Controversies that shape scientific progress: Does our brain make new neurons?

By: Aimilia Damaskou

A heated debate

The discussion surrounding the birth of new neurons (neurogenesis) in the adult human brain has been a source of controversy for decades. Although the existence of adult human neurogenesis has been debated since the 90s¹, contradictory evidence from the last six years has brought the topic back into the spotlight, leaving the community further divided. In this article, we will explore the origin of the debate, the publications that sparked the recent controversy, and answer the question: why is this still discussed today?

We can start by examining the potential implications of the existence of adult neurogenesis in humans. The human brain undergoes significant changes as we age. Most notably, it shrinks in size, due to neuronal cell death among other factors². While this is a normal physiological process, it is accelerated in many neurodegenerative disorders (including Alzheimer’s disease)³. Understanding how new neurons are born has provided some hope in potentially slowing or reversing the effects of such disorders. We know from numerous murine studies that decreases in neurogenesis are correlated with epilepsy, stroke, neurodegenerative disorders, and neuropsychiatric conditions, such as depression or stress disorders¹. Neurogenesis is also crucial for memory consolidation, learning flexibility, and even mood regulation⁴. Although the existence of neurogenesis in other adult mammals is widely accepted, and interesting research is being performed on how to increase neurogenesis in rodents, the jury is still out on its existence in adult human brains^5,6,7.

How are neurons born?

To understand the science behind the debate, let us start with the basics. Neurogenesis is defined as the process of de novo generation of neurons from neural stem cells in the central nervous system⁸. Neural stem cells are self-renewing and multipotent cells, meaning they can perform a vast number of divisions and generate a large variety of cell types found in the brain. These cells can divide either symmetrically, producing two cells identical to the original cell, or asymmetrically, producing one cell identical to the original and one specialised cell^8,9. If this specialised cell is a neuronal progenitor cell (NPC), it can differentiate and eventually become a mature neuron (Figure 1). This process happens mainly while an embryo is developing, and it is mostly found in two brain areas in mammals later in life, the so-called neurogenic niches. These niches provide the perfect microenvironment that will give the required signals to an NPC to guide its early differentiation¹⁰.

Setting the stage

With a grasp of the basics, it is time to start from the beginning of the discussion. Before the 1960s, neurogenesis was believed to only take place during embryonic development and in the first years of life. However, subsequent studies performed in rodents and songbirds showed that neurogenesis actually continues throughout life¹¹. These findings were considered controversial at the time, as it was believed that neuronal networks were stable and unchanging throughout life^3,11. Like the father of neuroscience, Ramón y Cajal, famously said: “Everything may die, nothing may be regenerated”¹². It wasn’t until 1998 that evidence supporting adult human neurogenesis first appeared. One notable study reported findings of actively dividing NPCs in postmortem human tissue of cancer patients treated with bromodeoxyuridine (a substance that labels dividing cells)¹³. Another important hallmark in this story came from a 2013 study, where scientists analysed postmortem tissue from individuals exposed to radioactive ¹⁴C—a byproduct of nuclear bomb testing. This radioactive marker integrates into dividing cells and allows the accurate calculation of the age of the cell. The study reported that approximately 700 new neurons are added to each human hippocampus daily¹⁴.

These two studies laid the groundwork for the recently reignited controversy. In 2018, two high-impact papers were published using the same methodology but reporting opposing results. On one hand, the study by Sorrels and colleagues, which used post-mortem and post-operative samples from individuals aged 19-77 years, reported that neurogenesis is extremely rare in the adult human hippocampus¹⁵. The additional use of fetal samples led them to conclude that human neurogenesis decreases rapidly between birth and the first year of life and is almost undetectable in adults. On the other hand, the study performed by Boldrini and colleagues, which also used post-mortem tissue from individuals aged 14-79 years, reported that there were similar levels of neurogenesis across their samples, identifying thousands of newborn neurons¹⁶.

The controversy

The publication of these two studies sparked an intense debate, prompting responses from the authors as well as the publication of numerous opinion papers and reviews within the next couple of years^{17,18,19,20,21}. As we dive into the details, the main technical points can be summarised in 3 categories: marker specificity, sample handling, and sample inclusion criteria.

