Gerd Kempermann

Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, North Rhine-Westphalia, Germany

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Publications (178)1196.96 Total impact

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    ABSTRACT: In much animal research, genetic variation is rather avoided than utilized as a powerful tool to identify key regulatory genes in complex phenotypes. Adult hippocampal neurogenesis is one such highly complex polygenic trait, for which the understanding of the molecular basis is fragmented and incomplete, and for which novel genetic approaches are needed. In the present study, we aimed at marrying the power of the BXD panel, a mouse genetic reference population, with the flexibility of a cell culture model of adult neural precursor proliferation and differentiation. We established adult-derived hippocampal precursor cell cultures from 20 strains of the BXD panel, including the parental strains C57BL/6J and DBA/2J. The rates of cell proliferation and neuronal differentiation were measured and transcriptional profiles were obtained from proliferating cultures. Together with the published genotypes of all lines, these data allowed a novel systems genetics analysis combining quantitative trait locus analysis with transcript expression correlation at a cellular level to identify genes linked with the differences in proliferation. In a proof-of-principle analysis, we identified Lrp6, the gene encoding the co-receptor to Frizzled in the Wnt pathway, as a potential negative regulator of precursor proliferation. Overexpression and siRNA silencing confirmed the regulatory role of Lrp6. As well as adding to our knowledge of the pathway surrounding Wnt in adult hippocampal neurogenesis, this finding allows the new appreciation of a negative regulator within this system. In addition, the resource and associated methodology will allow the integration of regulatory mechanisms at a systems level. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Stem Cells
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    ABSTRACT: Resveratrol (RVTL) is a flavonoid found in red wine and has been publicized heavily as an anti-aging compound. Indeed, basic research confirms that although there is much hype in the promotion of RVTL, flavonoids such as RVTL have a wide range of biological effects. We here investigated the effects of RVTL treatment on hippocampal plasticity and memory performance in female Balb/C mice, a strain with low baseline levels of adult neurogenesis. Two weeks of treatment with RVTL (40 mg/kg) induced the production of new neurons in vivo by increasing cell survival and possibly precursor cell proliferation. In addition, RVTL decreased the number of apoptotic cells. The number of doublecortin (DCX)-expressing intermediate cells was increased. RVTL stimulated neuronal differentiation in vitro without effects on proliferation. In the dentate gyrus, RVTL promoted the formation and maturation of spines on granule cell dendrites. RVTL also improved performance in the step down passive avoidance test. The RVTL-treated mice showed increase in the levels of two key signaling proteins, phospho-Akt and phospho-PKC, suggesting the involvement of these signaling pathways. Our results support the vision that flavonoids such as resveratrol deserve further examination as plasticity-inducing compounds in the context of successful cognitive aging.
    Preview · Article · Dec 2015 · PLoS ONE
  • Gerd Kempermann
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    ABSTRACT: Manipulating neurotransmitter release from astrocytes neighboring the developing new neurons in the course of adult hippocampal neurogenesis, Sultan et al. (2015) reveal that glial influence on neurogenesis ranges from controlling basic precursor cell function well into the establishment of functional circuitry. This extends the concept of the "neurogenic niche'' and its key role into advanced stages of adult neuronal development.
    No preview · Article · Dec 2015 · Neuron
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    Gerd Kempermann
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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.
    Preview · Article · Nov 2015 · Cold Spring Harbor perspectives in biology
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    ABSTRACT: This study investigates the effects of fitness changes on hippocampal microstructure and hippocampal volume. Fifty-two healthy participants aged 59-74 years with a sedentary lifestyle were randomly assigned to either of two levels of exercise intensity. Training lasted for six months. Physical fitness, hippocampal volumes, and hippocampal microstructure were measured before and after training. Hippocampal microstructure was assessed by mean diffusivity, which inversely reflects tissue density; hence, mean diffusivity is lower for more densely packed tissue. Mean changes in fitness did not differ reliably across intensity levels of training; hence data were collapsed across groups. Multivariate modeling of pretest-posttest differences using structural equation modeling (SEM) revealed that individual differences in latent change were reliable for all three constructs. More positive changes in fitness were associated with more positive changes in tissue density (i.e., more negative changes in mean diffusivity), and more positive changes in tissue density were associated with more positive changes in volume. We conclude that fitness-related changes in hippocampal volume may be brought about by changes in tissue density. The relative contributions of angiogenesis, gliogenesis and/or neurogenesis to changes in tissue density remain to be identified.
    Full-text · Article · Nov 2015 · NeuroImage
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    Fanny Ehret · Steffen Vogler · Gerd Kempermann
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    ABSTRACT: The niche concept of stem cell biology proposes a functional unit between the precursor cells and their local microenvironment, to which several cell types might contribute by cell-cell contacts, extracellular matrix, and humoral factors. We here established three co-culture models (with cell types separated by membrane) for both adherent monolayers and neurospheres to address the potential influence of different niche cell types in the neurogenic zone of the adult hippocampus of mice. Astrocytes and endothelial cells enhanced precursor cell proliferation and neurosphere formation. Endothelial factors also led to a prolonged increase in proliferation after growth factor withdrawal, which otherwise induces differentiation. All niche cell types enhanced cell survival in monolayer cultures, endothelial cells also stimulated neuronal differentiation. A parallel trend elicited by astrocytes did not reach conventional statistical significance. Pericytes had variable effects here. We did not observe changes in differentiation in neurosphere co-cultures. In summary, our data indicate that in precursor cell culture protocols survival could be improved by adding as yet unknown factors physiologically contributed by astrocytes and endothelial cells. Our findings also underscore the complexity of the niche and the differential impact of factors from the different sources on distinct aspects of neuronal development. With the help of the models presented here, identification of these factors and their specific biological activity can now be initiated.
