Ventral hippocampal control of behavioural flexibility, and its disruption by adolescent social isolation

青春期长时间的压力会导致成年后行为的巨大差异。例如，青春期长期的压力会损害所谓的灵活行为，即根据特定情况改变行动的能力。这是一个问题，因为这些行为上的改变被认为会增加对几乎所有最常见的精神健康障碍（如成瘾、抑郁和精神分裂症）的易感性。这导致近80%报告早期生活压力较大的年轻人随后被诊断出患有这些疾病之一。尽管这种现象非常普遍，但人们对生命早期的慢性压力究竟是如何导致这些行为缺陷的还不是很清楚。在人类和临床前模型（如小鼠）中，唯一一致的发现之一是，在长期持续的压力之后，比如在青春期长期的社会孤立之后，大脑中被称为海马体的部分的大小和功能会急剧缩小。然而，海马体回路的这种剧烈变化是如何以及是否会导致晚年的这些行为障碍，目前尚不清楚。在这个项目中，我们第一次提出直接回答这个问题。我们将训练老鼠执行用于研究人类压力诱发行为的相同任务。然后，我们将使用计算模型来准确地了解老鼠是如何执行这些任务的。通过使用这种建模方法，这将使我们能够直接将我们在老鼠身上的工作与人类的工作联系起来。然后，我们将利用在小鼠身上可用的大量最先进的技术来研究详细的神经回路，并确切地调查哪些海马神经元受到早期生活压力的影响，以及它们是如何改变的。最后，我们将利用这些新知识直接研究海马神经元的这些改变是如何导致行为改变的。为了做到这一点，我们将使用遗传学来进行操作，以“修复”由慢性压力引起的回路变化。然后，我们可以观察“固定”的老鼠如何执行我们的行为任务，看看修复海马体的缺陷是否可以修复行为问题。总的来说，我们这项研究的目的是确切地了解青少年压力改变了哪些神经元，以及这些改变是如何导致行为改变的。在未来，我们希望利用这些知识来开发针对这些疾病的更具体的治疗方法。

Long periods of stress during adolescence can result in profound differences in behaviour in adulthood. For example, long term stress during adolescence can impair what is termed flexible behaviour - the ability to alter what actions you take in response to a particular situation. This is a problem as these changes in behaviour are thought to increase susceptibility to almost all of the most common mental health disorders such as addiction, depression and schizophrenia. This results in almost 80 % of young adults that report significant early life stress subsequently being diagnosed with one of these disorders.Despite this remarkable prevalence, exactly how chronic stress early in life results in these behavioural deficits is not well understood. One of the only consistent findings in both humans, and also preclinical models such as mice, is that a part of the brain called the hippocampus is dramatically reduced in size and function after long lasting stress, for example after long periods of social isolation during adolescence. However, how and if this dramatic change in hippocampal circuitry results in these behavioural impairments later in life is unknown. In this project we propose to answer this problem directly for the first time. We will train mice to perform versions of the same tasks used to study stress-induced behaviour in humans. We will then use computational modelling to understand exactly how the mice are carrying out these tasks. By using this modelling approach, this will allow us to directly relate our work in mice to work in humans.We will then take advantage of the large range of state-of-the-art techniques available in mice to study detailed neuronal circuitry and investigate exactly which hippocampal neurons are affected by early life stress, and exactly how they are altered.Finally, we will use this new knowledge to directly investigate how these alterations in hippocampal neurons result in changes to behaviour. To do this we will use genetics to carry out manipulations that 'fix' the changes to the circuit induced by chronic stress. We can then look to see how 'fixed' mice carry out our behavioural tasks to see if repairing the deficits to the hippocampus can repair problems with behaviour.Overall our aim with this research is to understand exactly what neurons are altered by adolescent stress, and how these alterations result in changes to behaviour. In the future we hope to use this knowledge to develop more specific treatments for these disorders.