A large part of the debate surrounds the specificity of the markers used in both of these studies. A combination of immunohistochemistry markers known from murine studies allows the identification of actively proliferating NPCs by fluorescently tagging proteins expressed by neuronal cells at different maturational stages (Figure 2). However, since so little is known about human neurogenesis, it is possible that these markers may not directly translate to the human species¹⁹. Some scientists have argued that these markers might also identify glial cells based on morphology^15,17. Boldrini’s group responded that the interpretation of morphology might be subjective and used another marker specific to neuronal dendrites to prove that the identified cells were not glia¹⁸.

Setting aside this aspect of the debate, the question still stands: why were some groups able to find dividing NPCs and others not, using the same markers? When working with post-mortem tissue, careful fixation and handling are crucial. A key factor is the post-mortem delay (PMD), meaning the time between death and fixation of the brain. Sorrells and colleagues have been criticised because their samples had a larger PMD range compared to Boldrini’s group^19,20. Given that PMD has a large effect on protein degradation, it might have affected the identification of cellular markers^22,23. As a control for PMD effects, Sorrells and colleagues used epilepsy patient samples fixed within an hour and again failed to identify newborn neurons in the adult hippocampal samples. However, other researchers have commented that samples from epilepsy patients can be confounded by factors associated with the disease, and so do not reflect healthy adult neurogenesis^19,21.

Finally, the inclusion criteria of the samples and the medical history of the individuals could be a confounding factor. In their study, Boldrini and colleagues included only samples from subjects with no neuropsychiatric, chronic diseases, or treatment to avoid confounders, whereas the Sorrells study did not address the subjects’ medical history. Neurogenesis and the expression of some markers can be affected by neuropsychiatric conditions that cause inflammation in the brain^19,20,21.

Keeping up with the debate

But what is the state of the debate today? In 2021, two Dual Perspectives companion papers were published in the Journal of Neuroscience by Sorrels and colleagues, and Moreno-Jiménez and colleagues^24,25. Sorrels and colleagues maintain their stance that neurogenesis is extremely rare in the adult human hippocampus attributing discrepancies with other studies to misidentification of proliferating NPCs and protocol differences. They also point out inconsistencies in previous studies in terms of cell morphology and levels of neurogenesis across ages. On the other hand, Moreno-Jimenez and colleagues support that neurogenesis in the hippocampus persists until the 10th decade of life emphasizing the impact of preservation and methodology on sample quality. Finally, Boldrini’s group is currently focusing on how neuropsychiatric diseases affect adult neurogenesis^26,27.

The nature of science

Dissecting one of neuroscience’s most controversial questions displays that science is never black and white. Our opinions on a scientific topic do not solely stem from what the data shows, but from a combination of our interpretation of the data. When considering any scientific topic, we must consider the quality of the evidence provided and remain critical. Contradiction and dialogue can move science forward. In this case, especially, new groundbreaking methods such as single-cell transcriptomics will hopefully provide a clearer picture in the future²⁸. While it is tempting to accept scientific breakthroughs at face value, we need to remember that science is perpetually evolving. What we know now is bound to change.

