Antidepressive Effects and Gene Mechanisms of Early-life Enriched Environment

描述（由申请人提供）：重度抑郁症（MDD）是一种主要的疾病负担，需要更有效的预防/治疗。强化环境治疗（EET）包括体育锻炼、精神刺激和社会互动，是预防/治疗重度抑郁症的潜在干预措施。EET的神经营养作用已被广泛研究；然而，其抗抑郁作用和潜在的生物学机制尚不清楚。特别是，其年龄依赖性效应和（外）遗传机制仍有待建立。确定最大EET效应的生命周期及其抗抑郁机制对于制定更有效的MDD预防/治疗策略具有重要意义。我们的长期目标是阐明EET抗抑郁作用的年龄x （epi-）遗传干扰。本项目将明确早期EET的抗抑郁作用，重点关注脑源性神经营养因子（BDNF，脑内与MDD相关的主要神经元生长因子）和抑郁相关基因的长期表达变化。BDNF缺乏，特别是由表观遗传调控引起的BDNF启动子IV缺乏，已在MDD患者和应激动物中观察到。婴儿早期的虐待会导致启动子iv控制的外显子的DNA甲基化，并降低一生中BDNF的表达。母亲的虐待行为和先前获得的DNA甲基化模式会代代相传。我们最近发现了Bdnf启动子IV缺乏导致抑郁样行为的因果证据。此外，使用我们的启动子IV缺陷抑郁症模型小鼠（KIV），我们发现慢性EET，而不是慢性抗抑郁治疗，能够通过多种启动子驱动的BDNF来补偿启动子IV缺陷引起的BDNF水平降低，这与EET的抗抑郁行为作用相似。由于早期生活经历涉及动态基因表达调控，我们假设EET和Bdnf补偿机制的抗抑郁作用可能在生命早期发育期间提供最大，并且由于Bdnf和Bdnf-/抑郁相关基因的长期表达变化，这些作用将在以后的生活中持续存在。我们将以两个目的来检验这些假设：目的1)确定早期EET的抗抑郁、Bdnf和基因效应；目的2)检查在早期发展过程中提供EET时，这些效应是否会持续。在Aim 1中，我们将通过测量i)抑郁样行为，ii) BDNF水平，以及iii)与重度抑郁症相关的大脑区域中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（早期生活和两个（年轻或年老）成年阶段）的有效性。我们将使用一种新的高通量基因分析。在Aim 2中，我们将通过测量Aim1中的i-iii来确定在随后的4周标准条件治疗后8周EET的延长效果。一旦这个项目完成，我们将进一步明确有效的EET的确切关键时期和抗抑郁的基因机制。

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.