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

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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.