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Explosive research reveals the dynamics of adult human neurogenesis

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Original paper “Dynamics of Hippocampal Neurogenesis in Adult Humans” from Cell by Spalding et al.

In the last two decades the central dogma which dictated that no new neurons are born in the adult brain has been refuted, and the mammalian subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of the hippocampal dentate gyrus are now recognised sites of adult neurogenesis.   Newborn neurons from the SVZ migrate to the olfactory bulb to provide new granule cell neurons throughout life and adult-born hippocampal neurons are implicated in pattern separation (the ability to form and use memories arising from similar stimuli) and memory formation.   Yet while some evidence exists for this capacity in adult humans, the dynamics and functional contribution of these newly generated cells to brain function still elicits strong scientific debate.   An innovative technique1 developed by Kirsty Spalding and Jonas Frisen at the Karolinska Institute in Stockholm, Sweden, which utilises the radioactive carbon 14 isotope (14C) curve created by the dramatic increase in atmospheric 14C levels following above-ground nuclear bomb testing during the Cold War and subsequent decline following the Partial Nuclear Test Ban Treaty in 1963, has now been used to examine the cell turnover dynamics of the adult human hippocampus.2   Their method takes advantage of the fact that new cells incorporate 14C into their genomic DNA at a concentration that mirrors atmospheric 14C at the time of their birth, creating a ‘date mark’ in the DNA.   Extrapolation of 14C concentration to the atmospheric 14C curve can therefore allow the accurate determination of the period during which a cell was born.   In their article recently published in Cell, Spalding et al.2 report their findings and reveal that a surprising proportion of human neural cells are subject to turnover, which may indicate a cognitive role for these newly generated adult cells.

First, Spalding et al. obtained postmortem human hippocampi from individuals aged 19-92 years from which neural cell nuclei were isolated and stained for the neuronal marker NeuN.   Neuronal and non-neuronal nuclei were sorted, the DNA purified, then the concentration of 14C in genomic DNA determined by performing accelerated mass spectrometry analysis.   Mathematical modelling of 14C data then allowed the authors to fit the data with specific model scenarios, such as the constant turnover of all cells in a given population, or constant turnover in a fraction of cells only, while enabling the estimation of individual turnover rates.   Analysis of the genomic DNA from nonneuronal (NeuN-negative) hippocampal cells found that the 14C could be extrapolated to time points on the 14C curve that occurred after the birth of the individual, indicating postnatal cell turnover.   Mathematical modelling of this data determined the best fit with the scenario where a fraction of the population renews at a constant rate throughout life.   In fact, their models indicated that a substantial proportion (51%) of nonneuronal hippocampal cells is continuously renewed at an average turnover rate of 3.5% per year, although levels decline with age.   They next went on to look at the genomic DNA from the hippocampal neuronal (NeuN-positive) population, which again indicated postnatal cell renewal, unlike cortical and olfactory bulb neurons where 14C corresponded to the individual’s birthdate.   The study of individuals born prior to the above ground nuclear bomb testing, revealed 14C levels in neuronal cells that were higher than atmospheric 14C prior to 1955. This demonstrates that DNA synthesis and hence neuronal cell turnover into at least the fifth decade of life.   Surprisingly, no dramatic decline in hippocampal neurogenesis with ageing was detected. Their analysis found that almost all neurons of the dentate gyrus (equating to 35% of all hippocampal neurons) were subject to turnover, at an average rate of 1.75% of the renewing population per year during adulthood (or in other terms, a surprising 1400 new neurons per day per individual) with no differences found between the genders.   Further, there was no correlation between the rate of non-neuronal and neuronal turnover for individuals over 50 years of age, indicating that these processes are regulated independently.

The authors then describe their findings on the global dynamics of hippocampal neuronal turnover.   Meta-analysis of previously published studies, where cell number was counted in each of the hippocampal regions, revealed an overall decrease in neuronal numbers with age, but also that the dentate gyrus is somewhat privileged and largely maintains its neuronal fraction over the lifespan.   Fascinatingly, analysis of this data using their most detailed integrated model revealed that, when neuronal death occurs, adult-born neurons appear to be preferentially lost over those generated during development.   The half-life of adult born neurons was found to be 7.1 years, 10-fold shorter than that of the fixed developmentally-born population, which raises interesting questions about the long term stability of newly integrated adult-born neurons in the human hippocampus.   

This exciting work for the first time describes the extent and dynamics of the cell turnover in the adult human hippocampus, revealing substantial neurogenesis throughout life.   It demonstrates that while a higher rate of cell turnover exists within the renewing non-neuronal hippocampal population (double that of the renewing neuronal fraction), the neuronal population are surprisingly less affected by age-related slowing of cell turnover than their non-neuronal counterparts.   The lack of detectable cell turnover in the human olfactory bulb but steady supply of younger neurons in the human dentate gyrus which continues throughout life is surprising.   These results in fact highlight substantial differences between the neurogenic regions of mouse and human (10% of dentate gyral neurons in mouse are subject to exchange compared with 35% in humans, with a smaller decline in human hippocampal neurogenesis with ageing).   So is adult neurogenesis likely to have a function in humans?   Prof. Spalding suggests that ‘the levels of neurogenesis may be sufficient to convey similar functions as in the mouse, in which adult neurogenesis is important for cognitive adaptability’.   Interestingly, the authors discuss that inadequate pattern separation is indicated in human psychiatric disease, and reduced adult neurogenesis has been implicated, so this work provides a launch pad from which to investigate this phenomenon.   Overall, the definitive nature of this approach has provided confirmation of a long disputed phenomenon, and reveals that humans do indeed demonstrate levels of hippocampal neurogenesis that indicate some functional significance.   It remains to be seen whether other highly functioning mammals will yield similar results, but the measured differences between mouse and human raise questions regarding the suitability of mouse models for human neurological disease research.   Spalding, however, says ‘There are fundamental differences between mouse and human, but we also see many parallels between the two species, and so it appears that we may be able to learn a lot about the function of adult hippocampal neurogenesis in humans, from work in mice’.   Retrospective birth dating of cells using the 14C of genomic DNA to measure cell turnover is an extremely useful tool, however, does the shallow slope of the curve in recent times, which the authors discuss provides less resolution and greater variability, render this technique unsuitable for the analysis of recently born individuals as the levels of atmospheric 14C continue to decline?   Spalding explains ‘Since we are looking at long-lived populations of cells, the method will remain useful for many years to come.  14C levels in the atmosphere are still well above pre-bomb levels, continuing to make the method relevant.  In fact for a key patient population of interest, those with dementia, who are now often born before the bomb-testing, the 14C method will continue to get more powerful for detecting neurogenesis with time’.   This clever utilisation of historic atmospheric carbon isotope levels has provided important novel and ground breaking information, which resolves some key aspects of the hotly contested phenomenon of adult neurogenesis and paves the way for additional complimentary neurological research.   


References

1. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisén J. Retrospective birth dating of cells in humans. Cell 2005;122(1):133-43.

2. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013;153(6):1219-27.

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