权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Complement C3aR in adolescent synaptic pruning and risk for anxiety

补充 C3aR 在青少年突触修剪和焦虑风险中的作用

基本信息

批准号：
MR/W004607/1
负责人：
Laura Westacott
金额：
$ 27.65万
依托单位：
CARDIFF UNIVERSITY
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW004607%2F1
关键词：
Complement C3aR adolescent synaptic pruning

项目摘要

Anxiety disorders represent some of the most common and increasing health problems worldwide. Because their causes are poorly understood, current treatments are of limited benefit in a significant proportion of cases and thus there is an urgent need for more effective, targeted therapies. Anxiety disorders typically emerge during the teenage years and affected adolescents are at increased risk for other mental health disorders later in life. During adolescence, the brain undergoes significant changes in its structure and function brought about via a process known as 'synaptic pruning'. This process ensures that synapses (the connections between brain cells) that are infrequently used are eliminated or 'pruned', allowing the remaining connections to mature. We now know that the immune system, and in particular a branch known as complement (https://www.youtube.com/watch?v=BSypUV6QUNw&feature=emb_title) is critical to this process. Complement drives synaptic pruning by tagging weak synapses, which are then engulfed or 'phagocytosed' by microglia, the brain's immune cells. This process is essential for healthy brain function but there is potential for neuronal networks to be disturbed should the process go awry, which may contribute to the development of mental disorders. In this work we will investigate how a molecule known as the C3a receptor (C3aR), a member of the complement system, controls synaptic pruning during adolescence to influence the development of anxiety. Previously, we have found a novel role for C3aR in anxiety, whereby mice deficient in this receptor display increased anxiety. In addition, these mice have a reduced number of synapses throughout the brain. When their microglia were tested in the lab, these cells engulfed more synaptic proteins. This suggests that C3aR controls microglial phagocytosis, and we predict that reduced C3aR function leads to excessive synaptic pruning during adolescence leading to synapse loss and elevated anxiety.However, there are critical gaps in our knowledge which we must first address before we can test this prediction. So far, animal studies have measured complement driven synaptic pruning only during very early stages of brain development, roughly equivalent to human infancy, but there has been much less focus on adolescent brain development. Importantly, there is no existing information on adolescent synaptic pruning within brain areas implicated in anxiety such as the amygdala and hippocampus, which do not mature until adolescence. In this project, we will characterise the precise timing of synaptic pruning in these brain areas during adolescence, by documenting the evolving state of complement, synapse number and microglial engulfment over this period. We will then be able to test our prediction that reduced C3aR results in greater synapse engulfment in brain areas related to anxiety. Finally, the long-term effects of excessive synaptic pruning have not been well characterised but are likely to result in altered brain circuits and therefore abnormal functioning of brain networks. To this end, we will investigate the brain-wide effects of excessive synaptic pruning in C3aR-deficient mice at both adolescence and adulthood using clinically relevant brain imaging measures of brain structure and function. These studies will deliver much-needed information on the neurobiological mechanisms of anxiety, providing insight into how complement and synaptic pruning impact anxiety-associated brain areas during adolescence. Importantly, the data generated will be essential to inform our future work in which we aim to reduce excessive microglial synaptic pruning in C3aR-deficient mice to determine whether it prevents abnormal anxiety from developing. If so, drugs that enhance C3aR function could provide a novel means of treating anxiety and disorders associated with abnormal synaptic pruning.

焦虑症是世界范围内最常见和日益严重的健康问题之一。由于其原因知之甚少，目前的治疗方法在很大一部分病例中获益有限，因此迫切需要更有效的靶向治疗。焦虑症通常出现在青少年时期，受影响的青少年在以后的生活中患其他心理健康疾病的风险增加。在青春期，大脑的结构和功能会发生重大变化，这是通过一个被称为“突触修剪”的过程实现的。这个过程确保不经常使用的突触（脑细胞之间的连接）被消除或“修剪”，使剩余的连接成熟。我们现在知道免疫系统，特别是称为补体的分支（www.youtube.com/watch? v=BSypUV6QUNw&feature=emb_title）对于此过程至关重要。补体通过标记弱突触来驱动突触修剪，然后被大脑的免疫细胞小胶质细胞吞噬或“吞噬”。这一过程对健康的大脑功能至关重要，但如果这一过程出错，神经网络可能会受到干扰，这可能会导致精神障碍的发展。在这项工作中，我们将研究一种被称为C3a受体（C3aR）的分子，补体系统的一员，如何在青春期控制突触修剪，以影响焦虑的发展。此前，我们已经发现了C3aR在焦虑中的新作用，即缺乏这种受体的小鼠表现出焦虑增加。此外，这些小鼠在整个大脑中的突触数量减少。当他们的小胶质细胞在实验室中进行测试时，这些细胞吞噬了更多的突触蛋白。这表明，C3aR控制小胶质细胞的吞噬作用，我们预测，减少C3aR功能会导致过度突触修剪在青春期导致突触丢失和加剧anxiation.However，有关键的差距，在我们的知识，我们必须首先解决之前，我们可以测试这一预测。到目前为止，动物研究仅在大脑发育的早期阶段（大致相当于人类婴儿期）测量了补体驱动的突触修剪，但对青少年大脑发育的关注要少得多。重要的是，目前还没有关于青少年大脑中与焦虑有关的区域（如杏仁核和海马体）突触修剪的现有信息，这些区域直到青春期才成熟。在这个项目中，我们将通过记录这一时期补体、突触数量和小胶质细胞吞噬的演变状态，描述青春期这些大脑区域突触修剪的精确时间。然后，我们将能够测试我们的预测，即减少C3aR导致与焦虑相关的大脑区域的突触吞噬。最后，过度突触修剪的长期影响还没有得到很好的表征，但很可能会导致大脑回路的改变，从而导致大脑网络的功能异常。为此，我们将研究过度突触修剪在C3aR缺陷小鼠在青春期和成年期的脑结构和功能的临床相关的脑成像措施的影响。这些研究将提供关于焦虑的神经生物学机制的急需信息，深入了解补体和突触修剪如何影响青春期焦虑相关的大脑区域。重要的是，所产生的数据对于我们未来的工作至关重要，我们的目标是减少C3aR缺陷小鼠中过度的小胶质细胞突触修剪，以确定它是否可以防止异常焦虑的发展。如果是这样的话，增强C3aR功能的药物可以提供一种治疗焦虑和与异常突触修剪相关的疾病的新方法。