Modeling Core Behavioral, Neuroendocrine and Molecular Features of Depression

描述（由申请人提供）：尽管抑郁症是世界范围内致残的主要原因，而且临床有效的抗抑郁药物在50多年前就被发现了，但抑郁症的细胞和分子病理仍未被明确。因此，很少有新的药物类别出现，而且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，因为情绪调节的改变，抑郁症的核心特征，是由包括杏仁核在内的已确定的神经网络所控制的，是由环境因素（如慢性压力）沉淀的，包括神经内分泌功能障碍，并由已知的风险因素（女性，血清素转运体改变[SERT]和既往抑郁发作）调节的。因此，开发一种合理的动物模型来概括这种疾病的这些已知特征，对于促进识别抑郁症的相关生物学和分子干扰将是无价的。在啮齿类动物中，不可预测的慢性轻度应激（UCMS）以一种自然的方式模拟了心理社会压力在引发情绪相关行为改变方面的作用，这些行为改变让人想起抑郁症的症状，以及抗抑郁药物治疗反应的时间框架。我们现在表明，小鼠的UCMS也概括了与雌性或低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系统发育上是保守的。因此，为了研究抑郁症的因果机制，本提案将首先通过评估已知危险因素（女性，低SERT和既往抑郁发作）对UCMS的行为（Aim 1），神经内分泌（Aim 2）和分子（Aim 3）相关因素的贡献，将UCMS描述为人类抑郁症的综合啮齿动物模型。其次，该模型将与我们在人类杏仁核中确定的抑郁症生物特征相结合，以确定可能支持抑郁症病理生理学的共享下游生物学途径。与NIMH的目标一致，本R21提案研究了一个综合的啮齿动物抑郁症模型，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，这一建议也受益于一个积极研究人类死后病理学的研究小组。例如，我们在啮齿动物UCMS中发现了人类抑郁症的分子特征，这将直接验证啮齿动物在模拟人类抑郁症相关机制方面的分子发现。具体来说，一种生物学特征(1)与小鼠情绪相关行为的变化暂时相关，（2)受已知影响人类抑郁易感性的风险因素调节，(3)由与人类抑郁症相同的分子变化支持）将首先代表一个强大而有效的候选系统，用于未来研究导致抑郁症情绪状态改变的机制，(2)一个潜在的新药靶点。公共卫生相关性：为了更好地了解遗传、神经生物学、行为和环境因素对人类疾病发展和轨迹的影响，本研究计划调查了一种综合的啮齿动物抑郁症模型。具体而言，我们将研究与小鼠情绪相关行为变化暂时相关的生物学事件，这些事件受到已知影响人类抑郁易感性的风险因素的调节，并得到与人类抑郁症相同的分子变化的支持。这些研究的结果将首先确定稳健有效的候选神经生物学脑系统，用于未来抑郁症机制的研究，其次是潜在的新药物靶点。

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.