passive one. Rather, males may engage alternate transcriptional pathways providing a mechanism for acting coping. In this application, we will measure the detailed sex differences in stress-induced changes across the transcriptome using high resolution paired end RNA sequencing and advanced bioinformatics analysis to identify splicing events, alternative promoter usage and microRNA processing. All data sets will be further analyzed into functional biological clusters to determine sex differences in the major pathways regulated by stress. We believe that this work will provide an enormously important resource of information for future stress studies and initiate a program to test the functional relevance of these transcriptome differences. The latter will aide in the development of new personalized anti- anxiety and anti-depression therapeutic strategies.