MSGID: 1:317/3 642ba7eb   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    How do we know if our brain is capable of repairing itself?    
      
     Date:   
         April 3, 2023   
     Source:   
         Netherlands Institute for Neuroscience - KNAW   
     Summary:   
         Is our brain able to regenerate? And can we harness this   
         regenerative potential during aging or in neurodegenerative   
         conditions? These questions sparked intense controversy within   
         the field of neuroscience for many years. A new study shows why   
         there are conflicting results and proposes a roadmap on how to   
         solve these issues.   
      
      
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   FULL STORY   
   ==========================================================================   
   Is our brain able to regenerate? And can we harness this regenerative   
   potential during aging or in neurodegenerative conditions? These questions   
   sparked intense controversy within the field of neuroscience for many   
   years. A new study from the Netherlands Institute for Neuroscience shows   
   why there are conflicting results and proposes a roadmap on how to solve   
   these issues.   
      
      
   ==========================================================================   
   The notion of exploiting the regenerative potential of the human brain   
   in aging or neurological diseases represents a particularly attractive   
   alternative to conventional strategies for enhancing or restoring brain   
   function, especially given the current lack of effective therapeutic   
   strategies in neurodegenerative disorders like Alzheimer's disease. The   
   question of whether the human brain does possess the ability to   
   regenerate or not has been at the center of a fierce scientific debate   
   for many years and recent studies yielded conflicting results. A new   
   study from Giorgia Tosoni and Dilara Ayyildiz, under the supervision of   
   Evgenia Salta in the laboratory of Neurogenesis and Neurodegeneration,   
   critically discusses and re-analyzes previously published datasets. How   
   is it possible that we haven't yet found a clear answer to this mystery?   
   Previous studies in which dividing cells were labeled in postmortem human   
   brain, showed that new cells can indeed arise throughout adulthood in   
   the hippocampus of our brain, a structure that plays an important role   
   in learning and memory, and is also severely affected in Alzheimer's   
   disease. However, other studies contradict these results and cannot   
   detect the generation of new brain cells in this area. Both conceptual   
   and methodological confounders have likely contributed to these seemingly   
   opposing observations. Hence, elucidating the extent of regeneration in   
   the human brain remains a challenge.   
      
   New state-of-the-art technologies Recent advances in single-cell   
   transcriptomics technologies have provided valuable insights into   
   the different cell types found in human brains from deceased donors   
   with different brain diseases. To date, single-cell transcriptomic   
   technologies have been used to characterize rare cell populations   
   in the human brain. In addition to identifying specific cell types,   
   single-nucleus RNA sequencing can also explore specific gene expression   
   profiles to unravel full the complexity of the cells in the hippocampus.   
      
   The advent of single-cell transcriptomics technologies was initially   
   viewed as a panacea to resolving the controversy in the field. However,   
   recent single- cell RNA sequencing studies in human hippocampus yielded   
   conflicting results.   
      
   Two studies indeed identified neural stem cells, while a third study   
   failed to detect any neurogenic populations. Are these novel approaches --   
   once again - - failing to finally settle the controversy regarding the   
   existence of hippocampal regeneration in humans? Will we eventually be   
   able to overcome the conceptual and technical challenges and reconcile   
   these -seemingly- opposing views and findings?  Technical issues In this   
   study, the researchers critically discussed and re-analyzed previously   
   published single-cell transcriptomics datasets. They caution that   
   the design, analysis and interpretation of these studies in the adult   
   human hippocampus can be confounded by specific issues, which ask for   
   conceptual, methodological and computational adjustments. By re-analyzing   
   previously published datasets, a series of specific challenges were   
   probed that require particular attention and would greatly profit from   
   an open discussion in the field.   
      
   Giorgia Tosoni: 'We analyzed previously published single-cell   
   transcriptomic studies and performed a meta-analysis to assess whether   
   adult neurogenic populations can reliably be identified across different   
   species, especially when comparing mice and humans. The neurogenic   
   process in adult mice is very well characterized and the profiles of the   
   different cellular populations involved are known. These are actually   
   the same molecular and cellular signatures that have been widely used in   
   the field to also identify neurogenic cells in the human brain. However,   
   due to several evolutionary adaptations, we would expect the neurogenesis   
   between mice and humans to be different. We checked the markers for every   
   neurogenic cell type and looked at the amount of marker overlap between   
   the two species.'  'We found very little, if no, overlap between the two,   
   which suggests that the mouse-inferred markers we have been long using   
   may not be suitable for the human brain. We also discovered that such   
   studies require enough statistical power: if regeneration of neuronal   
   cells does happen in the adult human brain, we expect it to be quite   
   rare. Therefore, enough cells would need to be sequenced in order to   
   identify those scarce, presumably neurogenic populations.   
      
   Other parameters are also important, for example the quality of the   
   samples.   
      
   The interval between the death of the donor and the downstream   
   processing is critical, since the quality of the tissue and of the   
   resulting data drops over time.'  Reproducibility is key Dilara   
   Ayyildiz: 'These novel technologies, when appropriately applied,   
   offer a unique opportunity to map hippocampal regeneration in the   
   human brain and explore which cell types and states may be possibly   
   most amenable to therapeutic interventions in aging, neurodegenerative   
   and neuropsychiatric diseases. However, reproducibility and consistency   
   are key. While doing the analysis we realized that some seemingly small,   
   but otherwise very critical details and parameters in the experimental   
   and computational pipeline, can have a big impact on the results, and   
   hence affect the interpretation of the data.'  'Accurate reporting is   
   essential for making these single-cell transcriptomics experiments and   
   their analysis reproducible. Once we re-analyzed these previous studies   
   applying common computational pipelines and criteria, we realized that   
   the apparent controversy in the field may in reality be misleading:   
   with our work we propose that there may actually be more that we agree   
   on than previously believed.'   
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   ==========================================================================   
   Story Source: Materials provided by   
   Netherlands_Institute_for_Neuroscience_-_KNAW. Note: Content may be   
   edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Giorgia Tosoni, Dilara Ayyildiz, Julien Bryois, Will Macnair,   
      Carlos P.   
      
         Fitzsimons, Paul J. Lucassen, Evgenia Salta. Mapping human   
         adult hippocampal neurogenesis with single-cell transcriptomics:   
         Reconciling controversy or fueling the debate? Neuron, 2023; DOI:   
         10.1016/ j.neuron.2023.03.010   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/04/230403133506.htm   
      
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