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Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
The Curious Case of Human Hippocampal Neurogenesis Sonu Gandhi,*,† Jalaj Gupta,‡ and Prem Prakash Tripathi*,§,∥ †
DBT-National Institute of Animal Biotechnology (DBT-NIAB), Hyderabad 500032, India Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt, Germany § CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India ∥ IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India
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ABSTRACT: Neurogenesis in the human brain has been validated to occur throughout adulthood. Recently, the human hippocampal neurogenesis field has been shaken by two significant reports that have been published with opposite reports, and these path-breaking studies have flipped the bandwagon of the neurogenesis field upside down, by questioning the existence of human hippocampal neurogenesis. Here, we discuss the findings by these two prominent papers, dissecting the potential reasons for conflicting results, insisting on the need to understand new observations critically, and further highlighting in what way the existing knowledge of adult hippocampal neurogenesis relates to the human. KEYWORDS: Adult neurogenesis, hippocampus, human, dentate gyrus
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recent minireview that tries to discuss and highlight both studies but with limited perspective.4 In these recent studies, Sorrells et al. and Boldrini et al. evaluated postmortem human hippocampal tissue ranging from infants through old age and ages 14 to 79, respectively. Interestingly, Boldrini et al. found the existence of adult neurogenesis throughout the aged population, but in the Sorrells paper, the oldest brain sample that contained immature neurons was found in a 13 year old individual. This is in sharp contrast to popular doctrine that hippocampal neurogenesis exists throughout the adult human life and continues until late ages. Both Sorrells et al. and Boldrini et al. summarized adult neurogenesis on the basis of the expression of two markers DCX and PSA-NCAM, that are routinely used as a gold standard marker for neuroblast (a stage between intermediate progenitor cells and early immature neurons). It is important to note that fixation of the brain after postmortem is an important parameter as the level of DCX staining reduced significantly within a few hours after death. In the Sorrells paper, the postmortem interval (PMI) had a large variability ranging from less than 1 to 48 h while in the Boldrini paper PMI ranged from 4 to 26 h. It will be important to dissect if DCX+ neuroblast numbers have any significant correlation with PMI variability. Another important factor that is not clear in these two studies is the duration for which these brains were fixed in PFA or formalin. In fact, longer fixation may mask various antigens including PSA-NCAM which could possibly explain why PSA-NCAM was absent in the Sorrells paper. However, it is important to note that they detected hippocampal neurogenesis in neonatals and children, thus suggesting that fixation may not be an issue. Boldrini et al. have shown DCX+ cells young neuron as rounded cells without any leading process (Figure 3 in Boldrini
here are a growing number of articles in the neurogenesis field that have emphasized that adult hippocampal neurogenesis, once thought to be absent in mammals, persists throughout life in all adult mammals, including humans.1 Hippocampal neurogenesis is now recognized as a continual, robust process in the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus (see Figure 1). Recently, a
Figure 1. Lineage progression during adult hippocampal neurogenesis. Each radial astrocyte (rA) that has a cell body in the SGZ and process spreads through the granule cell layer (GCL), which ends in the molecular layer (ML) of DG. rAs divide to generate intermediate progenitor cells (IPCs). IPCs gradually differentiate into the postmitotic neuron (pN) to the immature granular neuron (IGN) and mature granule neurons (MGNs).
new study by Sorrells et al. suggests that production of new neurons reduces drastically after early development to undetectable levels in the SGZ of the adult human, contrary to what is observed in other mammalian species.2 However, to intensify an additional twist to the adult neurogenesis field, another recent study by Boldrini et al. came up with the opposite conclusion claiming that hippocampal neurogenesis is continued throughout life ranging from adulthood until late age in humans, despite a drop in quiescent neural stem cell population.3 These classical stories have been highlighted in a © XXXX American Chemical Society
Received: January 26, 2019 Accepted: January 30, 2019
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DOI: 10.1021/acschemneuro.9b00063 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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to develop a more quantitative way to access neurogenesis and brain plasticity in physiological as well as pathological conditions during adulthood. Additionally, each approach such as tissue preservation, postmortem delay, fixation, and neuron estimation using expression of a single marker/ combination of markers should be interpreted with a critical lens. This way we will be capable of not only transforming these far-reaching results into path-breaking discoveries but also developing strategies for repairing the injured brain.
