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，由数十亿个神经元相互连接，形成功能性的神经回路。正常的大脑功能依赖于神经元之间的有效交流，这一过程需要在神经回路中建立突触。一些影响大脑的疾病是由于神经元之间的交流受损造成的，这就是为什么理解神经回路是如何建立的以及回路可塑性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通性和功能。具体来说，我们的目标是验证存活神经元的活动可以引起神经回路内轴突和突触的再生，以克服损伤导致的功能缺陷的假设。我们之前已经证明，与其他神经元相比，某些皮质神经元群体表现出更强的自发再生能力，我们现在感兴趣的是了解不同神经元群体之间对损伤的差异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。为了开发增强损伤后功能再生的策略，我们还将通过直接刺激回路内的神经元来操纵神经活动。为了确定在结构和功能恢复方面最有效的参数，将采用不同的增产方案。我们将利用强大的遗传、成像和刺激工具来操纵神经活动，并在实验动物的活体大脑中可视化神经元。因此，本研究计划的最终目的是对调节皮层神经回路再生的细胞和分子机制获得新的和基本的见解，希望这些知识将在未来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.