How do we know if our brain is capable of repairing itself?

Summary: A new study examines the regenerative potential of the human brain in aging and neurological disease, which may provide an alternative to conventional strategies for improving or restoring brain function. Recent single-cell transcriptomic studies in the adult human hippocampus have yielded conflicting results, and researchers have found that the design, analysis, and interpretation of these studies in the adult human hippocampus may be confounded by specific issues that require special attention and would greatly benefit from an open discussion in the field.

Source: KNOW

Is our brain capable of regenerating itself? And can we harness this regenerative potential during aging or in neurodegenerative conditions? These questions have generated intense controversy in the field of neuroscience for many years.

A new study from the Netherlands Institute for Neuroscience shows why there are conflicting results and offers a roadmap on how to tackle these issues.

The idea of ​​exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly interesting alternative to conventional strategies for improving or restoring brain functions, especially given the current lack of effective therapeutic strategies in diseases neurodegenerative diseases such as Alzheimer’s disease.

Whether or not the human brain possesses the ability to regenerate has been the focus of fierce scientific debate for many years and recent studies have yielded conflicting results.

A new study by Giorgia Tosoni and Dilara Ayyildiz, under the supervision of Evgenia Salta in the Neurogenesis and Neurodegeneration Laboratory, critically discusses and reanalyzes 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 tagged in the postmortem human brain showed that new cells can indeed appear throughout adulthood in our brain’s hippocampus, a structure that plays a important role in learning and memory, and which 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. Conceptual and methodological confusions likely contributed to these seemingly contradictory observations. Therefore, elucidating the extent of regeneration in the human brain remains a challenge.

New advanced technologies

Recent advances in single-cell transcriptomics technologies have provided valuable insights into the different cell types found in the human brain of 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 the full complexity of hippocampal cells.

The advent of single-cell transcriptomics technologies was initially seen as a panacea to resolve the controversy in the field. However, recent single-cell RNA sequencing studies in the human hippocampus have yielded conflicting results.

Two studies indeed identified neural stem cells, while a third study detected no neurogenic population. Do these new approaches fail – once again – to definitively settle the controversy over the existence of hippocampal regeneration in humans? Will we ultimately be able to overcome the conceptual and technical challenges and reconcile these seemingly opposing views and conclusions?

Technical issues

In this study, researchers critically discussed and reanalyzed previously published single-cell transcriptomic datasets. They warn that the design, analysis and interpretation of these studies in the adult human hippocampus can be confounded by specific problems, which require conceptual, methodological and computational adjustments.

By reanalyzing previously published datasets, a series of specific challenges were probed that require special attention and would greatly benefit from an open discussion in the field.

Giorgia Tosoni: “We analyzed previously published single-cell transcriptomic studies and performed a meta-analysis to determine whether adult neurogenic populations can be reliably identified among different species, particularly when comparing mice and humans.

“The neurogenic process in adult mice is very well characterized and the profiles of the different cell populations involved are known. These are in fact 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 neurogenesis between mice and humans to be different. We checked the markers for each neurogenic cell type and examined the amount of marker overlap between the two species.

“We found very little, if any, overlap between the two, suggesting that the mouse-deduced markers that we have been using for a long time may not be suitable for the human brain. We also found that such studies require sufficient statistical power: if neuronal cell regeneration occurs in the adult human brain, we expect it to be quite rare. Therefore, enough cells should be sequenced to identify these rare, presumably neurogenic populations.

“Other parameters are also important, for example the quality of the samples. The interval between donor death and downstream processing is critical, as the quality of the resulting tissue and data declines over time.

Reproducibility is key

Dilara Ayyildiz: “These new technologies, when applied appropriately, offer a unique opportunity to map hippocampal regeneration in the human brain and explore which cell types and states may be most amenable to therapeutic interventions in aging, neurodegenerative and neuropsychiatric diseases. However, reproducibility and consistency are essential.

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 therefore affect the interpretation of the data.

“Accurate reporting is essential to make these single-cell transcriptomics experiments and their analysis reproducible. Once we reanalyzed these previous studies applying common pipelines and computational criteria, we realized that the apparent controversy in the field can actually be misleading: with our work, we propose that there may in fact be more about what we agree on than previously believed.

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About this neuroscience research news

Author: Press office
Source: KNOW
Contact: Press office – KNAW
Picture: Image is in public domain

Original research: Free access.
“Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: reconciling controversy or fueling debate?” by Giorgia Tosoni et al. Neuron

Abstract

Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: reconciling controversy or fueling debate?

Strong points

• Single-cell profiling of adult hippocampal neurogenesis may offer key insights
• Methodological and conceptual confounders can impact the resulting datasets
• Sample size and stratification, data processing and selection of markers are critical
• Efforts should focus on optimization and public sharing of protocols and pipelines

Summary

The idea of ​​exploiting the regenerative potential of the human brain in physiological aging or neurological diseases represents a particularly interesting alternative to classic strategies for improving or restoring brain functions. However, a first major question to address is whether the human brain has the capacity to regenerate itself.

The existence of human adult hippocampal neurogenesis (AHN) has been the focus of fierce scientific debate for many years. The advent of single-cell transcriptomic technologies was initially seen as a panacea to resolve this controversy. However, recent single-cell RNA sequencing studies in the human hippocampus have yielded conflicting results.

Here, we critically discuss and reanalyze previously published AHN-related single-cell transcriptomic datasets.

We argue that, although promising, single-cell transcriptomic profiling of AHN in the human brain may be confounded by methodological, conceptual, and biological factors that need to be consistently addressed across studies and openly discussed within the community. scientist.