The neurobiology of cognitive affective biases in depression and their role in antidepressant therapy

抑郁症是影响英国人的最重要的精神疾病。据估计，2009年的社会成本为86亿英镑，世界卫生组织预测，抑郁症将很快成为多年残疾的主要原因。尽管治疗抑郁症的药物在20世纪50年代就被发现了，但科学家们发现很难解释它们如何在大脑中起作用来治疗疾病的症状，以及为什么患者需要几周时间才能开始感觉好些。研究大脑以及它如何控制我们的行为，包括我们的情绪行为，是复杂的，精神疾病是最大的挑战之一。虽然对患者的研究使用问卷调查，访谈，大脑成像技术和心理学，但动物实验对于解开大脑的特定部分和所涉及的大脑化学物质非常重要。动物试验对于开发新的治疗方法也非常重要，并且对于确定药物是否可能对患者有效并因此适合临床试验至关重要。由于动物缺乏表达情感障碍的能力，因此在用于研究患者这些症状的方法方面，对抑郁情绪及其治疗的神经生物学理解的进展受到限制。最近的研究已经证明了测量大鼠情绪相关行为的可行性，本项目将使用我们实验室开发的一种测定方法，即情感偏差测试。 在这个项目中，我们将利用我们的任务来调查一个关于抑郁症的原因和治疗的新假设。我们还将研究这些认知变化是否与参与社会和环境互动的动机变化相关。抑郁症患者报告持续的消极情绪，这与以消极方式记住事物的倾向有关。因此，抑郁症患者会有与非抑郁症患者相同的经历，但当被要求回忆这些经历时，他们会比非抑郁症患者记住更多消极的事情。这被认为是由消极的认知过程引起的，而消极的认知过程反过来又影响了重新参与这些活动的动机，并导致与抑郁症相关的渐进的社会和环境退缩。现在人们也认为，抗抑郁药物可以改变心理过程，从而逆转这些负面的处理偏见，患者逐渐学习新的积极偏见记忆，从而增加重新参与社会和环境互动的动力。这一假说也可能有助于解释为什么药物治疗或认知行为疗法对某些抑郁症患者有效。使用我们的动物实验，我们能够测试这些想法，而不像研究抑郁症患者时遇到的控制其他因素的困难。我们还可以绘制情绪处理和行为变化的时间过程，并将这些与疾病发展和治疗逆转的可能机制联系起来。我们还计划了一系列实验，研究大脑的哪个部分在调节这些认知效应方面最重要，以及选择性地靶向该区域是否可以诱导抑郁症状的快速逆转。这些实验将为认知机制在抑郁症的病因和治疗中的作用提供新的信息。

Depression is the most significant psychiatric illness affecting people in the UK. Costs to society were estimated at £8.6 billion in 2009 and the World Health Organisation predicts that depression will soon be the leading cause of years lived with a disability. Although drugs to treat depression were discovered in the 1950s, scientists have found it difficult to explain how they act in the brain to treat the symptoms of the disease and why it takes several weeks before the patient starts to feel better. Studying the brain and how it controls our behaviour, including our emotional behaviour, is complicated and psychiatric disorders represent one of the biggest challenges. Whilst studies in patients use questionnaires, interviews, brain imaging techniques and psychology, experiments in animals are important to unlock the specific parts of the brain and brain chemistry involved. Animal tests are also very important for the development of new treatments and are essential to establishing whether a drug is likely to be effective in a patient and therefore suitable for clinical trials. Because animals lack the ability to express emotional impairments in terms of the methods used to study these symptoms in patients, progress towards understanding the neurobiology of depressed mood and its treatment has been limited. Recent research has demonstrated the feasibility of measuring emotion-related behaviour in rats and this project will build on this using an assay developed in our laboratory, the affective bias test. In this project we will use our task to investigate a novel hypothesis about the cause and treatment of depression. We will also investigate whether these changes in cognition are correlated with changes in motivation to engage in social and environmental interactions. Individuals with depression report persistent negative mood which is associated with a tendency to remember things in a negative way. Thus, a patient with depression will have the same experiences as a non-depressed patient but when asked to recall those experiences, they will remember more negative things than the non-depressed individual. This is thought to arise from negative cognitive processing which in turn affects motivation to re-engage in those activities and results in the progressive social and environmental withdrawal associated with depression. It is also now thought that antidepressant drugs act to modify psychological processes so these negative processing biases are reversed and the patient gradually learns new positively biased memories which increase motivation to re-engage in social and environmental interactions. This hypothesis may also help to explain why either drug treatment or cognitive behavioural therapies are effective in some patients with depression.Using our animal experiments, we are able to test these ideas without the difficulties of controlling other factors encountered when studying patients with depression. We can also map the time course of change in emotional processing and behaviour and relate these to a possible mechanism of disease development and treatment reversal. We have also planned a series of experiments which will look at which part of the brain is most important in mediating these cognitive effects and whether targeting this region selectively can induce a rapid reversal of depressed symptoms. Together these experiments will provide new information about the role of cognitive mechanisms in the cause and treatment of depression.