Can the Human Brain Repair Itself? – Insights from a new Meta-Analysis

The brain despite being an essential organ in our body has been a mystery for neuroscientists for decades.

Can the brain regenerate itself?

This question has bugged scientists for years and scientists studying neuroscience have divided opinions and have always sparked major controversies.

If the brain can regenerate itself why can’t we harness this property of the brain to treat neurodegenerative disorders like Alzheimer’s?

The presence of Adult Hippocampal Neurogenesis (AHN) has been a center of a keen debate, the appearance of single-cell transcriptomic technologies was initially viewed as a solution to solve this controversy, however, the results yielded from transcriptomic technologies were somewhat conflicting.

A research group from the Netherlands published an analytical study, ‘Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate?‘, on why the results conflict and provided a protocol to solve these issues.

Does AHN exist in Human Brain?

Exploiting the human brain’s regenerative potential in aging or neurological diseases is a particularly appealing alternative to traditional strategies for enhancing or restoring brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders such as Alzheimer’s disease.

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.

Also while identifying specific cell types, single-nucleus RNA sequencing can explore specific gene expression profiles to unravel full the complexity of the cells in the hippocampus.

Previous studies on post-mortem hippocampi suggested the existence of AHN or adult-born neurons, immunohistochemical studies provided evidence for neuronal precursors.

Although recent studies yielded contradicting results, two of the studies identified neural stem cells whereas another study failed to detect any neurogenic populations.

Researchers’ Meta-analysis on Humans Brains Regenerative Potential

Giorgia Tosoni and her team analyzed previously published datasets, and they argued that the fluctuations in results regarding AHN arise from methodological, conceptual, and even biological confounders.

In their meta-analysis, they thoroughly discussed how sample processing and experimental design may affect the definitive presence of rare neural populations.

By re-examining previously published datasets, several unique difficulties were identified that demand special attention and would benefit significantly from an open conversation in the field.

The neurogenic process in adult mice is well understood, and the characteristics of the many cellular populations involved are well understood. 

These are the same chemical and cellular characteristics that have previously been used to identify neurogenic cells in the human brain. 

Nonetheless, due to many evolutionary adaptations, one would expect mouse and human neurogenesis to differ. 

They examined the markers for each neurogenic cell type and the degree of marker overlap between the two species. 

It was found that there was little to no overlap between humans and mice which further suggests that the mouse-derived markers that we have long used may not be appropriate for the human brain^[1].

It was also observed that such studies require adequate statistical power; if regeneration of neuronal cells does happen in the adult human brain, we expect it to be rather rare.

As a result, sufficient cells must be sequenced to detect those sparse, probably neurogenic populations. Additional criteria, such as sample quality, are also significant.

The time between the donor’s death and the downstream processing is crucial because the quality of the tissue and the associated data deteriorates over time.

So what the Brain doing?

When used correctly, these revolutionary technologies provide a once-in-a-lifetime chance to map hippocampus regeneration in the human brain and investigate which cell types and states may be most receptive to therapeutic interventions in aging, neurodegenerative, and neuropsychiatric illnesses.

Accurate reporting is critical for reproducible single-cell transcriptomics studies and analysis. 

Following a re-analysis of past studies using standard computational pipelines and criteria, it was discovered that the apparent debate in the field may be misleading. 

The study proposed by researchers concludes that there may be more that we agree on than previously thought.

References

1. Giorgia Tosoni et al., ‘Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate?’, Neuron, 3 April 2023, “These observations were recently confirmed by snRNA-seq studies in adult macaque and human DG. Wang et al. reported a macaque-specific RGL signature not found in mice, whereas Zhou et al. observed only a minor overlap (15.5%) of orthologous genes shared between mouse and human ImNs.”, https://www.cell.com/neuron/fulltext/S0896-6273(23)00206-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627323002064%3Fshowall%3Dtrue#secsectitle0075[↩]