Modeling Core Behavioral, Neuroendocrine and Molecular Features of Depression

描述(申请人提供)：尽管抑郁症是世界范围内导致残疾的主要原因，临床上有效的抗抑郁药物在50多年前就被发现，但抑郁症的细胞和分子病理大部分仍未确定。因此，新的毒品类别很少出现，很大比例的抑郁症受试者得不到足够的缓解。然而，这是令人惊讶的，因为情绪调节的改变是抑郁症的核心特征，受到包括杏仁核在内的已识别神经网络的辅助，由环境因素(如慢性应激)引发，包括神经内分泌功能障碍，并受到已知风险因素(女性性别、改变的5-羟色胺转运体[SERT]和既往抑郁发作)的调节。因此，开发一种合理的动物模型来概括这些已知的疾病特征，对于识别抑郁症中相关的生物学和分子障碍将是非常宝贵的。在啮齿动物中，不可预测的慢性轻度应激(UCMS)以一种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中的作用，这些变化使人想起抑郁症的症状，以及抗抑郁药物治疗的治疗反应时间框架。我们现在表明，小鼠的UCMS还概括了与女性性别或低SERT相关的情绪状态变化的易感性增加，并且UCMS诱导杏仁核基因表达的变化，这些基因表达在系统发育上是保守的，具有人类抑郁症的分子特征。因此，以研究抑郁症的病因机制为长期目标，这项建议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)的相关性的贡献，将UCMS表征为人类抑郁的综合啮齿动物模型。其次，这一模型将与我们在人类杏仁核中识别的抑郁症的生物特征相结合，以确定可能支持抑郁症的病理生理学的共同下游生物通路。与NIMH的目标一致，这项R21提案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、行为和环境因素对精神障碍的发展和轨迹的贡献。重要的是，这一建议还得益于一个积极研究人类身体病理学的研究小组。例如，我们识别了在啮齿动物UCMS中保守的人类抑郁症的分子签名，这将允许在与人类抑郁症相关的建模机制中直接验证啮齿动物的分子发现。具体地说，一种生物学特征，即1)与小鼠情绪相关行为的变化在时间上相关，2)受已知的影响人类抑郁易感性的危险因素调节，以及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情绪状态改变的机制，第二，代表一个潜在的新药靶点。公共卫生相关性：这项研究计划调查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的发展和轨迹的贡献。具体地说，我们将研究与小鼠情绪相关行为的变化在时间上相关的生物事件，这些事件受到已知的影响人类抑郁易感性的风险因素的调节，并受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大脑系统，用于未来导致抑郁症的机制的研究，第二，潜在的新药靶点。

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.