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

• 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

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会导致成年后的行为发生深刻的差异。例如，青春期的长期压力会损害所谓的灵活行为——改变你针对特定情况采取的行动的能力。这是一个问题，因为这些行为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、抑郁和精神分裂症。这导致几乎 80% 报告存在显着的早期生活压力的年轻人随后被诊断患有其中一种疾病。尽管这种疾病的患病率非常高，但早期生活中的慢性压力究竟如何导致这些行为缺陷尚不清楚。在人类以及小鼠等临床前模型中唯一一致的发现之一是，在长期持续的压力后，例如在青春期长期的社会隔离后，大脑中称为海马体的部分的大小和功能会急剧下降。然而，海马回路的这种巨大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，我们建议首次直接回答这个问题。我们将训练小鼠执行与研究人类压力诱发行为相同的任务。然后，我们将使用计算模型来准确了解小鼠如何执行这些任务。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身上的工作与在人类身上的工作联系起来。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来直接研究海马神经元的这些改变如何导致行为的改变。为此，我们将利用遗传学进行操作，“修复”由慢性压力引起的回路变化。然后，我们可以观察“固定”小鼠如何执行我们的行为任务，看看修复海马体缺陷是否可以修复行为问题。这项研究的总体目标是准确了解青少年压力会改变哪些神经元，以及这些改变如何导致行为改变。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。

项目成果

Heron: A Knowledge Graph editor for intuitive implementation of python based experimental pipelines

Heron：知识图编辑器，用于直观地实现基于 python 的实验管道

• DOI: http://dx.10.7554/elife.91915.1
• 发表时间: 2024
• 作者: Dimitriadis G

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning.

伏隔核多巴胺释放反映了器乐学习期间的贝叶斯推理。

• DOI: http://dx.10.1101/2023.11.10.566306
• 发表时间: 2023
• 期刊: the preprint server for biology
• 作者: Qü AJ

Prefrontal Interneurons: Populations, Pathways, and Plasticity Supporting Typical and Disordered Cognition in Rodent Models

前额叶中间神经元：支持啮齿动物模型中典型和无序认知的群体、通路和可塑性

• DOI: 10.1523/jneurosci.1136-22.2022
• 发表时间: 2022-11-09
• 期刊: The Journal of Neuroscience
• 作者: D. Kupferschmidt;Kirstie A. Cummings;Max E. Joffe;A. MacAskill;Ruchi Malik;C;ela Sánchez;ela;H. Tejeda;Hector Yarur Castillo
• 通讯作者: Hector Yarur Castillo

Genetically distinct parallel projection populations from ventral hippocampus to prefrontal cortex

从腹侧海马到前额皮质的遗传上不同的平行投影群体

• DOI: http://dx.10.1101/2023.02.18.529052
• 发表时间: 2023
• 作者: Sánchez