Modeling Core Behavioral, Neuroendocrine and Molecular Features of Depression

描述（由申请人提供）：尽管抑郁症是全球残疾的主要原因，并且在50多年前发现了临床有效的抗抑郁药，但抑郁症的细胞和分子病理学仍然大多未表征。因此，很少有新的药物类别出现，很大一部分抑郁症患者没有得到充分的缓解。然而，这是令人惊讶的，因为改变的情绪调节，抑郁症的核心特征，是由确定的神经网络，包括杏仁核，是由环境因素，如慢性应激，包括神经内分泌功能障碍，并通过已知的风险因素（女性性别，改变血清素转运体[SERT]和先前的抑郁发作）调制沉淀。因此，开发一个合理的动物模型，概括这些已知的疾病特征，将是非常宝贵的，以促进识别相关的生物和分子障碍，抑郁症。啮齿类动物中不可预测的慢性轻度应激（UCMS）以自然主义的方式模拟了心理社会应激在引发情绪相关行为变化（使人联想到抑郁症症状）中的作用，以及抗抑郁治疗的治疗反应时间范围。我们现在表明，小鼠中的UCMS也重现了与女性性别或低SERT相关的情绪状态改变的脆弱性增加，并且UCMS诱导杏仁核中基因表达的变化，这些变化与人类抑郁症的分子特征在遗传学上是保守的。因此，随着调查抑郁症的因果机制的长期目标，本提案将首先通过评估已知风险因素（女性，低SERT和既往抑郁发作）对UCMS的行为（目标1），神经内分泌（目标2）和分子（目标3）相关性的贡献，将UCMS描述为人类抑郁症的综合啮齿动物模型。其次，将使用该模型，结合我们在人类杏仁核中识别的抑郁症生物特征，以识别可能支持抑郁症病理生理学的共享下游生物通路。与NIMH的目标一致，这项R21提案调查了一种综合的啮齿动物抑郁模型，以更好地了解遗传、神经生物学、行为和环境因素对精神障碍发展和轨迹的贡献。重要的是，这一提议也得益于一个积极研究人类死后病理学的研究团队。例如，我们对人类抑郁症的分子特征的鉴定在啮齿动物UCMS中是保守的，这将允许在与人类抑郁症相关的建模机制上直接验证啮齿动物分子发现。具体而言，i）与小鼠中情绪相关行为的变化在时间上相关，ii）由已知影响人类抑郁症易感性的风险因素调节，以及iii）由与人类抑郁症中等同的分子变化支持的生物特征将首先代表用于未来研究导致抑郁症中情绪状态改变的机制的稳健且有效的候选系统，并且，第二，一个潜在的新药靶点公共卫生相关性：这项研究计划调查了抑郁症的综合啮齿动物模型，以更好地了解遗传，神经生物学，行为和环境因素对人类疾病发展和轨迹的贡献。具体来说，我们将研究与小鼠情绪相关行为变化在时间上相关的生物事件，这些生物事件由已知影响人类抑郁症易感性的风险因素调节，并得到与人类抑郁症相同的分子变化的支持。这些研究的结果将确定第一个强大和有效的候选神经生物学脑系统，用于未来研究导致抑郁症的机制，第二，潜在的新药物靶点。

DESCRIPTION (provided by applicant): Although depression is a leading cause of disability worldwide and clinically-effective antidepressants were discovered over 50 years ago, the cellular and molecular pathology of depression remains mostly uncharacterized. As a result, very few new drug classes have emerged and a large proportion of depressed subjects do not get adequate relief. Yet, this is surprising since altered mood regulation, the core feature of depression, is subserved by identified neural networks including the amygdala, is precipitated by environmental factors such as chronic stress, includes neuroendocrine dysfunctions, and is modulated by known risk factors (female sex, altered serotonin transporter [SERT] and prior depressive episodes). Thus, to develop a plausible animal model that recapitulates these known features of the illness would be invaluable in facilitating the identification of relevant biological and molecular disturbances in depression. Unpredictable chronic mild stress (UCMS) in rodents mimics in a naturalistic way both the role of psycho- social stress in eliciting emotion-related behavioral changes that are reminiscent of symptoms of depression, and the timeframe of therapeutic response to antidepressant treatment. We now show that UCMS in mice also recapitulates the increased vulnerability to altered mood states associated with female sex or low SERT, and that UCMS induces changes in gene expression in the amygdala that are phylogenetically conserved with the molecular signature of human depression. Thus, with the long-term goal of investigating causal mechanisms of depression, this proposal will first characterize UCMS as an integrated rodent model of human depression by assessing the contribution of known risk factors (female sex, low SERT and prior depressive episodes) to the behavioral (Aim 1), neuroendocrine (Aim 2) and molecular (Aim 3) correlates of UCMS. Second, this model will be used, in combination with our identified biosignature of depression in the human amygdala, to identify shared downstream biological pathways that may support the pathophysiology of depression. Consistent with NIMH goals, this R21 proposal investigates an integrated rodent model of depression to better understand the contribution of genetic, neurobiological, behavioral and environmental factors to the development and trajectory of mental disorders. Importantly, this proposal also benefits from a research team actively investigating human postmortem pathology. For instance, our identification of a molecular signature of human depression that is conserved in rodent UCMS will allow direct validation of the rodent molecular findings at modeling mechanisms that are relevant to human depression. Specifically, a biological feature that is i) temporally correlated with changes in emotion-related behaviors in mice, ii) modulated by risk factors known to affect vulnerability to depression in humans, and iii) supported by equivalent molecular changes as in human depression, will represent first a robust and valid candidate system for future investigation of mechanisms leading to altered mood states in depression, and, second, a potential new drug target. PUBLIC HEALTH RELEVANCE: This research proposal investigates an integrated rodent model of depression in order to better understand the contribution of genetic, neurobiological, behavioral and environmental factors to the development and trajectory of the human illness. Specifically, we will investigate biological events that are temporally correlated with changes in emotion-related behaviors in mice, modulated by risk factors known to affect vulnerability to depression in humans, and supported by equivalent molecular changes as in human depression. Results from these studies will identify first robust and valid candidate neurobiological brain systems for future investigations of mechanisms leading to depression, and, second, potential new drug targets.