The Role of Neural Activity in Enhancing Axon and Presynaptic Regeneration in the Adult Injured Neocortex In Vivo

神经活动在增强成人损伤新皮质体内轴突和突触前再生中的作用

• 批准号: MR/P006434/1
• 负责人: Vincenzo De Paola
• 金额: $ 65.33万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP006434%2F1
• 关键词: Role; Neural; Activity; Enhancing; Axon

The human brain is a highly complex system comprised of billions of neurons interconnected to each other to form functional neural circuits. Normal brain function is dependent on effective communication between neurons, a process that requires the establishment of synapses within the circuit. Several diseases that affect the brain result from impairments in the communication between neurons, which is why it is essential to understand how neural circuits are established and the mechanisms underlying circuit plasticity. We are particularly interested in understanding how the regeneration of neural circuits can be enhanced to restore connectivity and function after a brain lesion. Specifically, we aim to test the hypothesis that the activity of surviving neurons can elicit the regeneration of axons and synapses within the circuits, in order to overcome the functional deficits that result from an injury. We have previously demonstrated that certain populations of cortical neurons exhibit enhanced spontaneous regenerative capacity in comparison to others, and we are now interested in understanding the cellular and molecular mechanisms responsible for this differential response to injury between diverse neuronal populations. This knowledge will help us identify targets for future therapeutic interventions. With the prospect of developing strategies to enhance functional regeneration after injury, we will also manipulate neural activity by directly stimulating neurons within a circuit. Different stimulation protocols will be employed, in order to identify the parameters that are most effective in restoring structural and functional recovery. We will take advantage of powerful genetic, imaging and stimulation tools that allow manipulating neural activity and visualizing neurons in the living brain of laboratory animals. The ultimate aim of this research proposal is therefore to gain new and fundamental insights into the cellular and molecular mechanisms that regulate the regeneration of cortical neural circuits, in the hope that this knowledge will, in the future, translate into new ways to promote neural plasticity and functional recovery after brain injury.

人类大脑是一个高度复杂的系统，由数十亿个相互连接的神经元组成，形成功能性神经回路。正常的大脑功能依赖于神经元之间的有效通信，这一过程需要在回路内建立突触。影响大脑的几种疾病是由神经元之间的通信障碍引起的，这就是为什么必须了解神经回路是如何建立的以及回路可塑性的机制。我们特别感兴趣的是了解如何增强神经回路的再生，以恢复大脑损伤后的连接和功能。具体来说，我们的目标是测试的假设，即存活的神经元的活动可以引起再生的轴突和突触内的电路，以克服功能缺陷，造成的伤害。我们以前已经证明，某些群体的皮质神经元表现出增强的自发再生能力相比，其他人，我们现在有兴趣了解的细胞和分子机制，负责不同的神经元群体之间的这种差异反应损伤。这些知识将帮助我们确定未来治疗干预的目标。随着前景的发展战略，以加强功能性再生损伤后，我们也将操纵神经活动，直接刺激神经元内的电路。将采用不同的刺激方案，以确定在恢复结构和功能恢复方面最有效的参数。我们将利用强大的遗传，成像和刺激工具，允许操纵神经活动和可视化实验室动物的活脑神经元。因此，这项研究提案的最终目的是获得对调节皮层神经回路再生的细胞和分子机制的新的基本见解，希望这些知识在未来能够转化为促进脑损伤后神经可塑性和功能恢复的新方法。

项目成果

Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex

• DOI: 10.1101/391425
• 发表时间: 2018-08
• 期刊: bioRxiv
• 作者: A. Canty;J. Jackson;L. Huang;A. Trabalza;C. Bass;G. Little;V. De Paola

Cohesin-dependence of neuronal gene expression relates to chromatin loop length.

• DOI: 10.7554/elife.76539
• 发表时间: 2022-04-26
• 期刊: eLife
• 影响因子: 7.7
• 作者: Calderon L;Weiss FD;Beagan JA;Oliveira MS;Georgieva R;Wang YF;Carroll TS;Dharmalingam G;Gong W;Tossell K;de Paola V;Whilding C;Ungless MA;Fisher AG;Phillips-Cremins JE;Merkenschlager M
• 通讯作者: Merkenschlager M

In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration.

• DOI: 10.1186/s12915-020-00869-2
• 发表时间: 2020-11-18
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Canty AJ;Jackson JS;Huang L;Trabalza A;Bass C;Little G;Tortora M;Khan S;De Paola V
• 通讯作者: De Paola V