About the author

Further reading

1. Kumar A, Pareek V, Faiq MA, Ghosh SK, Kumari C. ADULT NEUROGENESIS IN HUMANS: A Review of Basic Concepts, History, Current Research, and Clinical Implications. Innov Clin Neurosci. 2019 May 1;16(5-6):30–7. ↩︎
2. Peters R. Ageing and the brain: This article is part of a series on ageing edited by Professor Chris Bulpitt. Postgrad Med J. 2006 Feb 3;82(964):84–8. ↩︎
3. Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, et al. Brain atrophy in Alzheimer’s Disease and aging. Ageing Res Rev. 2016 Sep;30:25–48. ↩︎
4. Kempermann G. What Is Adult Hippocampal Neurogenesis Good for? Front Neurosci. 2022 Apr 15;16:852680. ↩︎
5. Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry. 2006 Jun 15;59(12):1136–43. ↩︎
6. Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus. 2006;16(3):250–60. ↩︎
7. Gage FH. Adult neurogenesis in mammals. Science. 2019 May 31;364(6443):827–8. ↩︎
8. Paridaen JT, Huttner WB. Neurogenesis during development of the vertebrate central nervous system. EMBO Rep. 3 2014;15:351–64. ↩︎
9. Götz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol. 2005 Oct;6(10):777–88. ↩︎
10. Vukovic J, Blackmore DG, Jhaveri D, Bartlett PF. Activation of neural precursors in the adult neurogenic niches. Neurochem Int. 2011 Sep;59(3):341–6. ↩︎
11. Owji S, Shoja MM. The History of Discovery of Adult Neurogenesis. Clin Anat. 2020 Jan;33(1):41–55. ↩︎
12. Ramón y Cajal S. Cajal’s Degeneration and Regeneration of the Nervous System. Oxford University Press; 1991. 769 p. ↩︎
13. Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nature Medicine 1998 4:11. 11 1998;4:1313–7. ↩︎
14. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of Hippocampal Neurogenesis in Adult Humans. Cell. 6 2013;153:1219–27. ↩︎
15. Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 3 2018;555:377–81. ↩︎
16. Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell. 4 2018;22:589–99.e5. ↩︎
17. Paredes MF, Sorrells SF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Does Adult Neurogenesis Persist in the Human Hippocampus? [Internet]. Vol. 23, Cell Stem Cell. Cell Press; 12 2018. p. 780–1. Available from: http://dx.doi.org/10.1016/j.stem.2018.11.006 ↩︎
18. Tartt AN, Fulmore CA, Liu Y, Rosoklija GB, Dwork AJ, Arango V, et al. Considerations for Assessing the Extent of Hippocampal Neurogenesis in the Adult and Aging Human Brain. Cell Stem Cell. 12 2018;23:782–3. ↩︎
19. Kempermann G, Gage FH, Aigner L, Song H, Curtis MA, Thuret S, et al. Human Adult Neurogenesis: Evidence and Remaining Questions [Internet]. Vol. 23, Cell Stem Cell. Cell Press; 7 2018. p. 25–30. Available from: http://dx.doi.org/10.1016/j.stem.2018.04.004 ↩︎
20. Lucassen PJ, Toni N, Kempermann G, Frisen J, Gage FH, Swaab DF. Limits to human neurogenesis—really? Mol Psychiatry. 1 2019;25:2207–9. ↩︎
21. Lucassen PJ, Fitzsimons CP, Salta E, Maletic-Savatic M. Adult neurogenesis, human after all (again): Classic, optimized, and future approaches. Behav Brain Res. 3 2020;381:112458. ↩︎
22. Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006 Oct;24(1):1–14. ↩︎
23. Gonzalez-Riano C, Tapia-González S, García A, Muñoz A, DeFelipe J, Barbas C. Metabolomics and neuroanatomical evaluation of post-mortem changes in the hippocampus [Internet]. Vol. 222, Brain Structure & Function. Springer; 8 2017. p. 2831. Available from: http://dx.doi.org/10.1007/S00429-017-1375-5 ↩︎
24. Sorrells SF, Paredes MF, Zhang Z, Kang G, Pastor-Alonso O, Biagiotti S, et al. Positive Controls in Adults and Children Support That Very Few, If Any, New Neurons Are Born in the Adult Human Hippocampus. Journal of Neuroscience. 3 2021;41:2554–65. ↩︎
25. Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. Evidences for Adult Hippocampal Neurogenesis in Humans [Internet]. Vol. 41, Journal of Neuroscience. Society for Neuroscience; 3 2021. p. 2541–53. Available from: http://dx.doi.org/10.1523/JNEUROSCI.0675-20.2020 ↩︎
26. Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M. Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry. 2022 Jun;27(6):2689–99. ↩︎
27. Tartt A, Galfalvy H, Dwork A, Rosoklija G, Fulmore C, Carazo Arias E, et al. Blunted neurogenesis in major depression and normal levels in high functioning antidepressant-treated subjects. SSRN Electron J [Internet]. 2021; Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3770098 ↩︎
28. Giorgia Tosoni, Dilara Ayyildiz, Julien Bryois, Macnair W, Fitzsimons CP, Lucassen PJ, et al. Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate? Neuron (Cambridge, Mass). 2023 Jun 1;111(11):1714-1731.e3. ↩︎

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