How has our understanding of neurogenesis in the adult brain changed in the last century?
“Once development was ended, the fonts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centres, the nerve paths are something fixed, and immutable: everything may die, nothing may be regenerated.” Santiago Ramon y Cajal, 1928
This model put forward by Nobel prize winning neuroscientist Ramon y Cajal was the scientific consensus held, that is to say that the concept of new neurons being born after brain development did not happen, the brain does not regenerate, rather, neurons go into apoptosis throughout life and are not replaced. That was of course until the techniques evolved to prove otherwise.
The possibility of neurogenesis, the concept whereby the brain does indeed regenerate neurons, that new neurons are born throughout life facilitating neuroplasticity, was proposed over 30 years after Ramon y Cajal’s influential statement, by Joseph Altman.
Altman injected brain-injured rats with the cell proliferation marker thymidine-H3 which showed labelling of neuroblasts, to which he proposed the likelihood of neurogenesis into adulthood (Altman, 1962). Altman went on to publish subsequent papers highlighting the same results and with a small group of proponents publishing their own studies in support of neurogenesis including Shirley Bayer, J.W Harper, Michael Kaplan and Fernando Nottebohm.
However, this group was not able to gain footing within the scientific community who rejected their findings. A vocal and influential opponent of neurogenesis was Spanish neuroscientist Pasko Rakic. Rakic performed a study on 12 rhesus monkeys in 1985 using radio-labelled thymidine concluding “not a single new neuron was observed in the brain of any adult animal” (Rakic, 1985).
Rakic published subsequent papers essentially yielding the same conclusion that neurogenesis did not occur. Thus, whilst key proponents of neurogenesis persevered in their research, the concept remained controversial, with supporters of the theory very much in the minority until the late 1990s.
Up until that point research had been conducted on animal models and the controversy regarding the existence of neurogenesis was also expounded around whether or not any debatable findings in animals could be extrapolated to humans. Eriksson et al (1998) used post-mortem brain tissue from cancer patients injected with the proliferation marker bromodeoxyuridine (BrdU). BrdU is an analogous of the thymidine used by Altman and colleagues. Building on the work performed in rodents and primates, this study showed the existence of hippocampal neurogenesis in human adults for the first time. Whilst they stated the uncertainty around the implications of neurogenesis in the human brain they rightly acknowledged that possibility of its regulation was worthy of ongoing investigation.
Around the same time, Elizabeth Gould and her group used adult monkeys and BrdU to demonstrate for the first time that neurogenesis took place in the hippocampus, specifically the dentate gyrus (Gould et al., 1999).
These studies seem to be pivotal to the general acceptance of neurogenesis with even the previously oppositional Rakic replicating Gould’s findings in the hippocampus of the adult macaque monkey (Kornack, D.R. & Rakic, P., 1999) and his subsequent studies researching in support of neurogenesis, and specifically hippocampal neurogenesis. Even to this day much of the research into neurogenesis focusses on the hippocampus, with over one third of the papers listed on PubMed for example, featuring adult neurogenesis being specific to adult hippocampal neurogenesis (AHN).
Since then, research largely shifted away from attempting to disprove neurogenesis, to instead moving towards expanding the knowledge of neurogenesis, and as Eriksson et al (1998) stated, investigating its possible implications.
Spalding et al (2013) determined one such implication in their study utilising brain tissues from deceased donors who had been exposed to 14C due to above-ground nuclear bomb testing during 1955-1963. Using this form of carbon-dating, they showed a rate of 700 new hippocampal neurons daily and that the rate of neurogenesis only modestly declines during one’s lifetime. They therefore concluded that neurogenesis must indeed have a functional role in the human brain, and if comparable to neurogenesis studies in mice, then this role may be one involved in cognitive functioning.
However, the controversy around the existence of neurogenesis was by no means over. Sorrells et al (2018) conducted a study using post-mortem brains of patients or samples from patients who had had a portion of their hippocampus surgically removed as treatment for epilepsy. They strongly concluded that AHN into adulthood did not occur and sharply declined after childhood. That same year Boldrini et al (2018) published a paper also utilising human post-mortem hippocampal tissue, strongly concluding the exact opposite, that AHN remained throughout adulthood without sharp decline, persisting even into the eighth decade.
