New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus1,2,3,4,5. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease6,7,8,9,10. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day11, whereas other studies find many fewer putative new neurons12,13,14. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18–77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.
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We thank the families who donated the tissue samples used in this study, and J. Rodriguez, V. Tang, J. Cotter and C. Guinto for technical support. S.F.S. was supported by F32 MH103003 and M.F.P. was supported by K08 NS091537. A.A.-B. was supported by NIH grants P01 NS083513, R01 NS028478 and a gift from the John G. Bowes Research Fund. He is the Heather and Melanie Muss Endowed Chair and Professor of Neurological Surgery at UCSF and is a co-founder and serves on the scientific advisory board of Neurona Therapeutics. G.W.M. was partly supported by the Davies/Crandall Endowed Chair For Epilepsy Research at UCLA. G.W.M. and J.C. were supported by NIH NINDS (NS083823 and U01 MH108898). M.C.O. was supported by a Scholar Award from the UCSF Weill Institute for Neurosciences. We acknowledge NSFC grants to Z.Y. (31425011, 31630032, and 31421091). S.M. was supported by fellowships from the European Molecular Biology Organization (EMBO Long-Term Fellowship, ALTF_393-2015) and the German Research Foundation (DFG, MA 7374/1-1). J.M.G.-V. and A.C.-S. were supported by MINECO/FEDER Grant BFU2015-64207-P, Red de Terapia Celular TerCel, Instituto de Salud Carlos III (ISCIII2012-RED-19-016 and RD12/0019/0028) and PROMETEOII/2014/075.
The authors declare no competing financial interests.
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Extended data figures and tables
Extended Data Figure 1 Additional marker and ultrastructural analysis of early fetal development of the human DG.
a–c, Human brain of an individual at 14 gestational weeks. a, Schematic of the dorsal (dHP) and ventral (vHP) hippocampus in a coronal section. Precursor cells labelled with nestin, SOX2 and vimentin are organized in ribbons between the dNE and GCL. Ki-67+ cells expressing SOX1 and vimentin or SOX2 and BLBP are present in the GCL and hilus (inset 1), along the wall of the lateral ventricle (LV) (inset 2) and between the GCL and the dNE (inset 3). The dNE is located at the edge of the ammonic neuroepithelium (aNE) closest to the fimbria. A similar organization is present in the vHP where nestin+SOX2+vimentin+ cells connect the dNE to the developing GCL. Ki-67+SOX1+vimentin+ cells are present in a strip along the ventricular wall and fill the region between the dNE and the GCL. b, Left, hemisphere at 14 gestational weeks, Nissl-stained horizontal sections. Right, Ki-67+ cells expressing SOX2 (arrows). c, 3D reconstruction of the dHP showing the field of Ki-67+ and SOX2+ cells between the dNE and GCL. d–h, Human brain at 22 gestational weeks, coronal (d) and horizontal (e) sections. The hilus and GCL contain Ki-67+SOX2+ cells (d, e (insets)) as well as nestin+SOX2+vimentin+ cells (f). These populations are asymmetrically distributed; sparse in the medial (proximal) GCL and hilus (top insets in e, f) but abundant in the lateral (distal) GCL and hilus (bottom insets in e, f). g, DCX+TUJ1+ cells and NeuN+ cells in the DG at 22 gestational weeks. NeuN+ GCL neurons in the distal GCL (arrow). h, A toluidine-blue-stained semi-thin section (top) and TEM micrographs showing the ultrastructural characteristics of DCX immunogold-labelled cells (pseudocoloured, bottom) at 22 gestational weeks. Insets of the semi-thin section show the proximal (1) and distal (2) ends of the GCL. Most DCX+ cells in the hilus and the proximal GCL have little cytoplasm, few organelles and a small, irregular nucleus (i, ii); some DCX+ cells in the hilus have an elongated, fusiform morphology (i). Some DCX+ cells in the GCL have mature neuronal characteristics such as a round nucleus, more cytoplasm, ribosomes, rough endoplasmic reticulum and mitochondria (iii); this cell type was more common in the distal GCL. At this stage, the round and more mature neuronal morphologies were observed in the distal, but not in the proximal, blade. Scale bars, 200 μm (a–h (left images)), 2 μm (a–h (insets)) and 2 μm (h (TEM)).
