Enhancing induced neurogenesis in the damaged mouse cerebral cortex by activation of local microcircuits

通过激活局部微电路增强受损小鼠大脑皮层的诱导神经发生

• 批准号: 357058359
• 负责人: Professor Dr. Benedikt Berninger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/357058359?language=en
• 关键词: Enhancing; induced; neurogenesis; damaged; mouse

During the last decade we and others have demonstrated the feasibility of converting parenchymal glia into induced neurons in brain regions devoid of canonical adult neurogenesis via direct lineage reprogramming. We recently discovered that cortical damage faciliates the conversion of glia into neurons upon forced expression of the neurogenic transcription factors Sox2 and Ascl1. Yet, unknown mechanisms prevent the maturation of these induced neurons towards complete functionality and proper network integration. The laboratory of Dr. Schinder has recently shown that functional integration of newly generated neurons in a canonical neurogenic niche of the adult brain such as the dentate gyrus of the hippocampus is greatly facilitated by electrical activity of the host microcircuits. This project combines the findings and expertise of both groups with the aim of investigating the effects of electrical activity on the development and integration of induced neurons in the damaged adult cerebral cortex and thereby optimizing strategies for future brain repair. Here we hypothesize that the maturation and functional integration of neurons derived from lineage reprogrammed glia follows a similar logic as that of endogenously generated neurons, and that therefore electrical activity will play a pivotal role in promoting their morphofunctional development and ultimately appropriate connectivity into the pre-existing network. To this end, we will utilize state-of-the-art technologies for manipulating in vivo the activity of local cortical microcircuits. We will combine different viral vector systems (retroviruses, adenoassociated viruses, rabies virus) and genetically modified mice with opto- and chemogenetics in vivo and ex vivo. This will allow us to manipulate selectively specific circuit components within the cerebral cortex, such as pyramidal neurons versus parvalbumin-positive interneurons, and to study the resulting anatomical and functional properties of induced neurons. Although initially each laboratory will contribute different experimental approaches and exertise, the proposed project will emphasize the exchange of know-how to allow for training of human resources to equalize the capacities of both groups.

在过去的十年里，我们和其他人已经证明了通过直接谱系重新编程在缺乏典型成人神经发生的脑区将实质胶质细胞转化为诱导神经元的可行性。我们最近发现，在神经源性转录因子Sox2和Ascl1被迫表达的情况下，皮质损伤有助于神经胶质细胞向神经元的转化。然而，未知的机制阻碍了这些诱导神经元的成熟，使其走向完整的功能和适当的网络整合。Schinder博士的实验室最近表明，宿主微电路的电活动极大地促进了成年大脑中典型的神经源性利基区域(如海马齿状回)中新生成神经元的功能整合。该项目结合了两个小组的发现和专业知识，旨在研究电活动对受损成人大脑皮层诱导神经元的发育和整合的影响，从而优化未来大脑修复的策略。在这里，我们假设从谱系重新编程的胶质细胞衍生的神经元的成熟和功能整合遵循与内源性产生的神经元相似的逻辑，因此电活动将在促进它们的形态功能发育和最终适当地连接到预先存在的网络中发挥关键作用。为此，我们将利用最先进的技术在体内操纵局部皮质微电路的活动。我们将把不同的病毒载体系统(逆转录病毒、腺相关病毒、狂犬病病毒)和转基因小鼠与体内和体外的光和化学遗传学结合起来。这将使我们能够有选择地操纵大脑皮层内特定的电路组件，如锥体神经元和小白蛋白阳性中间神经元，并研究由此产生的诱导神经元的解剖和功能特性。虽然最初每个实验室将贡献不同的实验方法和努力，但拟议的项目将强调交流知识，以便对人力资源进行培训，以使两组的能力相等。