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）是最普遍和最令人衰弱的精神综合征。他们表现出广泛的共病和重叠的遗传起源，但他们的分子病因和功能的相互关系知之甚少。这两种类型的障碍的脆弱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，这两种类型的疾病的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，在MDD的神经元亚型中最明显的GABA浓度降低，以及主要GABA受体（GABAAR）的亚基组成的改变。此外，我们实验室对GABAAR γ 2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。这些小鼠表现出这种模型预期的行为、认知和细胞改变，包括胆固醇MDD的内分泌和药理学特征。重要的是，条件基因消融实验表明，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期间使用GABA能传递的药理学操作来产生MDD的新型非遗传小鼠模型，其独特地i）模拟MDD的发育病因学，ii）允许抑郁相关的病理学与焦虑相关的病理学分离，并且iii）导致成年后的永久/稳定表型，其适于跨学科研究（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（P）和P21天之间用地西泮（DZP）处理小鼠选择性地导致焦虑样行为增加。相比之下，DZP治疗P29-35导致在应激条件下选择性增加不动性，这与药理学抗抑郁样作用相反。因此，我们假设，在不同的出生后发育关键期，焦虑和抑郁相关的行为特征是由相似的机制独立控制的。我们建议建立P29-35 DZP治疗的小鼠作为一种新的和独特的MDD小鼠模型，适合于监测成年期MDD易感性的发育分子后遗症，并区分MDD的分子病因学与高度焦虑。在目的1中，我们将更充分地建立P29-35 DZP处理的小鼠的抑郁样行为、内分泌和药理学表型。在目的2中，我们将使用P10-24和P29-35 DZP处理的小鼠的扣带皮层的转录组分析来比较焦虑与抑郁样脑状态的分子特征。提出的工作将奠定基础，深入分析的发展机制的潜在脆弱性MDD。

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.