Periodic Reporting for period 4 - FUNCOPLAN (Functions of plasticity in adult-born neurons)
Okres sprawozdawczy: 2021-12-01 do 2022-05-31
The problem addressed by this project was the role played by adult-generated brain cells, or neurons, in information processing in the nervous system. Only a few areas of the brain continue to generate new neurons throughout life, in a process known as adult neurogenesis. But why? Why, when this capacity has been lost in almost all parts of the adult brain, do some areas still produce newborn neurons? One hypothesis is that these adult-generated neurons bring something different to the circuits into which they integrate. In particular, immature neurons tend to be more plastic than their mature counterparts – they are more able to change their properties in response to alterations in the inputs they receive. This project aimed to determine whether this is the case for a particular type of adult-born cells which are involved in processing smell information, and which release the neurotransmitter dopamine. We asked whether these ‘dopaminergic’ adult-born neurons are more plastic when they are immature, and then aimed to determine the influence of any extra plastic capacity on information-processing in their host circuits.
This question is important because it pertains to new cells being added to old brain networks. This is precisely the scenario that occurs in attempts to repair the brain where new brain cells are added to dysfunctional networks. By studying a phenomenon where such cell addition happens naturally, we hope to learn lessons that will be useful when trying to add new neurons to damaged brains.
Our overall objectives were to: 1) Find whether adult-born dopaminergic cells in the olfactory bulb are especially plastic when they are immature; 2) Characterise the effects of any such plasticity on the sensory response properties of adult-born dopaminergic neurons. And 3) Precisely control activity in adult-born dopaminergic cells to understand how their plasticity might change the way that whole networks process sensory information. Are extra-plastic immature adult-born neurons crucial to the way in which the brain detects smells?
Our somewhat surprising conclusion from the action was that immature adult-born dopaminergic neurons were not especially plastic when compared to their mature, pre-existing dopaminergic neighbours. Immature adult-generated cells did, however, display distinct structural and functional properties from mature dopaminergic neurons under baseline conditions. This suggests that at least some types of adult-generated cells may specifically contribute to network function, not by virtue of being especially malleable, but because of features brought by their immaturity as they integrate into resident networks.
This question is important because it pertains to new cells being added to old brain networks. This is precisely the scenario that occurs in attempts to repair the brain where new brain cells are added to dysfunctional networks. By studying a phenomenon where such cell addition happens naturally, we hope to learn lessons that will be useful when trying to add new neurons to damaged brains.
Our overall objectives were to: 1) Find whether adult-born dopaminergic cells in the olfactory bulb are especially plastic when they are immature; 2) Characterise the effects of any such plasticity on the sensory response properties of adult-born dopaminergic neurons. And 3) Precisely control activity in adult-born dopaminergic cells to understand how their plasticity might change the way that whole networks process sensory information. Are extra-plastic immature adult-born neurons crucial to the way in which the brain detects smells?
Our somewhat surprising conclusion from the action was that immature adult-born dopaminergic neurons were not especially plastic when compared to their mature, pre-existing dopaminergic neighbours. Immature adult-generated cells did, however, display distinct structural and functional properties from mature dopaminergic neurons under baseline conditions. This suggests that at least some types of adult-generated cells may specifically contribute to network function, not by virtue of being especially malleable, but because of features brought by their immaturity as they integrate into resident networks.
The action comprised 3 Key Objectives:
Key Objective 1 investigated activity-dependent plasticity in dopaminergic neurons in the olfactory bulb. Work on this Key Objective contributed to a paper showing key baseline structural and functional differences between olfactory bulb dopaminergic neurons born in embryonic development versus those born in adulthood (Galliano et al., eLife 2018 https://doi.org/10.7554/eLife.32373; associated Open Data: http://dx.doi.org/10.5061/dryad.b5hg8d6). A second paper then showed differential capacity for experience-dependent structural and functional plasticity in these dopaminergic sub-types (Galliano et al., Journal of Neuroscience 2021 https://doi.org/10.1523/JNEUROSCI.1606-20.2020; associated Open Data http://doi.org/doi:10.18742/RDM01-757). Core work on this Key Objective was the doctoral project of Candida Tufo, who obtained her PhD in June 2022, contributed to our 2021 paper, and first-authored a high-impact review on olfactory bulb development (Tufo et al., Development 2022 https://doi.org/10.1242/dev.200210). Dr Tufo’s investigation of activity-dependent plasticity in adult-born olfactory bulb dopaminergic neurons found, somewhat surprisingly, that immature adult-generated cells were not more plastic than their older, pre-existing neighbours. They were, however, distinguished by functional differences associated with their immature status. This work is currently being prepared for submission.
Key Objective 2 addressed the olfactory sensory response properties of adult-born olfactory bulb dopaminergic cells. Data collection on this Key Objective ran right up to the termination of the action, and is currently undergoing analysis for submission in 2023.
