summary: A new study examines the regenerative potential of the human brain in aging and neurological diseases, which could provide an alternative to traditional strategies to enhance or restore brain function. Recent single-cell transcriptional studies in the adult human hippocampus have yielded conflicting results, and the authors find that the design, analysis, and interpretation of these studies in the adult human hippocampus can overlap with specific issues that require special attention and would greatly benefit from an open discussion in the field.
source: Knaw
Is our brain able to regenerate? Can we harness this regenerative capacity during aging or in neurodegenerative conditions? These questions have fueled intense debate in the field of neuroscience for many years.
A new study from the Netherlands Institute of Neuroscience shows why there are conflicting results and suggests a roadmap for how to solve these problems.
The idea of exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly attractive alternative to conventional strategies to enhance or restore brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders such as Alzheimer’s disease.
The question of whether or not the human brain has the ability to regenerate has been at the center of intense scientific debate for many years, and recent studies have yielded conflicting results.
A new study from Giorgia Tosoni and Dilara Ayyildiz, supervised by Evgenia Salta in the Laboratory of Neurogenesis and Neurodegeneration, critically discusses and re-analyzes previously published datasets. How is it possible that we have not yet found a clear answer to this riddle?
Previous studies in which dividing cells were sorted in the human brain postmortem have shown that new cells can indeed arise throughout adulthood in our brain’s hippocampus, a structure that plays an important role in learning and memory and is also heavily affected by Alzheimer’s disease.
However, other studies contradict these findings and cannot detect the generation of new brain cells in this area. Both conceptual and methodological confusions likely contributed to these seemingly opposing observations. Hence, elucidating the extent of regeneration in the human brain remains challenging.
Latest technology
Recent advances in single-cell transcription technologies have provided valuable insights into the different cell types present in human brains from deceased donors suffering from various brain diseases.
To date, single-cell transcription techniques have been used to characterize rare cell populations in the human brain. In addition to identifying specific cell types, mononuclear RNA sequencing can also probe specific gene expression profiles to reveal the complexity of cells in the hippocampus.
The advent of single-cell transcription technologies was initially seen as a panacea to resolve the controversy in this field. However, recent single-cell RNA-sequencing studies in the human hippocampus have yielded conflicting results.
Two studies have already identified neural stem cells, while a third failed to detect any neuronal populations. Have these new methods – again – finally failed to settle the debate about the existence of hippocampal regeneration in humans? Will we finally be able to overcome conceptual and technical challenges and reconcile seemingly opposing viewpoints and outcomes?
Technical problem
In this study, the researchers critically discussed and re-analyzed previously published single-cell transcriptome datasets. They caution that the design, analysis, and interpretation of these studies in the adult human hippocampus can be confused with specific issues that require conceptual, methodological, and computational modifications.
Through re-analysis of previously published datasets, a series of specific challenges that require special attention and would greatly benefit from an open discussion in this field were investigated.
Giorgia Tosoni: ‘We analyzed previously published single-cell transcriptome studies and performed a meta-analysis to assess whether adult neuronal populations could be reliably identified across different species, particularly when comparing mice and humans.
The neuronal process in adult mice is very well characterized, and the features of the different cell groups involved are known. These are in fact the same molecular and cellular signatures that have been used extensively in the field as well to identify neurons in the human brain.
However, due to the many evolutionary adaptations, we would expect neurogenesis between mice and humans to be different. We examined the markers for each type of neuron and examined the amount of overlapping markers between the two types.
We found very little, if any, overlap between the two, suggesting that the mouse-inferred signs we’ve been using for a long time might not be appropriate for the human brain. We also discovered that such studies require sufficient statistical power: if regeneration of neurons occurs in the adult human brain, we would expect it to be very rare. Therefore, enough cells would need to be sequenced in order to identify those rare, presumably neuronal populations.
Other parameters are also important, for example the quality of the samples. The time interval between donor death and definitive processing is critical, because the quality of tissue and resulting data declines over time.
Reproduction is the key
Dilara Ayyildiz: “These new technologies, when applied appropriately, provide 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 key.
While conducting the analysis, we realized that some seemingly small, yet very important details and parameters in the experimental and computational pipeline can have a significant impact on the results, and thus affect the interpretation of the data.
Accurate reporting is essential to making these single-cell transcription experiments and their analyzes reproducible. Once we re-analyzed these previous studies using common computational pipelines and standards, we realized that the apparent controversy in this area might actually be misleading: with our work, we’re suggesting that there may actually be more to agree on than we previously thought.
The summary was generated with the help of ChatGPT AI technology
About this research in Neuroscience News
author: press office
source: Knaw
communication: Press Office – KNAW
picture: The image is in the public domain
Original search: open access.
“Mapping hippocampal neurogenesis in human adults using single-cell transcriptomes: reconciling or fueling controversy?” By Giorgia Tosoni et al. nervous
a summary
Mapping adult hippocampal neurogenesis using single-cell transcriptomes: reconciling or fueling controversy?
Highlights
- Single-cell profiling of neurogenesis in the adult hippocampus can provide key insights
- Methodological and conceptual confusions can affect the resulting datasets
- Sample size, stratification, data processing and selection of markers is 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 attractive alternative to conventional strategies to enhance or restore brain function. However, the first major question that needs to be addressed is whether the human brain has the ability to regenerate.
The existence of neurogenesis in the adult hippocampus has been at the center of intense scientific debate for many years. The advent of single-cell transcription 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 re-analyze previously published AHN-related single-cell transcriptome datasets.
We argue that, although promising, single-cell transcriptional profiling of AHN in the human brain can be confounded by methodological, conceptual, and biological factors that must be consistently addressed across studies and openly discussed within the scientific community.