Organization of Sex Differences in Major Depression

重度抑郁症的性别差异组织

• 批准号: 8149879
• 负责人: Marianne L Seney
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2012-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149879
• 关键词: Adult; Affect; Amygdaloid structure; Animal Model; Animals; Antidepressive Agents; Anxiety; Behavior; Behavioral; Biological; Biology; Brain; Brain region; Cessation of life; Chronic; Data; Depressed mood; Development; Developmental Process; Dimensions; Disease; Emotional; Emotions; Exposure to; Female; Gender; Gene Expression; Gonadal Steroid Hormones; Hormones; Human; Human Characteristics; Individual; Injection of therapeutic agent; Lasers; Lead; Life; Life Stress; Major Depressive Disorder; Measures; Mental Depression; Modeling; Molecular; Molecular Profiling; Mood Disorders; Mus; Neonatal; Neurosecretory Systems; Physiology; Predisposition; Prevention; Research; Risk Factors; Rodent; Rodent Model; Role; Running; Serotonin; Sex Characteristics; Stress; Structure; Symptoms; Syndrome; Techniques; Testing; Testosterone; Time; United States; Validation; Woman; base; behavior test; capsule; cohort; cost; depressive symptoms; disability; experience; human female; human subject; male; men; mood regulation; mouse model; neonatal exposure; neuropsychiatry; postnatal; programs; public health relevance; sex; sexual dimorphism

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.

描述（由申请人提供）：重度抑郁症（MDD）是一种使情绪调节改变的衰弱障碍。尽管MDD承担了重大的财务和情感负担，但了解这种疾病的病理和分子特征仍然是神经精神病学研究中的巨大挑战。抑郁症的一个主要危险因素是性别：四分之一的女性，但只有十分之一的男性会在一生中经历MDD的令人衰弱的事件。研究这种主要危险因素和相关机制的过去局限性是缺乏动物模型，不仅模仿了该疾病的复杂性，而且还可以复制女性脆弱性。除了模仿症状维度，抗抑郁药的逆转以及人类MDD的分子谱特征外，我们现在表明，小鼠中不可预测的慢性轻度压力​​（UCM）不可预测，概述了女性情绪上的女性差异和易受抑郁症的差异，使UCMS对UCMS造成了适当的模型，使UCMS对涉及性别差异的适当模型调查了涉及性别差异。情绪定义为与人类情绪同源的啮齿动物行为和生理学的测量参数。尽管有证据表明，循环性激素对女性情绪的部分贡献，但该提案旨在使用UCMS模型来测试替代性的替代性，较少研究的假设，即对情感性的性二态性的发展起源的假设和对抑郁症的脆弱性。人类受试者和啮齿动物模型中的研究提出了情绪障碍的发展起源。有趣的是，由于发育过程中的睾丸激素暴露于包括杏仁核在内的几个大脑区域的结构，发展过程也会在大脑中建立性别差异。该项目将1）确定男性/女性脑的发展组织（通过产后睾丸激素暴露）是否是基线和/或压力引起的小鼠情绪的成人性别差异的基础，而2）确定发育确定的分子相关性是否在女性MDD受试者和发育中的女性MDD受试者的类似变化的雌性小鼠中是否会改变的分子相关性，并通过发育率进行了逆转。 公共卫生相关性：如果严重抑郁症的性别差异是由于生物学性别差异的基本差异，则需要更好地了解生物学，以发展更好的治疗，甚至预防重力抑郁症。在啮齿动物中研究抑郁症的一个主要问题是缺乏复制有据可查的人类女性对抑郁症的脆弱性的模型。重要的是，西比尔实验室现在表明，不可预测的慢性轻度小鼠模型概括了女性对重度抑郁症的脆弱性，因此，拟议的研究将使用该模型来研究抑郁症性别差异的可能生物学原因。