A novel developmental mouse model of major depressive disorder

描述(由申请人提供)：焦虑障碍和严重抑郁障碍(MDD)是最普遍和最虚弱的精神症状之一。它们表现出广泛的共病和重叠的遗传起源，但它们的分子病因学和功能相互关系却知之甚少。在我的早期生活中，这两种类型的障碍的脆弱性都大大加剧，这表明它们主要是发育障碍。越来越多的证据表明，在两种类型的疾病中，GABA能传递的缺陷都起到了因果作用。特别是，MDD伴随着GABA能中间神经元功能的降低和丢失，以忧郁的MDD亚型最为明显的GABA浓度降低，以及主要GABA受体(GABA受体)亚单位组成的改变。此外，我们实验室对GABAAR y2亚基杂合子小鼠的广泛分析表明，通过这些受体的GABA能传递的适度发育缺陷可能是MDD的原因。这些小鼠表现出预期的行为、认知和细胞变化，包括忧郁性MDD的内分泌和药理学特征。重要的是，条件性基因消融实验表明，这种表型的发育起源于出生后。在这里，我们建议使用出生后发育期间GABA能传递的药理学操作来产生一种新的非遗传MDD小鼠模型，该模型独特地i)模拟MDD的发育病因，ii)允许分离与抑郁相关的和焦虑相关的病理，以及iii)导致成年期的永久/稳定的表型，可以进行跨学科的研究(行为，认知，分子，神经解剖学，药理学等)。初步实验表明，在出生后第10天至第21天期间使用安定(DZP)治疗小鼠，选择性地导致焦虑样行为增加。相比之下，从P29-35开始的DZP治疗导致在应激条件下选择性地增加不动，这与药物抗抑郁药的作用相反。因此，我们假设焦虑和抑郁相关的行为特征在不同的出生后发育关键期由类似的机制独立控制。我们建议建立P29-35 DZP处理的小鼠作为一种新颖和独特的MDD小鼠模型，适合于监测成年后MDD易感性的发育分子后遗症，并区分MDD的分子病因和高度焦虑的分子病因。在目标1中，我们将更全面地建立P29-35 DZP处理的小鼠的抑郁样行为、内分泌和药理表型。在目标2中，我们将使用转录组分析P10-24和P29-35 DZP处理的小鼠的扣带回皮质，以比较焦虑和抑郁等大脑状态的分子特征。拟议的工作将为深入分析MDD脆弱性的发展机制奠定基础。

DESCRIPTION (provided by applicant): Anxiety Disorders and Major Depressive Disorder (MDD) are among the most prevalent and debilitating psychiatric syndromes. They exhibit extensive comorbidity and overlapping genetic origins, yet their molecular etiology and functional interrelationship are poorly understood. The vulnerability for both types of disorders i greatly exacerbated in early life, indicating that they are primarily developmental disorders. Mounting evidence points to a causal role of deficits in GABAergic transmission for both types of disorders. In particular, MDD is accompanied by reduced function and loss of GABAergic interneurons, reduced GABA concentration most pronounced in the melancholic subtype of MDD, and alterations in the subunit composition of the principal GABA receptors (GABAARs). Moreover, extensive analyses of GABAAR y2 subunit heterozygous mice by our lab suggest that modest developmental deficits in GABAergic transmission through these receptors may be causal for MDD. These mice exhibit behavioral, cognitive and cellular alterations expected of such a model, including endocrine and pharmacologic characteristics of melancholic MDD. Importantly, conditional gene ablation experiments indicate a postnatal developmental origin of this phenotype. Here we propose to use pharmacological manipulation of GABAergic transmission during postnatal development to generate a novel non-genetic mouse model of MDD that uniquely i) mimics a developmental etiology of MDD, ii) allows separation of depression-related from anxiety-related pathology, and iii) leads to a permanent/stable phenotype in adulthood that is amenable to investigation across disciplines (behavioral, cognitive, molecular, neuroanatomical, pharmacological, etc.). Preliminary experiment indicate that treatment of mice with diazepam (DZP) between postnatal day (P)10 and P21 leads selectively to increased anxiety-like behavior. By contrast, DZP treatment from P29-35 leads to selectively increased immobility under stressful conditions, which is the inverse of a pharmacological antidepressant-like effect. Thus, we hypothesize that anxiety- and depression- related behavioral traits are independently controlled by similar mechanisms during distinct postnatal developmental critical periods. We propose to establish P29-35 DZP treated mice as a novel and unique mouse model of MDD that is suited to monitor the developmental molecular sequelae underlying vulnerability to MDD in adulthood, and to distinguish the molecular etiology of MDD from that of heightened anxiety. In Aim 1 we will more fully establish the depressive like behavioral, endocrine and pharmacologic phenotype of P29-35 DZP treated mice. In Aim 2 we will use transcriptome analyses of the cingulate cortex of P10-24 and P29-35 DZP treated mice to compare the molecular signature of anxious vs. depressive like brain states. The work proposed will lay the foundation for an in depth analysis of the developmental mechanism underlying vulnerability to MDD.