Dynamics of Hippocampal Neurogenesis in Adult Humans
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. Cell
(Impact Factor: 32.24).
06/2013; 153(6):1219-27. DOI: 10.1016/j.cell.2013.05.002
Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived (14)C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function.
Available from: bmcneurosci.biomedcentral.com
- "in the setting of injury or disease is dependent on the activity of neural stem and progenitor cells that reside in a specialized , regulatory neurovascular environment67891011. Optimizing the cellular and molecular factors that control the neural stem cell niche has evolved as an attractive strategy to promote central nervous system (CNS) repair following focal and diffuse brain injury. "
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A major area of unmet need is the development of strategies to restore neuronal network systems and to recover brain function in patients with neurological disease. The use of cell-based therapies remains an attractive approach, but its application has been challenging due to the lack of suitable cell sources, ethical concerns, and immune-mediated tissue rejection. We propose an innovative approach that utilizes gut-derived neural tissue for cell-based therapies following focal or diffuse central nervous system injury.
Enteric neuronal stem and progenitor cells, able to differentiate into neuronal and glial lineages, were isolated from the postnatal enteric nervous system and propagated in vitro. Gut-derived neural progenitors, genetically engineered to express fluorescent proteins, were transplanted into the injured brain of adult mice. Using different models of brain injury in combination with either local or systemic cell delivery, we show that transplanted enteric neuronal progenitor cells survive, proliferate, and differentiate into neuronal and glial lineages in vivo. Moreover, transplanted cells migrate extensively along neuronal pathways and appear to modulate the local microenvironment to stimulate endogenous neurogenesis.
Our findings suggest that enteric nervous system derived cells represent a potential source for tissue regeneration in the central nervous system. Further studies are needed to validate these findings and to explore whether autologous gut-derived cell transplantation into the injured brain can result in functional neurologic recovery.
Electronic supplementary material
The online version of this article (doi:10.1186/s12868-016-0238-y) contains supplementary material, which is available to authorized users.
Available from: cshperspectives.cshlp.org
- "The proportion of one-third of newly born cells is, however, consistent with an estimate from a lineage-tracking study in mice (Ninkovic et al. 2007). Although the amount of adult neurogenesis in humans turned out to be bigger than assumed (Goritz and Frisen 2012; Spalding et al. 2013), the absolute numbers are still very low. The big question is what the functional contribution of so few new neurons over so long periods can be. "
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ABSTRACT: Age and activity might be considered the two antagonistic key regulators of adult neurogenesis. Adult neurogenesis decreases with age but remains present, albeit at a very low level, even in the oldest individuals. Activity, be it physical or cognitive, increases adult neurogenesis and thereby seems to counteract age effects. It is, thus, proposed that activity- dependent regulation of adult neurogenesis might contribute to some sort of “neural reserve,” the brain’s ability to compensate functional loss associated with aging or neurodegeneration. Activity can have nonspecific and specific effects on adult neurogenesis. Mechanistically, nonspecific stimuli that largely affect precursor cell stages might be related by the local microenvironment, whereas more specific, survival-promoting effects take place at later stages of neuronal development and require the synaptic integration of the new cell and its particular synaptic plasticity. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
- "The hippocampus is critically involved in cognition as well as in processes such as anxiety and depression (Moser and Moser, 1998; Fanselow and Dong, 2010; Calabresi et al., 2013), suggesting increased hippocampal vulnerability in the course of the disease. The dentate gyrus (DG) of the hippocampus bears the potential to generate new neurons throughout adulthood (Zhao et al., 2008; Spalding et al., 2013). Adult neural precursor cells (aNPCs) are multipotent cells (Ehninger and Kempermann, 2008) and, after asymmetric division, migrate as doublecortin (DCX)expressing neuroblasts from the subgranular zone into the granular cell layer of the DG, where they differentiate into functional neurons (Kuhn et al., 1996). "
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ABSTRACT: Nonmotor symptoms of cognitive and affective nature are present in premotor and motor stages of Parkinson's disease (PD). Neurogenesis, the generation of new neurons, persists throughout the mammalian life span in the hippocampal dentate gyrus. Adult hippocampal neurogenesis may be severely affected in the course of PD, accounting for some of the neuropsychiatric symptoms such as depression and cognitive impairment. Two important PD-related pathogenic factors have separately been attributed to contribute to both PD and adult hippocampal neurogenesis: dopamine depletion and accumulation of α-synuclein (α-syn). In the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model, altered neurogenesis has been linked merely to a reduced dopamine level. Here, we seek to determine whether a distinct endogenous α-syn expression pattern is associated, possibly contributing to the hippocampal neurogenic deficit. We observed a persistent reduction of striatal dopamine and a loss of tyrosine hydroxylase-expressing neurons in the substantia nigra pars compacta in contrast to a complete recovery of tyrosine hydroxylase-immunoreactive dopaminergic fibers within the striatum. However, dopamine levels in the hippocampus were significantly decreased. Survival of newly generated neurons was significantly reduced and paralleled by an accumulation of truncated, membrane-associated, insoluble α-syn within the hippocampus. Specifically, the presence of truncated α-syn species was accompanied by increased activity of calpain-1, a calcium-dependent protease. Our results further substantiate the broad effects of dopamine loss in PD-susceptible brain nuclei, gradually involved in the PD course. Our findings also indicate a detrimental synergistic interplay between dopamine depletion and posttranslational modification of α-syn, contributing to impaired hippocampal plasticity in PD. © 2015 Wiley Periodicals, Inc.
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