Key Objective 3 was slightly re-focused given the unexpected results obtained in Key Objective 1, as is entirely appropriate for a basic scientific project of this duration. Remaining fully in line with the overall aims of the action, we established new, state-of-the-art techniques for examining multi-omic plasticity in dopaminergic neurons (Lipovsek et al., Star Protocols 2020 https://doi.org/10.1016/j.xpro.2020.100146; associated Open Data http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151709) found evidence for molecular-level plasticity in this cell type (Byrne et al., European Journal of Neuroscience 2022 https://doi.org/10.1111/ejn.15684; associated Open Data https://doi.org/10.18742/19698187.v1) and are currently analysing, for forthcoming publication, exciting data linking plasticity in gene expression to neuronal function at the single-cell level. This work also contributed to a highly cited publication which - in a great demonstration of how ERC-funded basic research can tackle previously unanticipated translational problems - investigated the potential mechanisms underlying anosmia in COVID-19 (Brann et al., Science Advances 2020 https://doi.org/10.1126/sciadv.abc5801; associated Open Data http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151709). Finally, work on Key Objective 3 also uncovered novel mechanisms by which neuronal circuits – including dopaminergic neurons – can change in response to naturally-occurring regeneration of sensory inputs (Browne et al. bioRxiv 2022 https://doi.org/10.1101/2022.06.09.493421). We have harnessed the regenerative potential of the mammalian olfactory system to discover ways in which newly-grown inputs can re-connect with and drive functional information processing in their target circuits, and this will remain a key focus of our work going forward.
Throughout the action, we have disseminated our findings at the earliest possible opportunity to the widest possible audience. We have presented preliminary work at national and international conferences, and have deposited all manuscripts at first submission in the Open Access preprint server bioRxiv. Our peer-reviewed publications have all been immediate Gold Open Access, and the full raw datasets from our primary research publications have all been published and made publicly available (see links above) as per the Open Data Pilot. We have also taken opportunities to publicise our findings via press releases, interviews, and social media.
Key Objective 1 investigated activity-dependent plasticity in dopaminergic neurons in the olfactory bulb. Work on this Key Objective contributed to a paper showing key baseline structural and functional differences between olfactory bulb dopaminergic neurons born in embryonic development versus those born in adulthood (Galliano et al., eLife 2018 https://doi.org/10.7554/eLife.32373; associated Open Data: http://dx.doi.org/10.5061/dryad.b5hg8d6). A second paper then showed differential capacity for experience-dependent structural and functional plasticity in these dopaminergic sub-types (Galliano et al., Journal of Neuroscience 2021 https://doi.org/10.1523/JNEUROSCI.1606-20.2020; associated Open Data http://doi.org/doi:10.18742/RDM01-757). Core work on this Key Objective was the doctoral project of Candida Tufo, who obtained her PhD in June 2022, contributed to our 2021 paper, and first-authored a high-impact review on olfactory bulb development (Tufo et al., Development 2022 https://doi.org/10.1242/dev.200210). Dr Tufo’s investigation of activity-dependent plasticity in adult-born olfactory bulb dopaminergic neurons found, somewhat surprisingly, that immature adult-generated cells were not more plastic than their older, pre-existing neighbours. They were, however, distinguished by functional differences associated with their immature status. This work is currently being prepared for submission.
Key Objective 2 addressed the olfactory sensory response properties of adult-born olfactory bulb dopaminergic cells. Data collection on this Key Objective ran right up to the termination of the action, and is currently undergoing analysis for submission in 2023.
Key Objective 3 was slightly re-focused given the unexpected results obtained in Key Objective 1, as is entirely appropriate for a basic scientific project of this duration. Remaining fully in line with the overall aims of the action, we established new, state-of-the-art techniques for examining multi-omic plasticity in dopaminergic neurons (Lipovsek et al., Star Protocols 2020 https://doi.org/10.1016/j.xpro.2020.100146; associated Open Data http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151709) found evidence for molecular-level plasticity in this cell type (Byrne et al., European Journal of Neuroscience 2022 https://doi.org/10.1111/ejn.15684; associated Open Data https://doi.org/10.18742/19698187.v1) and are currently analysing, for forthcoming publication, exciting data linking plasticity in gene expression to neuronal function at the single-cell level. This work also contributed to a highly cited publication which - in a great demonstration of how ERC-funded basic research can tackle previously unanticipated translational problems - investigated the potential mechanisms underlying anosmia in COVID-19 (Brann et al., Science Advances 2020 https://doi.org/10.1126/sciadv.abc5801; associated Open Data http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151709). Finally, work on Key Objective 3 also uncovered novel mechanisms by which neuronal circuits – including dopaminergic neurons – can change in response to naturally-occurring regeneration of sensory inputs (Browne et al. bioRxiv 2022 https://doi.org/10.1101/2022.06.09.493421). We have harnessed the regenerative potential of the mammalian olfactory system to discover ways in which newly-grown inputs can re-connect with and drive functional information processing in their target circuits, and this will remain a key focus of our work going forward.
Throughout the action, we have disseminated our findings at the earliest possible opportunity to the widest possible audience. We have presented preliminary work at national and international conferences, and have deposited all manuscripts at first submission in the Open Access preprint server bioRxiv. Our peer-reviewed publications have all been immediate Gold Open Access, and the full raw datasets from our primary research publications have all been published and made publicly available (see links above) as per the Open Data Pilot. We have also taken opportunities to publicise our findings via press releases, interviews, and social media.
This project went beyond the state-of-the-art in its study of plasticity in a single, distinct, and genetically-defined population of adult-born neurons in the mammalian brain. Our outputs, outlined in full above, have gone significantly beyond the state of the art in uncovering multiple aspects of the fundamental function, maturation and plasticity of olfactory bulb dopaminergic cells. We have also used the basic scientific findings of the action to make an important contribution to our understanding of anosmia in COVID-19.