Periodic Reporting for period 4 - Neurogenesis (Exploration and promotion of neurogenesis in the adult brain) Reporting period: 2021-04-01 to 2022-03-31 Summary of the context and overall objectives of the project The vast majority of nerve cells in the human brain are generated during fetal development, and it is only in very restricted areas of the brain where neurogenesis continues after birth and throughout life. The current project aims to characterize neurogenesis in the adult brain in health and disease. We furthermore address whether there is a latent neurogenic potential in other parts of the brain, mainly by studies in mice, which potentially could be used to induce the replacement of neurons in neurological diseases. There are many diseases that result in the loss of neurons and neurological impairment, for example stroke and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. There is today limited possibilities to treat these diseases and they often cause a high degree of functional impairment and much suffering These conditions mainly affect the elderly, and with an increasing proportion of the population in EU being of high age, this will be an increasing problem not only for the the afflicted individuals and their families, but also for society in terms of costs for care. It is very important to find better treatments for conditions in which neurons are lost, and the overall objective of the project is to contribute knowledge that will facilitate the development of such new treatments. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far It is possible to induce generation of neurons in the striatum in mice, a part of the brain where this normally does not occur in this species. This can serve as a model for how neurogenesis can be triggered in the adult brain. We have in this project made a detail characterization of how astrocytes, a type of supporting cells in the brain, can be triggered to start producing neurons. We have found that these cells can enter a neural stem cell-like state, which then enables them to generate neurons. Astrocytes are present throughout the brain, but it is almost only astrocytes in the striatum than can be induced to give rise to neurons. We have compared astrocytes in the striatum and somatosensory cortex, a part of the brain that is responsible for controlling our movements of our body. We have found that astrocytes also in this part of the brain can give rise to immature neurons if additional signals are provided. We have characterised the molecular signals that allow astrocytes to generate neurons. Neurogenesis by astrocytes can be triggered by reducing signalling by the Notch pathway. We successfully demonstrated that this knowledge can be translated to promote replacement of neurons lost to stroke (or injury) by blocking Notch signalling in mice. A major technological achievement was the development of a strategy to uniquely label large numbers of individual neural stem/progenitor cells with expressed molecular barcodes, which allowed tracing clonal relationships between cells.The results from these studies have been published in scientific journals and reported at conferences. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) There were several findings during the course of the project that were unanticipated, most importantly:- Wheareas we and others previously had shown that astrocytes could give rise to neurons under certain conditions, it was not known whether this was the result of direct transdifferentiation of astrocytes to neurons, or whether the astrocytes gained stem cell properties. We found that the latter was true. This is quite remarkable and important as it demonstrates that there is a large reservoir of latent neural stem cells in the adult brain.- At the onset of this project, we thought that the potential of astrocytes to generate neurons was restricted to the striatum, but we found that this is possible also in the cerebral cortex, when additional stimuli were added. This further expands the reservoir of latent neural stem cells available for possible therapeutic interventions.- We identified a molecular pathway, the Notch signaling pathway, that regulates the transformation of astrocytes to neural stem cells and their initiation of neurogenesis. We demonstrated in an experimental model in mice that promote the replacement of lost neurons by inhibiting the Notch signaling pathway, as a proof of principle of a new paradigm for replacing lost neurons in neurological disease. Related documents Neurogenesis.png