Extended Data Figure 2 A coalesced proliferative SGZ does not form in the human DG; additional marker expression.
a, Toluidine-blue-counterstained semi-thin sections of the human GCL from fetal to adult ages. Note that a discrete cellular layer does not form next to the GCL and the small dark cells characteristic of SGZ precursors are not present (compare to Extended Data Fig. 9b in the macaque). b, BLBP+ cells are distributed broadly in the DG from birth to 1 year, many of these cells have a radial morphology (see insets) and some co-express Ki-67 at birth and 1 month (double-positive cells are indicated by the arrows). By 7 years and in adults, most BLBP is present in the molecular layer in stellate protoplasmic astrocytes. c, DCX+Ki-67+ cells in the GCL are rare at 17 gestational weeks (orthogonal views, inset) but were abundant in the ganglionic eminence at the same age (data not shown). DCX+Ki-67+ cells were absent in the GCL from 22 gestational weeks to 55 years. Scale bars, 100 μm (a–c) and 10 μm (a–c (insets)).
Extended Data Figure 3 Additional marker expression for astroglial cells and progenitor cells in the human DG at different ages.
a, Vimentin+ and GFAP+ cells in the hippocampus from 22 gestational weeks to 35 years. Vimentin is widely expressed during fetal and early postnatal development and is mostly restricted to protoplasmic astrocytes in the molecular layer in adults. GFAP is not expressed at 22 gestational weeks, but at birth a few vimentin+GFAP+ cells are present in the hilus and GCL (arrowhead). Interestingly, some vimentin+GFAP− cells with a radial morphology (arrow) are observed in samples at 1 year of age, but not at the other ages. In adults, GFAP and vimentin are not co-expressed (right, high-magnification of thin GFAP+vimentin− fibres within the GCL). b, Vimentin+Sox2+ simpler elongated cells in the hilus at 1 month (arrow) and protoplasmic astrocytes in the molecular layer at 35 years of age (arrow). c, SOX2+ cells are abundant in the GCL and hilus at 22 gestational weeks, and co-express ALDH1L1 in the brain at birth and in older individuals (arrows). d, At birth, there are few ALDH1L1+GFAP+ cells in the DG, but by 13 years of age many stellate astrocytes express both of these markers. Right, z stack of radial GFAP+ processes that are surrounded by ALDH1L1 staining. Scale bars, 100 μm (a (top row)), 10 μm (a (bottom row and insets), b–d) and 2 μm (d (z-stack)).
Extended Data Figure 4 TEM analysis of cell types in the DG of human brains obtained from a 13-year-old individual and an adult; absence of SGZ precursor cells or immature neurons.
a, Reconstruction of 5 ultrathin sections (separated by 1.5 μm) from the GCL of the 13-year-old individual with outlines of cell membranes. Colours corresponding to the different cell types defined by their ultrastructural characteristics are indicated in the key. No clusters or isolated cells with a young neuronal ultrastructure were found. Cells associated in small groups were identified as astrocytes, oligodendrocytes or microglia. b, c, Reconstructions of astroglial cells next to the GCL, searching for possible examples of radial astrocytes in the DG of an adult human. b, Example of an astrocyte with radial morphology in the adult GCL. Five serial semi-thin sections of this astrocyte (black arrows) next to the GCL of the DG of a 48-year-old individual are shown; alternating semi-thin sections show that this cell is GFAP+. This cell extends a thin radial fibre through the GCL, but has multiple processes (stellate morphology) in the hilus. Boxed area shows the ultrastructure from the indicated semi-thin section of this astrocyte (pseudocoloured in blue) and the bundles of intermediate filaments present in the expansion (arrows). c, Another example of a serially reconstructed astrocyte in the DG of a 30-year-old individual with epilepsy (separated by 1.4 μm), showing a short radial expansion and processes into the hilus. Scale bars, 10 μm (a, b, semi-thin sections and TEM micrographs), 5 μm (c), 2 μm (b, soma) and 500 nm (b, intermediate filaments).
a, DAB staining in the hippocampus at birth reveals many young neurons in the GCL. b, DCX+PSA-NCAM+ cells are distributed in clusters across the GCL at 1 year of age. Most PSA-NCAM+ cells are DCX+, but some are DCX−PSA-NCAM+ (arrows). c, In the samples from a 13-year-old individual, DCX+ cells have a more mature neuronal morphology. The cell shown is NeuN+ and has dendrites in the molecular layer (arrowheads) and an axon projecting into the hilus (arrow). d, At 35 years of age, the DG does not contain DCX+PSA-NCAM+ cells, but does contain many DCX−PSA-NCAM+ cells that do not have the morphology of young neurons. e, PSA-NCAM+ staining in the human DG from 3 weeks to 77 years; in adults, these cells have a more mature neuronal morphology and are localized in the hilus. f, PSA-NCAM+ cells in the DG are NeuN+ in samples of 19- and 77-year-old individuals. g, At 3 weeks of age, the GCL and hilus were filled with clusters of DCX+NeuroD+ cells, and many of the DCX− GCL neurons were NeuroD+. At 35 years, no DCX+NeuroD+ cells were observed; antibody labelling for NeuroD was non-specific. Scale bars, 200 μm (a, d–g), 20 μm (b, c, and d, f, g (inset)).
