Organization of Sex Differences in Major Depression

描述(申请人提供)：严重抑郁障碍(MDD)是一种情绪调节改变的衰弱障碍。尽管MDD带来了巨大的经济和情感负担，但在神经精神病学研究中，了解这种疾病的病理和分子特征仍然是一个相当大的挑战。抑郁症的一个主要风险因素是性：四分之一的女性，但只有十分之一的男性，会在一生中经历一段令人衰弱的MDD发作。过去研究这一主要危险因素和相关机制的局限性是缺乏一种动物模型，不仅能模拟这种疾病的复杂性，还能复制女性的脆弱性。除了模拟人类MDD的症状维度、抗抑郁药逆转和分子图谱特征外，我们现在还表明，小鼠不可预测的慢性轻度应激(UCMS)概括了女性在情绪性和抑郁易感性方面的差异，使UCMS成为研究MDD性别差异的合适模型。情绪性被定义为啮齿动物行为和生理的测量参数，这些参数与人类的情绪是一致的。尽管有证据表明，循环性激素对女性情绪性有部分贡献，但这项提议的目的是使用UCMS模型来检验另一种且研究较少的假说，即情绪性和抑郁易感性的性别二型性起源的发育起源。在人类受试者和啮齿动物模型上的研究表明，情绪障碍的发育起源。有趣的是，发育过程还会在大脑中建立性别差异，因为发育过程中暴露在睾丸素下会永久性地使包括杏仁核在内的几个大脑区域的结构男性化。该项目将1)确定男性/女性大脑的发育组织(通过出生后睾丸激素暴露)是否导致成年小鼠基线和/或应激诱导的情绪变化的性别差异，以及2)确定发育决定的分子与雌性小鼠潜在的情绪变化相关是否预测人类女性MDD受试者的类似变化，并被发育睾丸激素治疗逆转。 公共卫生相关性：如果严重抑郁症的性别差异是由于潜在的生物性别差异，则有必要更好地了解生物学，以开发更好的治疗甚至预防严重抑郁症的方法。在啮齿动物身上研究抑郁症的一个主要问题是，缺乏复制有充分证据的人类女性易患抑郁症的模型。重要的是，西比勒实验室现在表明，不可预测的慢性轻度应激小鼠模型概括了女性对严重抑郁症的易感性，因此，拟议的研究将使用该模型来调查抑郁症性别差异的可能生物学原因。

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a debilitating disorder of altered mood regulation. Despite the substantial financial and emotional burden of MDD, understanding the pathological and molecular features of this disorder remains a considerable challenge in neuropsychiatry research. One major risk factor for depression is sex: one in four women, but only one in ten men, will experience a debilitating episode of MDD in the course of a lifetime. A past limitation to investigate this major risk factor and associated mechanisms was the lack of an animal model that not only mimics the complexity of the disorder but also replicates the female vulnerability. In addition to mimicking symptom dimensions, antidepressant reversal, and molecular profile characteristics of human MDD, we now show that unpredictable chronic mild stress (UCMS) in mice recapitulates the female differences in emotionality and vulnerability to depression, making UCMS the appropriate model to investigate underlying mechanisms involved in sex differences in MDD. Emotionality is defined as measured parameters for rodent behavior and physiology that are homologous to human emotions. Although evidence suggests a partial contribution of circulating sex hormones to female emotionality, this proposal aims to use the UCMS model to test the alternative and less investigated hypothesis of a developmental origin of the sexual dimorphism of emotionality and vulnerability to depression. Studies in human subjects and in rodent models suggest a developmental origin for mood disorders. Interestingly, a developmental process also establishes sex differences in the brain, as developmental exposure to testosterone permanently masculinizes the structure of several brain regions, including the amygdala. This project will 1) determine whether developmental organization of the male/female brain (through postnatal testosterone exposure) underlies adult sex differences in baseline and/or stress induced emotionality in mice, and 2) determine whether the developmentally determined molecular correlates underlying altered emotionality in female mice predict similar changes in human female MDD subjects and are reversed by developmental testosterone treatment. PUBLIC HEALTH RELEVANCE: If gender differences in major depression are due to underlying biological sex differences, a better understanding of the biology is warranted to develop better treatment or even prevention of major depression. One major problem with studying depression in rodents has been the lack of models that replicate the well documented human female vulnerability to depression. Importantly, the Sibille lab now shows that the unpredictable chronic mild stress mouse model recapitulates the female vulnerability to major depression, and thus, the proposed studies will use this model to investigate possible biological causes for sex differences in depression.