et al. 2018) that is contrary to the fundamental characteristic feature of young neurons, i.e., cells having extended nuclei with leading processes (Knoth et al., 2010). Thus, there is a need of further study to clarify these rounded cells without the leading process, which seems to be expressing DCX. In many of the images, Boldrini et al. have shown Ki67 staining in the cytoplasm and in the leading processes that is again unexpected as Ki67 staining is strictly nuclear. Additionally, Ki67 is shown to be expressed in the nuclei of the granular cell layer of DG (Figure 1K, 1L, in Boldrini et al. 2018). Neurons were estimated by direct quantitative approach in Sorrells et al. while Boldrini et al. used an unbiased stereological approach across entire DG regions. Indeed, there is a benefit of using the stereological method but only if those DCX+ young neurons or Ki67+ cytoplasmic staining is classified correctly. Recent evidence indicates that hippocampal neurogenesis is upregulated in the SGZ of the hippocampus in several brain injury models including epilepsy. It has been speculated that this neurogenesis may contribute to the recovery that is observed. Sorrells et al. have examined tissue from 22 patients with epilepsy, which may itself cause substantial change in neurogenesis and restructuring of hippocampal circuitry. Because of the discrepancy between healthy and epileptic tissue, it is hard to draw conclusions with affirmation. Carbon dating reveals that 700 new neurons are replaced per day in the DG of the adult human; however, it is important to point out that C14 dating is not a foolproof method to access neurogenesis, and it is vulnerable to how you process the sample. In fact, increased aging is strongly correlated with a decline in DCX+ cells and decreased hippocampal neurogenesis, observed by carbon dating, and this decline is conserved in rodents as well as humans.5 Surprisingly, Boldrini et al. did not find any reduction of proliferation and neurogenesis with aging, suggesting that magnitude of human adult neurogenesis is more robust than what was previously thought by other studies. Therefore, this minor but vital technical information must be taken into deliberation before reaching a final conclusion. Most of the theoretical perspective appears from possible species variation. There is no precise association between ki67+ cell proliferation, Tbr2+ neurogenic transcription factor, DCX+ migratory neuroblast, and overall neurogenesis across species. It has been shown that the rat has higher hippocampal neurogenesis despite having lesser DCX+ cells, due to faster neuronal maturation. The red fox has a very low number of proliferative population, but has high numbers of DCX-positive cells. Both authors have used brain samples ranging from a very young to an aged population. However, the balance between proliferative population, migratory neuroblast, and neurogenic potential is likely to be altered across the lifespan. Therefore, it is not very well-defined at the moment if DCX expression can fully forecast the neurogenesis outcome across interspecies, which might partially clarify the differences between poorly understood human data and well-understood rodent results. At the moment we have many unanswered questions related with human hippocampal neurogenesis. In fact, human data from Sorrells et al. clearly points out the species differences, which are not only recalibrating our long-standing thoughts but also opening up various future directions of hippocampal neurogenesis in humans. Thus, there is an urgent need to classify various stages of proliferation, migration, and differentiation using an additional marker or combination of markers in human hippocampal neurogenesis. We also need
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] *E-mail:
[email protected]. Funding
P.P.T. and S.G. gratefully acknowledge the financial assistance from DST/ECR/2017/000466 and DST/ECR/2016/000075, respectively. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS P.P.T. originated the concept of writing the manuscript. P.P.T. and S.G. wrote the manuscript. J.G. helped in the discussion during writing of the manuscript.
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REFERENCES
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DOI: 10.1021/acschemneuro.9b00063 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