a, TEM micrographs of DCX immunogold staining at birth and 7 years of age. At birth, the GCL contains small DCX+ cells with little cytoplasm, rough endoplasmic reticulum (RER) cisternae and a fusiform or round nucleus. At 7 years of age, DCX+ cells closer to the hilus have characteristics of immature neurons, including few organelles and a long expansion towards the GCL. DCX+ cells located within the GCL have mature neuron characteristics, including a large, round nucleus, rough endoplasmic reticulum, mitochondria and microtubules consistent with a more mature neuronal morphology (see Extended Data Fig. 5). At higher magnification, the more mature-appearing DCX-labelled cells are adjacent to DCX− GCL neurons. b, No DCX+ cells in the hilus and GCL (stained by NeuN antibodies; left insets) were found in the brain of a 35-year-old individual that showed exceptional preservation. In this sample, rare DCX+ cells with the features of young migratory neurons were present in the ventricular–subventricular zone (right insets). SVZ, subventricular zone. c, DCX+TUJ1+ cells were present in the GCL and hilus at 3 weeks of age, but were not detected in the adult DG. d, RNA-scope detection of DCX mRNA revealed many cells in the DG at 14 gestational weeks, but weakly labelled cells distributed throughout in the DG and other regions of the hippocampus at 13 years of age. Scale bars: 1 mm (b (left)), 100 μm (b (middle right inset)), 20 μm (b (right insets), c), 10 μm (d), 5 μm (a (left)) and 500 nm (a (right, TEM)).
a, Comparison of citrate antigen retrieval using three DCX antibodies from this study (SC-8066, CS-4604S and AB2253) in the GCL obtained from individuals at 22 gestational weeks and 13 years of age. The 13 year old DCX+ cell (Extended Data Fig. 5c) is shown in the lower right panel and adjacent sections were stained with the other antibodies. b, Example of a DCX+PSA-NCAM+ neuron in the GCL and DCX+PSA-NCAM− staining in the sample from the 13-year-old individual (arrows). c, Examples of DCX+OLIG2+ cells in the GCL and hilus of the 13-year-old individual. Immunogold-labelled DCX+ cells viewed by TEM had single short endoplasmic reticulum cisternae (arrows), a very irregular contoured membrane and a round nucleus with condensed chromatin characteristic of oligodendrocytes. d, In some samples (see Extended Data Fig. 5g, bottom right inset), we found DCX+ immunoreactivity in many small multipolar cells. This staining was not limited to the hilus, or GCL, but was present in cells across the tissue and co-localized with the microglial marker IBA1 (arrows). e, TEM micrographs of DCX and IBA1 immunogold-labelled cells in an adult DG of a 30-year-old individual with epilepsy. DCX+ and IBA1+ cells have similar characteristics: elongated nucleus with clumps of chromatin beneath the nuclear envelope and throughout the nucleoplasm, irregular contour and the presence of lysosomes and lipofucsin (arrows). Note that these features are typical of microglial cells. f, Human hippocampus stained with NeuN followed by processing for BrdU detection (with no primary or secondary antibodies) shows round fluorescent signal (arrowheads indicate signal that is NeuN−) occasionally overlapping with NeuN staining (arrow). Scale bars, 200 μm (b (left column and wide column)), 20 μm (a, b (left-middle columns, right column), d, f), 10 μm (c (top row)) and 1 μm (c (bottom row), e).
