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Antidepressive Effects and Gene Mechanisms of Early-life Enriched Environment

生命早期丰富环境的抗抑郁作用和基因机制

基本信息

批准号：
8867289
负责人：
KAZUKO SAKATA
金额：
$ 7.5万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867289
关键词：
Aftercare Age Animal Model Animals Antidepressive Agents Anxiety Disorders Behavior Behavioral Biochemical Biological Birth Brain Brain region Brain-Derived Neurotrophic Factor Chronic Code DNA DNA Methylation Depressed mood Development Disease Drug Addiction Effectiveness Elderly Environment Epigenetic Process Exercise Exons Financial compensation Functional disorder Funding Future Gene Expression Gene Expression Regulation Generations Genes Genetic Genotype Goals Growth Factor Health Hippocampus (Brain)Infant Intervention Life Life Experience Long-Term Depression Longevity Major Depressive Disorder Maternal Behavior Measures Medicine Mental Depression Methylation Motivation Mus Patients Pharmaceutical Preparations Prefrontal Cortex Pregnancy Prevention Proteins Psyche structure Resistance Resistance development Sampling Schizophrenia Social Interaction Staging Stress Systems Analysis Testing Treatment outcome Weaning age related burden of illness critical period effective intervention effective therapy effectiveness measure epigenetic regulation maltreatment methylation pattern mouse model neuronal growth novel prevent promoter social treatment effect young adult

项目摘要

DESCRIPTION (provided by applicant): A more effective prevention/treatment is needed for major depressive disorder (MDD), a leading disease burden. Enriched environment treatment (EET), which includes physical exercise, mental stimulation, and social interactions, is a potential intervention to prevent/treat MDD. The neurotrophic effects of EET have been extensively studied; however, its antidepressant effects and underlying biological mechanisms are unclear. In particular, its age-dependent effects and (epi-)genetic mechanisms remain to be established. Identifying the life period for maximal EET effects and its antidepressive mechanisms is important in helping develop strategies for a more effective prevention/treatment of MDD. Our long-term goal is to clarify age x (epi-)genetic interference of the antidepressive effects of EET. This project will specifically aim to clarify the antidepressive effects of early-lfe EET, focusing on long-lasting expression changes of brain-derived neurotrophic factor (BDNF; a major neuronal growth factor in the brain related to MDD) and depression-related genes. BDNF deficiency, particularly, Bdnf promoter IV deficiency caused by epigenetic regulation, has been observed in MDD patients and stressed animals. Early-life maltreatment of infants results in DNA methylation of the promoter IV-controlled exons and reduces BDNF expression throughout life. Abusive maternal behavior and previously acquired DNA methylation patterns then transmit perpetually from generation to generation. We recently showed causal evidence whereby Bdnf promoter IV deficiency leads to depression-like behavior. Further, using our promoter IV-deficient depression-model mice (KIV), we showed that chronic EET, but not chronic antidepressant treatment, was able to compensate for the reduced BDNF levels caused by promoter IV deficiency through multiple promoter-driven BDNF, which paralleled antidepressive behavioral effects of EET. Since early-life experiences involve dynamic gene expression regulations, we hypothesize that the antidepressive effects of EET and Bdnf compensation mechanisms may be maximized when EET is provided during early-life development and that these effects will endure in later life due to long-lasting expression changes of Bdnf and Bdnf-/depression-related genes. We will test these hypotheses with two aims: Aim 1) to determine antidepressant, Bdnf, and gene effects of early-life EET, and Aim 2) to examine whether these effects of EET endure when EET is provided during early-life development. In Aim 1, we will determine the effectiveness of EET across ages-during early-life and at two (young or old) adult stages-in both normal and depressed (KIV) mice, by measuring i) depression-like behavior, ii) BDNF levels, and iii) expression changes in Bdnf-/depression-related genes in the brain regions related to MDD. We will use a novel high-throughput gene analysis. In Aim 2, we will determine prolonged effects of 8 weeks of EET after a subsequent 4 weeks of standard condition treatment, by measuring i-iii as in Aim1. Once this project is completed, we will further clarify te precise critical period for effective EET and the gene mechanisms underlying depression resistance.

描述(由申请人提供)：需要对严重抑郁障碍(MDD)进行更有效的预防/治疗，这是一种主要的疾病负担。丰富环境疗法(EET)包括身体锻炼、精神刺激和社会互动，是一种潜在的预防/治疗MDD的干预措施。EET的神经营养作用已被广泛研究，但其抗抑郁作用及其潜在的生物学机制尚不清楚。特别是，其年龄依赖效应和(表观)遗传机制仍有待建立。确定EET最大效应的生命周期及其抗抑郁机制对于制定更有效地预防/治疗MDD的策略非常重要。我们的长期目标是阐明EET抗抑郁作用的年龄x(epi-)基因干扰。该项目将明确早期服用EET的抗抑郁作用，重点关注脑源性神经营养因子(BDNF；大脑中与MDD相关的主要神经生长因子)和抑郁相关基因的长期表达变化。在MDD患者和应激动物中已观察到BDNF缺乏，特别是由表观遗传调节引起的BDNF启动子IV缺乏。早期虐待婴儿会导致启动子IV控制的外显子DNA甲基化，并在整个生命过程中减少BDNF的表达。虐待母亲的行为和先前获得的DNA甲基化模式会永久地在一代又一代人中传播。我们最近展示了BDNF启动子IV缺乏导致抑郁样行为的因果证据。此外，在我们的启动子IV缺陷型抑郁模型小鼠(KIV)中，我们发现慢性EET，而不是慢性抗抑郁药物治疗，能够通过多个启动子驱动的BDNF来补偿因启动子IV缺乏而导致的BDNF水平的降低，这与EET的抗抑郁行为作用是平行的。由于早期生活经历涉及动态的基因表达调控，我们假设当在生命早期发育期间提供EET时，EET和BDNF补偿机制的抗抑郁作用可能最大化，并且由于BDNF和BDNF-/抑郁相关基因的长期表达变化，这些影响将持续到以后的生活。我们将以两个目的验证这些假说：目的1)确定早期EET的抗抑郁剂、BDNF和基因效应，以及2)检验当在早期发育期间提供EET时，EET的这些影响是否持续。在目标1中，我们将通过测量i)抑郁样行为，ii)BDNF水平，以及iii)与MDD相关的大脑区域中BDNF/抑郁相关基因的表达变化，来确定EET在正常和抑郁(KIV)小鼠中跨年龄的有效性-在生命早期和两个成年阶段(年轻或老年)。我们将使用一种新的高通量基因分析。在目标2中，我们将通过测量I-III来确定在随后的4周标准条件治疗后8周的EET的延长效果，就像在Aim1中一样。一旦这个项目完成，我们将进一步阐明有效EET的确切关键期和抑郁抵抗的基因机制。