A novel developmental mouse model of major depressive disorder

描述（由申请人提供）：焦虑症和重度抑郁症（MDD）是最普遍和最衰弱的精神综合征之一。它们表现出广泛的合并症和重叠的遗传起源，但它们的分子病因学和功能相互关系尚不清楚。这两种疾病的易感性在生命早期大大加剧，表明它们主要是发育障碍。越来越多的证据表明，在这两种类型的疾病中，gaba能传递缺陷的因果作用。特别是，MDD伴随着GABA能中间神经元的功能降低和丧失，GABA浓度的降低在MDD的忧郁亚型中最为明显，以及主要GABA受体（GABAARs）亚基组成的改变。此外，我们实验室对GABAAR y2亚基杂合小鼠的广泛分析表明，通过这些受体的GABAAR能传递的适度发育缺陷可能是MDD的原因。这些小鼠表现出这种模型所期望的行为、认知和细胞改变，包括忧郁型重度抑郁症的内分泌和药理学特征。重要的是，条件基因消融实验表明了这种表型的出生后发育起源。在这里，我们建议在出生后发育过程中使用gaba能传递的药理学操作来产生一种新的非遗传性MDD小鼠模型，该模型独特地1)模仿MDD的发育病因，2)允许抑郁相关病理与焦虑相关病理分离，以及3)导致成年后永久/稳定的表型，可用于跨学科（行为，认知，分子，神经解剖学，药理学等）的研究。初步实验表明，地西泮（DZP）在出生后第10天(P)至第21天(P)之间治疗小鼠可选择性地增加焦虑样行为。相比之下，从P29-35开始的DZP治疗导致应激条件下选择性地增加不动性，这与药物抗抑郁样作用相反。因此，我们假设焦虑和抑郁相关的行为特征在不同的产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治疗的小鼠作为一种新的、独特的MDD小鼠模型，适用于监测成年期MDD易感性的发育分子后遗症，并区分MDD的分子病因与高度焦虑的病因。在Aim 1中，我们将更充分地建立P29-35 DZP治疗小鼠的抑郁样行为、内分泌和药理学表型。在Aim 2中，我们将对DZP治疗小鼠的P10-24和P29-35扣带皮层进行转录组分析，以比较焦虑和抑郁样大脑状态的分子特征。提出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. PUBLIC HEALTH RELEVANCE: Major depressive disorder (MDD) represents the second most common cause of total disability with a lifetime prevalence of approximately 12-20% of the population worldwide. The estimated costs to the US economy are over 100 billion dollars annually. Suicide, which is mainly caused by MDD, is the third and fourth cause of death in the 15-24 and 25-44 age groups, respectively. Antidepressant drugs currently used for the treatment of both anxiety and mood disorders act with a delay of several weeks and are effective in about two thirds of patients only, with fewer MDD patients even experiencing remission. Thus, research into the etiology and more effective treatments of MDD should be a major public health priority. We here propose the establishment of a new mouse model of depression that is designed to help understand specifically the developmental aspects of depressive disorders, an aspect that has been largely neglected due to the lack of broadly applicable animal models.