A novel developmental mouse model of major depressive disorder

一种新型的重度抑郁症发育小鼠模型

基本信息

批准号：
8473285
负责人：
BERNHARD LUSCHER
金额：
$ 17.88万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-24 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473285
关键词：
Ablation Address Adult Amygdaloid structure Animal Model Antidepressive Agents Anxiety Anxiety Disorders Area Behavior Behavioral Brain Candidate Disease Gene Cause of Death Characteristics Chronic Cognitive Comorbidity Consumption Corticosterone Depressive disorder Desipramine Development Diazepam Discipline Disease Disease remission Endocrine Etiology Exhibits Figs - dietary Fluoxetine Foundations GABA Receptor Gene Expression Gene Expression Profile Genes Genetic Interneurons Investigation Laboratories Life Locomotion Major Depressive Disorder Mental Depression Messenger RNA Modeling Molecular Molecular Profiling Monitor Mood Disorders Mus Pathology Patients Phenotype Population Positioning Attribute Prevalence Proteinase 3 RNA Sequences Research Role Serum Social Interaction Sucrose Suicide Swimming Syndrome Tail Suspension Testing Time Work age group cingulate cortex cost critical developmental period depressive symptoms design developmental disease disability effective therapy experience follow-up frontal lobe gamma-Aminobutyric Acid loss of function mouse model neglect next generation non-genetic novel postnatal public health priorities receptor research study teration trait transcriptome sequencing transmission process

项目摘要

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.

描述（由申请人提供）：焦虑症和严重抑郁症（MDD）是最普遍，令人衰弱的精神综合症之一。它们表现出广泛的合并症和重叠的遗传起源，但他们的分子病因和功能相互关系却鲜为人知。两种疾病的脆弱性我在早期生命中极大地加剧了它们，表明它们主要是发育障碍。安装证据表明，两种类型的疾病的缺陷在GABA能传播中的因果作用。特别是，MDD伴随着功能降低和GABA能中间神经元的丧失，在MDD的忧郁亚型中最明显的GABA浓度以及主要GABA受体（GABAARS）的亚基组成的改变。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GABA能传播中适度的发育缺陷可能是MDD的原因。这些小鼠表现出这种模型的行为，认知和细胞改变，包括忧郁症MDD的内分泌和药物特征。重要的是，条件基因消融实验表明该表型的产后发育起源。 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,认知，分子，神经解剖学，药理等）。初步实验表明，在产后日（P）10和P21之间用地西ep（DZP）治疗小鼠的小鼠有选择地导致焦虑样行为增加。相比之下，P29-35的DZP处理导致在压力条件下有选择地增加固定性，这是药理学抗抑郁样作用的相反。因此，我们假设焦虑和抑郁症相关的行为特征在不同的产后发育关键时期内由相似机制独立控制。我们建议建立P29-35 DZP处理的小鼠作为一种新颖而独特的MDD小鼠模型，适用于在成年期监测MDD的潜在脆弱性的发育分子后遗症，并区分MDD的分子病因与焦虑症的增强。在AIM 1中，我们将更充分地建立P29-35 DZP处理的小鼠的行为，内分泌和药理表型等抑郁症。在AIM 2中，我们将使用P10-24和P29-35 DZP处理的小鼠的扣带皮质的转录组分析来比较焦虑与抑郁症的分子特征。提出的工作将为对MDD脆弱性的发展机制进行深入分析奠定基础。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice.

DOI：
10.1016/j.neuropharm.2014.07.019
发表时间：
2015-01
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Ren Z;Sahir N;Murakami S;Luellen BA;Earnheart JC;Lal R;Kim JY;Song H;Luscher B
通讯作者：
Luscher B