Adult hippocampal neurogenesis, the lifelong generation of new neurons in a brain region that is central to learning and memory (), exerts a strong fascination for scientists and the public alike. Knowledge about this process has fundamentally changed our ideas about how the hippocampus works and, by extension, our ideas about the structural substrates that underlie human cognition, cognitive aging, and the loss of hippocampal functions in, for example, Alzheimer’s disease or stress-related disorders and depression.

Two prominently published studies have now reignited the scientific debate about adult neurogenesis in humans. A report byconcluded that neurogenesis in the human hippocampal dentate gyrus drops to undetectable amounts during childhood, and that the human hippocampus must function differently from that in other species, in which adult neurogenesis is conserved (). In another study,came to the opposite conclusion and reported lifelong neurogenesis in humans. Thus, in the space of only a few weeks, two reports have been published that could not be more different. Herein, we discuss how the current state of knowledge about adult hippocampal neurogenesis applies to the human situation ( Figure 1 ).

Data from rodents suggest a particular and specific function for adult-generated neurons of the dentate gyrus, which would be of great relevance to human cognition in health and disease (green box). Three birthdating studies confirm the idea that adult hippocampal neurogenesis exists in humans (dark green box, top), and a much larger set of studies based on ex vivo analyses of precursor cells and marker expression provide supportive evidence (light green box, bottom).have questioned the validity of marker studies (red X), and we discuss evidence for and against human hippocampal adult neurogenesis in this Minireview.

The Evidence for Adult Neurogenesis in the Human Brain

Eriksson et al., 1998 Eriksson P.S.

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Gage F.H. Neurogenesis in the adult human hippocampus. 14C into DNA could theoretically be caused by processes other than duplication of DNA during mitosis, such as DNA repair or methylation. However, BrdU does not appear to be significantly incorporated during DNA repair and is not taken up by dying neurons ( Bauer and Patterson, 2005 Bauer S.

Patterson P.H. The cell cycle-apoptosis connection revisited in the adult brain. 14C incorporation during extensive DNA repair in cortical neurons after stroke was below the level detected by carbon dating ( Huttner et al., 2014 Huttner H.B.

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Méhes

et al. The age and genomic integrity of neurons after cortical stroke in humans. 14C levels in the DNA of adult human hippocampal neurons to be explained by DNA repair or methylation, the entire genome would have had to be exchanged in 35% of the neurons by these processes (Spalding et al., 2013), which is by a very large margin beyond any type of DNA modification described. In 1998, Eriksson and colleagues applied the current “gold standard” adult hippocampal neurogenesis method, which was previously established in animal studies, on the human hippocampus (). They identified patients who had received infusions of the thymidine analog bromodeoxyuridine (BrdU) for tumor-staging purposes, but did not receive any treatment that is thought to affect cell generation, and they analyzed the brains postmortem. Their conclusion from five brains was that adult neurogenesis could be detected in the human hippocampus in the same location and numbers as expected based on work in rats. BrdU and other halogenated thymidine analogs, such as IdU or CldU, are incorporated into the DNA of dividing precursor cells and can be detected immunohistochemically. Detecting a BrdU-positive neuron thus indicates that the neuron has originated from a cell that underwent division at exactly the time at which BrdU was applied, since BrdU has a short biological half-life. Incorporation of thymidine analogues orC into DNA could theoretically be caused by processes other than duplication of DNA during mitosis, such as DNA repair or methylation. However, BrdU does not appear to be significantly incorporated during DNA repair and is not taken up by dying neurons (), andC incorporation during extensive DNA repair in cortical neurons after stroke was below the level detected by carbon dating (). For theC levels in the DNA of adult human hippocampal neurons to be explained by DNA repair or methylation, the entire genome would have had to be exchanged in 35% of the neurons by these processes (Spalding et al., 2013), which is by a very large margin beyond any type of DNA modification described.

While such birthdating methods are cornerstones of demonstrating adult neurogenesis, especially in undescribed regions of the brain or in new species, they alone are not sufficient as proof but require support by methodologically independent lines of evidence.

Knoth et al. (2010) Knoth R.

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Kempermann G. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. Knoth et al., 2010 Knoth R.

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Kempermann G. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. Sorrells et al. (2018) Sorrells S.F.

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et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Dennis et al., 2016 Dennis C.V.

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Sutherland G.T. Human adult neurogenesis across the ages: An immunohistochemical study. Knoth et al., 2010 Knoth R.

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Double K.L. Evidence for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers. 14C) birthdating of neuronal DNA ( Spalding et al., 2013 Spalding K.L.

Bergmann O.

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et al. Dynamics of hippocampal neurogenesis in adult humans. 14C data from 55 individuals, and this broad range of samples and alternative method of quantitation serves as independent validation for adult neurogenesis in the human hippocampus. Another study by the same group, though focused on striatal neurogenesis, also contained a replication of Eriksson’s findings using the thymidine analog IdU in four more subjects (Figure S2 of Ernst et al., 2014 Ernst A.

Alkass K.

Bernard S.

Salehpour M.

Perl S.

Tisdale J.

Possnert G.

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Frisén J. Neurogenesis in the striatum of the adult human brain. Sorrells et al. and Boldrini et al. use the approach first reported by, who assessed 54 samples across the lifespan of 0 to 100 years using combinations of 14 markers (). In contrast to, Knoth et al. and now Boldrini et al. found DCX-positive cells co-expressing other neurogenesis markers. But while Sorrells et al. and several other studies pointed out an age-related decrease in marker overlap and a sharp decline in proliferating cells (), Boldrini et al. employed additional validation methods that did not find an association between labeled cells and increasing age. In contrast to previous studies, they applied stereology, a method for unbiased quantification within a tissue volume. The conclusion still stands in contrast to quantitative estimates, based on carbon 14 (C) birthdating of neuronal DNA (). That study by Spalding, Bergmann, and colleagues notably assessedC data from 55 individuals, and this broad range of samples and alternative method of quantitation serves as independent validation for adult neurogenesis in the human hippocampus. Another study by the same group, though focused on striatal neurogenesis, also contained a replication of Eriksson’s findings using the thymidine analog IdU in four more subjects (Figure S2 of).

The studies by Eriksson et al., Ernst et al., and Spalding et al. used a form of lineage tracing in which the DNA of dividing precursor cells was labeled (by 14C, BrdU, or IdU) and their progeny was analyzed for the expression of neuronal markers. Thus, these studies focus on identifying the presence of newly formed neurons. In contrast, Sorrells et al. and other studies base their conclusions about neurogenesis on histological analysis of markers for precursor cells and their proliferative status, as well as early immature stages.