Many authors have since proposed reasons for the outlaying results Sorrells et al (2018) achieved, including Lee, H. & Thuret, S. (2018) who highlight the differences in the methodologies used, with Boldrini et al (2018) using the more advanced ‘stereology’ technique; Sorrells et al (2018) use of tissue from non-healthy donors versus Boldrini et al (2018) use of only healthy donors; and the differences in post-mortem delay, with Sorrells et al (2018) being 20 hours longer. The fixation method used by Sorrells et al (2018) was likely too long, inhibiting the labelling of neuroblasts (Moreno-Jiménez et al, 2019).
These two studies highlight the need for a gold standard in the study of neurogenesis, including around the methodologies, selection criteria, limitations and the use of post-mortem tissue, not least because human brain samples must be utilised with the utmost care, respect and maximation of utility. There are risks involved in setting a gold standard, ensuring that the repeatability issues have been resolved, as this has been an ongoing issue in neuroscience and psychology (Barch & Yarkoni, 2013).
Due to the invasive nature, studying neurogenesis in living humans is currently highly limited, however, controversy exists around the use of animal models and the extrapolation of observed conclusions to human adult neurogenesis. One such example is regarding a well-known location of neurogenesis in the brain – the olfactory bulb. The neurogenic niche of the olfactory bulb is well studied and proven in rodents, and makes sense (pardon the pun) with regards to the importance of smell in a rodent’s survival, socialisation, ability to distinguish between odours and memories of odours (Ming & Song, 2011).
However, the controversy exists in relation to the olfactory bulb niche in humans. A recent study by Bergmann, Spalding & Frisén (2015) using human olfactory bulb neuronal DNA tissue and analysing the 14C levels, showed neurogenesis in this region of the human brain as being virtually non-existent, with mathematical modelling yielding a 1% replacement rate as the upper limit. A possible explanation for the difference between this and the results seen in rodents is that the modern-day human relies a lot less on its sense of smell for survival and socialisation, compared to that of a rodent, therefore it is important neurogenesis occurs here in the rodent’s brain, far more so than for the modern-day human. Human ancestors from hunter-gatherer days may well have had increased neurogenesis in this region.
By the same token, conversely, are there undiscovered niches in the human brain, undiscovered because rodents do not have the need for that particular niche for their survival, therefore have not yet been discovered?
This study was given as an example of a controversy surrounding the transference of animal model results to that of human models, however, it also lends itself as an example of a controversy between researchers of human neurogenesis itself. In stark comparison to results of Bergmann, Spalding & Frisén’s (2015) study, Durante et al (2020) published data with strong evidence of neurogenesis in the olfactory neuroepithelium niche by analysing single-cell RNA sequencing and identified neural stem cell, neural progenitor cell pools and neurons.
As advances in technology and imaging continue to improve allowing for non-invasive methods to study humans, these and other controversaries and questions surrounding human neurogenesis may soon become a moot point. As with almost any area of science, nothing is proven until it is.
Since Altman’s steady and dedicated campaign began in the early 1960’s to overturn the dogma of the day, advances in the study of human neurogenesis have paralleled the advances in technology and available techniques, allowing the progression of knowledge across a range of understandings whether proven or still controversial, from human neurogenic niches; the mechanisms; functionality; inhibiting factors, such as poor nutrition, lack of sleep, cancer treatments (Dias et al, 2014); restorative factors, such as good nutrition including a diet rich in flavonoids (Vauzour et al, 2008), quality sleep, exercise and learning (Zainuddin & Thuret, 2012); regulation and control of neurogenesis including the effect of neuro-inflammation (Borsini et al, 2015) and the relevance of gut microbiota (Leung & Thuret, 2015); and importantly, the interconnected and interrelated factors, implications and role of neurogenesis in human brain health and vitality, from stress and mood (Synder et al, 2011) through to neurodegenerative disease such as Alzheimer’s disease (Moreno-Jiménez et al, 2019) and Parkinson’s Disease (Borsini et al, 2015).
Tools to answer the controversy around the points above are still under development and validation therefore the debate remains. It is future technologies utilising advanced imaging techniques, cell signalling, proteomics and others not yet imagined, to enable investigation of neurogenesis in the living human that hold the key to this incredibly important function, offering crucial insights into the potential causes of mental ill-health, neurodegeneration and therefore clinical applications and individualised treatments.
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