Organization of Sex Differences in Major Depression

描述（由申请人提供）：重度抑郁症（MDD）是一种情绪调节改变的衰弱性障碍。尽管重度抑郁症带来了巨大的经济和情感负担，但在神经精神病学研究中，理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，会在一生中经历一次使人衰弱的重度抑郁症发作。过去研究这一主要风险因素和相关机制的局限性在于，缺乏既能模拟这种疾病复杂性又能复制女性脆弱性的动物模型。除了模仿人类MDD的症状维度、抗抑郁逆转和分子特征外，我们现在发现小鼠的不可预测的慢性轻度应激（UCMS）概括了女性在情绪和抑郁易感性方面的差异，使UCMS成为研究MDD性别差异的潜在机制的合适模型。情绪被定义为啮齿类动物行为和生理的测量参数，与人类情绪相对应。尽管有证据表明循环性激素对女性情绪的部分贡献，但本提案旨在使用UCMS模型来测试另一种较少研究的假设，即情绪的两性二态性和抑郁易感性的发育起源。对人类受试者和啮齿动物模型的研究表明情绪障碍的发育起源。有趣的是，一个发育过程也在大脑中建立了性别差异，因为发育过程中暴露于睾丸激素会使包括杏仁核在内的几个大脑区域的结构永久地男性化。该项目将1)确定雄性/雌性大脑的发育组织（通过出生后睾酮暴露）是否导致了小鼠在基线和/或应激诱导的情绪方面的成年性别差异，2)确定雌性小鼠情绪改变的发育决定的分子相关性是否预测了人类女性重度抑郁症受试者的类似变化，并通过发育睾酮治疗逆转。

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.