a, Ki-67+SOX1+vimentin+ cells are located in the hilus and GCL at 10 months but are not present at 11 years of age. b, Ki-67+SOX2+BLBP+ cells are located in the hilus and GCL at 10 months but are not present at 11 years of age. c, Maps of DCX+PSA-NCAM+ cells (yellow dots) and representative immunostaining at 10 months, 7 years and 13 years (bottom rows). d, In the 10-month-old DG of a patient with epilepsy, DCX+ cells co-expressing PSA-NCAM or TUJ1 are distributed throughout the NeuN+PROX1+ GCL, but do not co-express Ki-67 or GFAP. In the DG of a 13-year-old patient with epilepsy, DCX+ cells co-expressing PSA-NCAM or TUJ1 were not present. Few Ki-67+ cells were visible throughout the DG. e–g, Quantification of Ki-67+ (e), Ki-67+SOX2+ (f) and DCX+PSA-NCAM+ (g) cells in the DG of surgically resected hippocampuses. h, TEM micrographs of the brain of a 30-year-old patient with epilepsy showing astroglial expansions with high number of intermediate filaments (blue) ensheathing GCL neuronal bodies. A dense network of astrocytic expansions in the hilus, containing dense bundles of intermediate filaments (blue), fills the region proximal to the GCL with no evidence of SGZ progenitor cells. i, Mitotic cells are very rare and not restricted to the hilus or GCL. A toluidine-blue-stained 1.5-μm section from the DG of a 30-year-old brain shows a dividing cell in the molecular layer, adjacent to the GCL. The TEM micrograph shows the dividing cell in metaphase with a light cytoplasm, few organelles and an irregular contour with a small expansion (arrows), which are characteristic of astrocytes (shown at higher magnification). N, neuron. For quantifications, staining replicates (≥3) are shown by dots (each age, n = 1). Scale bars, 1 mm (c (maps)), 200 μm (a, b (top), d (left)), 20 μm (a–c (bottom), d (right)) and 10 μm (h, i (left)), 1 μm (h, i (middle and right)).
Extended Data Figure 9 Development of the macaque DG and evidence of the presence of a proliferative SGZ and postnatal neurogenesis with a sharp decline in adulthood.
a, The E150 macaque hippocampus has many Ki-67+ cells in the SGZ as well as vimentin+ fibres and DCX+ cells between the dNE and the GCL (arrow). b, Toluidine-blue-stained semi-thin sections of the macaque DG reveal small and dark condensed nuclei (arrows) in the SGZ from fetal ages (E150) to 1.5 years; few are visible in the DG at 7 years of age and these cells are very rare in the DG of a 23-year-old macaque (compare with human data in Extended Data Fig. 2a). c, Profiles of the cellular populations in the macaque DG at 6 months, 1.5, 7 and 23 years of age. As in the human DG, DCX+ cells decrease markedly with age and have little cytoplasm and a smaller nucleus compared to mature granule neurons. d, Top, example of a DCX+NeuN+ cell with mature dendrites in the GCL of a 5-year-old macaque. Middle, bottom, two examples of DCX+PSA-NCAM+ cells with dendritic arborization present in the GCL of a 7.5-year-old macaque. An axonal extension (arrow) into the hilus is visible. e, The ventricular–subventricular zone (SVZ) and olfactory bulb (OB) of a 23-year-old macaque contain some DCX+SP8+ cells with the morphology of young neurons, but similar cells are rare in the GCL of the 23-year-old macaque (Fig. 4b, d). f, DCX+ cells in the SGZ of a 1.5-year-old macaque express transcription factors in common with those in the mouse SGZ. g, Percentages of DCX+ cells expressing markers shown in f. h, Immunostaining images of BrdU+ cells and cell proliferation (Ki-67, MCM2), progenitor cell markers (SOX2, ASCL1) or DCX, in the 1.5-year-old macaque euthanized 2 h after BrdU injection. BrdU+DCX+ and BrdU+NeuN+ cells could be identified 10 or 15 weeks after BrdU exposure, respectively. i, DAB-staining for BrdU in the ventricular–subventricular zone and SGZ of a 1.5-year-old macaque, 2 h after BrdU injection. j, Example of a rare DCX+BrdU+ cell in the 7.5-year-old macaque. Scale bars, 1 mm (a (left)) 200 μm (a (right), e (top left, bottom left), i (left)), 100 μm (b (left)), 20 μm (d, e (middle left and right), f, h, i (right), j) and 10 μm (b (right), c).
Extended Data Figure 10 Decline in markers associated with neurogenesis in the macaque and human hippocampus (gene-expression profiling).
a, Markers of dividing or precursor cells. b, Markers of young neurons. c, Markers of mature neurons. Human RNA-seq (http://brainspan.org/) and macaque expression profiling (dataset from ref. 33) developmental data from hippocampus for the indicated genes. Human data are averaged over biological replicates by developmental period (as defined in ref. 34). Normalized data are plotted on the same developmental event scale. Loess-fit curves are displayed with data points (mean ± s.e.m.). Dashed lines indicate birth.
This file contains Supplementary Tables 1-4, a Supplementary Discussion and Supplementary References. (PDF 233 kb)
The developing dentate gyrus (blue), CA region (orange), dentate neuroepithelium (yellow) are shown and each coloured dot represents the presence of Ki67+ (green), SOX2+ (red) and PAX6+ (white) cells. (MP4 12662 kb)
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Sorrells, S., Paredes, M., Cebrian-Silla, A. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018). https://doi.org/10.1038/nature25975
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