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

人脑是一个高度复杂的系统，由相互连接的数十亿个神经元组成，形成功能神经电路。正常的大脑功能依赖于神经元之间的有效沟通，这一过程需要在电路中建立突触。几种影响大脑的疾病是由神经元之间的通信障碍引起的，这就是为什么理解神经电路是如何建立的以及电路可塑性背后的机制是至关重要的。我们特别感兴趣的是了解如何加强神经回路的再生，以恢复脑损伤后的连接和功能。具体地说，我们的目标是检验这一假设，即存活神经元的活动可以诱导电路内轴突和突触的再生，以克服损伤造成的功能缺陷。我们以前已经证明，某些皮质神经元群体比其他群体表现出更强的自发再生能力，现在我们有兴趣了解导致不同神经元群体对损伤的这种不同反应的细胞和分子机制。这些知识将帮助我们确定未来治疗干预的目标。随着发展增强损伤后功能再生的策略的前景，我们还将通过直接刺激回路中的神经元来操纵神经活动。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，允许操纵神经活动并可视化实验室动物活着的大脑中的神经元。因此，这项研究计划的最终目的是对调节皮质神经回路再生的细胞和分子机制获得新的基本见解，希望这些知识在未来将转化为促进脑损伤后神经可塑性和功能恢复的新方法。

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.