The Neurobiology of Susceptibility to Depression

抑郁症易感性的神经生物学

• 批准号: 7894714
• 负责人: Nicole M. Edgar
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894714
• 关键词: Address; Adult; Affect; Amygdaloid structure; Anhedonia; Animal Model; Antidepressive Agents; Anxiety; Autopsy; Behavior; Behavior assessment; Behavioral; Biological; Biological Assay; Brain; Brain region; Chronic; Chronic stress; Code; Corticosterone; Development; Disease; Emotional; Emotions; Endogenous depression; Environment; Environmental Risk Factor; Event; Experimental Designs; Experimental Models; Feedback; Female; Functional disorder; Future; Gender Role; Gene Expression Profile; Gene Pool; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Human; Individual; Investigation; Knock-out; Laboratories; Lead; Life; Life Stress; Major Depressive Disorder; Measures; Mental Depression; Modeling; Molecular; Molecular Profiling; Moods; Mus; Neurobiology; Neurons; Neurosecretory Systems; Pathology; Pathway interactions; Pattern; Phenotype; Predisposition; Protocols documentation; Recovery; Recurrence; Regulation; Relative (related person); Reporting; Risk; Risk Factors; Rodent; Rodent Model; Role; Sampling; Serotonin; Site; Stress; Sucrose; Symptoms; Syndrome; System; Testing; Time; base; biological adaptation to stress; depressive symptoms; feeding; human female; hypothalamic-pituitary-adrenal axis; male; maternal separation; mood regulation; mouse model; mutant; preference; pup; research study; role model; serotonin transporter; sex

DESCRIPTION (provided by applicant):Major depressive disorder (MDD) is a debilitating disorder of altered mood regulation that is precipitated by chronic stress, modulated by serotonin and of unknown molecular pathophysiology. Four prominent risk factors have been consistently reported to influence rates of vulnerability to develop depression: sex, genetic make-up, prior MDD episodes, and early life stress; however no single animal model has comprehensively combined these vulnerability factors. Using the unpredictable chronic mild stress (UCMS) protocol and behavioral assessments of anxiety/depression-like behaviors in serotonin transporter (SERT) mutant and control mice, I have modeled the interactions of sex, SERT genetic make-up, and stress in eliciting depressive-like behaviors, including the increased vulnerability to clinical depression observed in human female subjects and the risk that is conferred by low SERT levels. Furthermore, gene microarray studies performed by our laboratory on the amygdala of postmortem human MDD subjects and UCMS-treated mice have identified ~40 genes whose changes are specific to human MDD and rodent UCMS, and reversed by antidepressant treatment in rodents, thus representing a critical pool of genes differentially expressed according to altered mood. Therefore, in addition to modeling aspects of human susceptibility to develop depression (sex and SERT genetic make-up), the rodent UCMS paradigm induces molecular changes that are predictive of ?depressive states? across species. Using a comprehensive UCMS-based experimental design in the mouse, I will first confirm the role of sex and SERT as risk factors to UCMS-induced altered mood regulation and then extend my investigation to two additional factors: disease recurrence and early life stress (Aim 1). Using samples generated in Aim 1, I will then begin characterizing neurobiological phenotypes that underlie the UCMS-evoked depressive-like state (Aim 2), including neuroendocrine changes and quantitative assessment of the amygdala gene expression signature. I hypothesize that while risk factors may differentially increase the susceptibility for developing MDD, the ultimate state of altered mood regulation affects a common set of biological and/or molecular disturbances. Results from these studies will begin characterizing changes in these putative common molecular and neuroendocrine disturbances, will reveal the relative contribution of these susceptibility factors to this common phenotype, and will form the basis of future causative studies aimed at investigating the cellular and molecular basis of MDD.

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使人衰弱的疾病，由慢性应激引起，由5-羟色胺和未知分子病理生理学调节。始终据报道，四个突出的危险因素会影响抑郁症的脆弱性：性别，遗传构成，先前的MDD发作和早期生活压力；但是，没有任何动物模型可以全面结合这些脆弱性因素。 Using the unpredictable chronic mild stress (UCMS) protocol and behavioral assessments of anxiety/depression-like behaviors in serotonin transporter (SERT) mutant and control mice, I have modeled the interactions of sex, SERT genetic make-up, and stress in eliciting depressive-like behaviors, including the increased vulnerability to clinical depression observed in human female subjects and the risk that is conferred by low SERT levels.此外，我们的实验室对尸体人类MDD受试者和UCMS处理的小鼠进行的基因微阵列研究已经确定了约40个基因，其变化特定于人类MDD和啮齿动物UCMS，并通过抗抑郁治疗中的抗抑郁药中的抗抑郁剂反转，从而代表了对基因的抗抑郁量，从而代表了对基因的差异性，以差异性地表达了反应。因此，除了建模人类发展抑郁症的敏感性（性别和SERT遗传构成）外，啮齿动物UCMS范式还会引起可预测抑郁状态的分子变化吗？跨物种。我将使用基于UCMS的全面实验设计，首先确认性别和SERT作为UCMS引起的风险因素的作用，从而改变了情绪调节的改变，然后将我的研究扩展到两个其他因素：疾病复发和早期生活压力（AIM 1）。然后，使用AIM 1中产生的样品，然后我将开始表征UCMS引起的类似抑郁状态的神经生物学表型（AIM 2），包括神经内分泌的变化和杏仁核基因表达签名的定量评估。我假设，尽管风险因素可能会差异增加发展MDD的敏感性，但改变情绪调节的最终状态会影响一组常见的生物学和/或分子障碍。这些研究的结果将开始表征这些假定的共同分子和神经内分泌障碍的变化，将揭示这些敏感性因素对这种常见表型的相对贡献，并将构成旨在研究MDD细胞和分子基础的未来病因研究的基础。