Neurogenesis Drops Sharply in Children to Adults

 

Nature volume 555, pages 377–381 (15 March 2018)

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults

Shawn F. Sorrells, et.al.

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA

Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143, USA

Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA

Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia, 46980, Spain

State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

David Geffen School of Medicine, Department of Neurosurgery, Intellectual Development and Disabilities Research Center, University of California Los Angeles, Los Angeles, California 90095, USA

Unidad de Cirugía de la Epilepsia, Hospital Universitario La Fe, Valencia 46026, Spain

Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA

Department of Psychiatry and Biobehavioral Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA

Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA

[paraphrase]

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. 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 neurons. 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.

We used 59 post-mortem and post-operative samples of the human hippocampus to investigate the presence of progenitor cells and young neurons from fetal to adulthood stages. At 14 gestational weeks, at the peak of proliferation in the fetal dentate gyrus (DG), many dividing (Ki-67⁺) neural progenitors (SOX1⁺ and SOX2⁺ were observed in the dentate neuroepithelium . A continuous region of Ki-67⁺SOX1⁺ and Ki-67⁺SOX2⁺ cells, associated with ribbons of nestin+vimentin+ fibres and cells, was observed between the dNE and the proximal blade of the DG. At 22 gestational weeks, the proliferating cells between the dNE and the DG were greatly diminished, and most Ki-67⁺SOX1⁺ or Ki-67⁺SOX2⁺ cells in the hippocampus were found in the hilus. By this age, most young neurons (DCX⁺PSA-NCAM⁺ cells), were concentrated in the granule cell layer (GCL) proximal to the dNE. By contrast, the distal GCL contained higher numbers of mature NeuN⁺ neurons, suggesting a gradient of maturation.

We next investigated the presence of young neurons in the postnatal, human DG. At birth, DCX⁺PSA-NCAM⁺ cells were located across the GCL, frequently in clusters. The number of DCX⁺PSA-NCAM⁺ cells in the GCL decreased from 1,618 ± 780 (mean ± s.d.) cells per mm² at birth to 292.9 ± 142.8 cells per mm2 at 1 year of age. By 7 years of age, 12.4 ± 5.3 DCX⁺PSA-NCAM⁺ cells per mm² were found in the GCL and at 13 years of age, the GCL contained 2.4 ± 0.74 DCX⁺PSA-NCAM⁺ cells per mm² (that is, approximately 1–2 DCX⁺PSA-NCAM⁺ cells per section. DCX+ cells in the DG of infants (1 year old or less) not only expressed PSA-NCAM, but also frequently had the simple elongated morphology of young neurons. By contrast, light and electron microscopy images of sections from the brain of a 7-year-old individual showed that the DG contained DCX⁺ cells in different stages of maturation. DCX⁺ cells in the hippocampus of a 13-year-old individual had a more mature morphology, expressed NeuN and had distinct axons and dendrites. We examined hippocampuses of 17 individuals that were between 18 and 77 years old when they died for evidence of young neurons. In two adults we also studied the ventricular wall and found rare DCX⁺ cells with a migratory morphology in the ventricular–subventricular zone, providing a positive control. We found no evidence of DCX⁺PSA-NCAM⁺ young neurons in the hilus or GCL of the hippocampuses from these individuals. At three weeks of age, there were many DCX⁺TUJ1⁺ young neurons in the GCL, however, we did not detect these cells at 19 or 36 years of age. In adults, we observed TUJ1⁺ fibres that belonged to many mature neurons. PSA-NCAM⁺ cells were present in the hilus and GCL of adult brains, but these cells had a mature neuronal morphology and were NeuN⁺Using single-molecule in situ hybridization labelling of DCX transcripts, we detected many DCX⁺ cells in the GCL at 14 gestational weeks, but only weak signal in very few, widely distributed cells at 13 years. A subpopulation of cells with round nuclei was occasionally labelled by DCX antibodies. These DCX⁺ cells had multiple processes, were not restricted to the hippocampus, expressed the glial markers IBA1 or OLIG2, and had ultrastructural features of glia.

The above findings do not support the notion that robust adult neurogenesis continues in the human hippocampus. ¹⁴C dating on sorted NeuN⁺ nuclei has suggested that many new neurons continue to be generated in the adult human hippocampus, with little decline with age, but additional evidence for high levels of progenitors or young neurons was not shown. Interestingly, considerable interindividual variation was observed in this study, and many individual samples had ¹⁴C levels consistent with no, or little, postnatal neuronal addition. Labelled neuronal cells in the GCL in patients that received a low dose of BrdU, could possibly be explained by processes not associated with cell division. Other groups find a sharp decline with age in proliferation and markers of DG neurogenesis, consistent with the above findings. It has been suggested that a few new neurons continue to be produced in adults based on DCX expression detected by PCR or western blot. However, glial cells can express DCX, possibly explaining some of these expression data. The lack of young neurons in our adult human DG samples could be due to processes linked to disease and/or death. However, similar results were obtained in DG from intraoperative samples or from patients with diverse causes of death. By contrast, young neurons were found in epilepsy samples from children and in our control paediatric cases, despite diverse clinical histories. In contrast to our observations in humans, we observed a germinal SGZ in the young macaques. We found that neurogenesis continues postnatally in macaques, but like humans, this process declined in juveniles and adults, consistent with previous 3H-thymidine and BrdU studies. If neurogenesis continues in the adult human hippocampus, this is a rare phenomenon, raising questions of how human DG plasticity differs from other species in which adult hippocampal neurogenesis is abundant. Interestingly, a lack of neurogenesis in the hippocampus has been suggested for aquatic mammals (dolphins, porpoises and whales), species known for their large brains, longevity and complex behaviour. Understanding the limitations of adult neurogenesis in humans and other species is fundamental to interpreting findings from animal models.

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