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

腹侧海马对行为灵活性的控制及其因青少年社会孤立而受到的破坏

基本信息

批准号：
MR/W02005X/1
负责人：
Andrew MacAskill
金额：
$ 74.69万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW02005X%2F1
关键词：
Ventral hippocampal control behavioural flexibility

项目摘要

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.

青春期的长期压力可能导致成年后行为的深刻差异。例如，青春期的长期压力会损害所谓的灵活行为-改变你对特定情况的反应的能力。这是一个问题，因为这些行为的变化被认为会增加对几乎所有最常见的心理健康疾病的易感性，如成瘾，抑郁症和精神分裂症。这导致近80%的年轻人报告了显着的早期生活压力，随后被诊断为这些疾病之一。尽管这种显着的患病率，究竟如何慢性压力在生命早期导致这些行为缺陷还没有得到很好的理解。在人类和临床前模型（如小鼠）中唯一一致的发现之一是，大脑中称为海马体的一部分在长期压力后，例如在青春期长时间的社会隔离后，其大小和功能显着减少。然而，海马电路的这种戏剧性变化如何以及是否会在以后的生活中导致这些行为障碍尚不清楚。在这个项目中，我们首次直接回答这个问题。我们将训练小鼠执行用于研究人类压力诱导行为的相同任务。然后，我们将使用计算建模来准确了解小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小鼠中的工作与在人类中的工作联系起来。然后，我们将利用小鼠中可用的大量最先进的技术来研究详细的神经元回路，并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如何导致行为的改变。为了做到这一点，我们将使用遗传学来进行操作，“修复”由慢性压力引起的电路变化。然后，我们可以观察“固定”小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了解青少年压力改变了哪些神经元，以及这些改变如何导致行为改变。在未来，我们希望利用这些知识来开发更具体的治疗这些疾病。