Stress Resilience in an Animal Model of Depression

描述（由申请人提供）：重性抑郁症是最常见的精神疾病，在其一生中影响超过17%的人。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，决定了个体对抑郁症的脆弱性。这种遗传信息的使用可以测量为从单个基因产生的信使RNA（mRNA）的量，该过程被描述为“基因表达分析”。 在本研究中，我们将使用抑郁症的动物模型，强迫游泳实验，研究环境应激和慢性抗抑郁治疗对大鼠海马基因表达的影响。 我们假设，对抑郁症的恢复力是大脑适应性变化的结果。我们将通过大规模的基因表达分析，使用寡核苷酸微阵列和定量逆转录聚合酶链反应（RT-PCR）来观察这些适应性变化。我们进一步假设，如果这些基因表达的适应性变化未能发生，动物就会表现出行为抑郁。 我们还将测试这一假设，即抗抑郁药物的慢性治疗通过促进这种适应性的基因表达变化模式起作用。 这是对抑郁症的传统思维方式的背离。传统观点认为，抑郁症的发生是受影响受试者大脑中代谢或神经元回路变化的结果。我们的建议恰恰相反：压力恢复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。 我们的方法是新颖的，因为它专注于调查保护个人免受抑郁症的因素，而不是由于疾病而发生的变化。如果我们的假设是正确的，这将意味着我们对情感性疾病的理解发生了范式转变，这可能会将治疗的重点从目前的症状管理转变为预防

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