Stress Resilience in an Animal Model of Depression

抑郁症动物模型的压力恢复能力

• 批准号: 6596494
• 负责人: RUTH KOHEN
• 金额: $ 12.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6596494
• 关键词: antidepressants; behavioral /social science research tag; body physical activity; differential display technique; disease /disorder model; environmental adaptation; escape reaction; gene environment interaction; hippocampus; laboratory rat; learned helplessness; major depression; messenger RNA; microarray technology; neurochemistry; pharmacokinetics; stress

DESCRIPTION (provided by applicant): Major depression is the most common psychiatric disorder, affecting over 17% of individuals over the course of their lifetime. Genetic and environmental factors working in concert determine an individual's vulnerability to depression by affecting the use of genetic information in the brain. This use of genetic information can be measured as the amount of messenger RNA (mRNA) that is produced from a single gene, a process described as 'gene expression analysis'. In the proposed study we will use an animal model of depression, the forced swim test, to investigate the influence of environmental stress and chronic antidepressant treatment on gene expression in rat hippocampus. We hypothesize that resilience to depression occurs as a result of adaptive changes in the brain. We will observe these adaptive changes by large-scale gene expression analysis, using oligonucleotide microarrays and quantitative reverse transcription polymerase chain reaction (RT-PCR). We further hypothesize that animals show behavioral depression if and when these adaptive changes in gene expression fail to occur. We will also test the hypothesis that chronic treatment with antidepressant drugs works by facilitating this adaptive pattern of gene expression changes. This is a departure from the traditional way of thinking about depressive illness. The traditional view suggests that depressive illness occurs as a result of a change of metabolism or neuronal circuitry in the brain of affected subjects. We propose just the opposite: that stress resilience is accompanied by an adaptive change in brain neurochemistry that is missing in depressed individuals. Hence, depressed subjects resemble controls that have not been challenged with environmental stress. Our approach is novel because it focuses on investigating factors that protect the individual from depression, rather than on changes that occur as a result of the disease. If our hypothesis is true, it would mean a paradigm shift in our understanding of affective illness that could alter the focus of treatment from the current management of symptoms to their prevention

描述（由申请人提供）：重度抑郁症是最常见的精神疾病，影响超过 17% 的人一生。遗传和环境因素共同作用，通过影响大脑中遗传信息的使用来决定个体是否容易患抑郁症。这种遗传信息的使用可以通过单个基因产生的信使 RNA (mRNA) 的量来衡量，这一过程被称为“基因表达分析”。 在拟议的研究中，我们将使用抑郁症动物模型（强迫游泳试验）来研究环境压力和长期抗抑郁治疗对大鼠海马体基因表达的影响。 我们假设对抑郁症的恢复力是大脑适应性变化的结果。我们将使用寡核苷酸微阵列和定量逆转录聚合酶链反应（RT-PCR）通过大规模基因表达分析来观察这些适应性变化。我们进一步假设，如果基因表达的这些适应性变化未能发生，动物就会表现出行为抑郁。 我们还将检验这样一个假设，即抗抑郁药物的长期治疗通过促进这种基因表达变化的适应性模式而发挥作用。 这背离了对抑郁症的传统思考方式。传统观点认为，抑郁症的发生是由于受影响受试者大脑中的新陈代谢或神经元回路发生变化而导致的。我们的观点恰恰相反：压力恢复能力伴随着大脑神经化学的适应性变化，而抑郁症患者则缺乏这种变化。因此，抑郁的受试者类似于没有受到环境压力挑战的对照组。 我们的方法很新颖，因为它侧重于调查保护个体免受抑郁症影响的因素，而不是疾病导致的变化。如果我们的假设成立，这将意味着我们对情感疾病的理解发生了范式转变，可能会将治疗​​重点从当前的症状管理转向预防