    Full-text · Article · Oct 2015 · Stem Cell Research
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    Full-text · Dataset · Oct 2015
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    ABSTRACT: In the context of television consumption and its opportunity costs the question arises how far experiencing mere representations of the outer world would have the same neural and cognitive consequences than actively interacting with that environment. Here we demonstrate that physical interaction and direct exposition are essential for the beneficial effects of environmental enrichment. In our experiment, the mice living in a simple standard cage placed in the centre of a large enriched environment only indirectly experiencing the stimulus-rich surroundings (IND) did not display increased adult hippocampal neurogenesis. In contrast, the mice living in and directly experiencing the surrounding enriched environment (DIR) and mice living in a similar enriched cage containing an uninhabited inner cage (ENR) showed enhanced neurogenesis compared to mice in control conditions (CTR). Similarly, the beneficial effects of environmental enrichment on learning performance in the Morris Water maze depended on the direct interaction of the individual with the enrichment. In contrast, indirectly experiencing a stimulus-rich environment failed to improve memory functions indicating that direct interaction and activity within the stimulus-rich environment are necessary to induce structural and functional changes in the hippocampus.
    Full-text · Article · Sep 2015 · Scientific Reports
  • Gerd Kempermann · Hongjun Song · Fred H. Gage
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    ABSTRACT: Of the neurogenic zones in the adult brain, adult hippocampal neurogenesis attracts the most attention, because it is involved in higher cognitive function, most notably memory processes, and certain affective behaviors. Adult hippocampal neurogenesis is also found in humans at a considerable level and appears to contribute significantly to hippocampal plasticity across the life span, because it is regulated by activity. Adult hippocampal neurogenesis generates new excitatory granule cells in the dentate gyrus, whose axons form the mossy fiber tract that links the dentate gyrus to CA3. It originates from a population of radial glia-like precursor cells (type 1 cells) that have astrocytic properties, express markers of neural stem cells and divide rarely. They give rise to intermediate progenitor cells with first glial (type 2a) and then neuronal (type 2b) phenotype. Through a migratory neuroblast-like stage (type 3), the newborn, lineage-committed cells exit the cell cycle and enter a maturation stage, during which they extend their dendrites into a the molecular layer and their axon to CA3. They go through a period of several weeks, during which they show increased synaptic plasticity, before finally becoming indistinguishable from the older granule cells. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    No preview · Article · Sep 2015 · Cold Spring Harbor Perspectives in Medicine
  • Alexander Garthe · Ingo Roeder · Gerd Kempermann
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    ABSTRACT: We here show that living in a stimulus-rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss-of-function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals' behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro-neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end-point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Aug 2015 · Hippocampus
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    Full-text · Dataset · Jun 2015
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    ABSTRACT: We previously reported that inbred, genetically identical mice living in one enriched environment develop individual behavioral trajectories, indicating increasingly different levels of spatial exploratory behavior as quantified by roaming entropy. Cumulative roaming entropy (cRE) correlated positively with adult hippocampal neurogenesis, a type of plasticity involved in the flexible integration of new information into existing contexts (Freund et al., 2013). The study on which we report here was done in parallel to that first experiment, but here we acquired detailed observational data on the behavior of individual mice. Roaming entropy (RE) was again assessed in real-time with an antenna-based system over the entire experimental period of 3 months. Compared to the least active mice in the enclosure (low number of antenna contacts), the most active animals showed tendencies of increased socially interactive behavior in the final observation block whereas least active mice displayed more self-related behavior (non-social local exploration and play). When looking at roaming behavior, we discovered that RE correlated negatively with latent factors representing social exploratory and non-social exploratory and play behavior. Adult neurogenesis could not be studied in the present cohort but we do know that under identical conditions, cumulative RE correlated positively with adult hippocampal neurogenesis. We can thus hypothesize that the mice with more exploratory experience in terms of areal coverage (as quantified by RE) and related greater levels of adult hippocampal plasticity, might also be the ones that were less involved in interactions within the group and, hence, more individualistic. While this remains to be confirmed experimentally, the present data suggest that the described mechanism of individualization, which has previously been shown to be hippocampus-dependent, has a social component.
    Full-text · Article · May 2015 · Neuroscience
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    Zeina Nicola · Klaus Fabel · Gerd Kempermann
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    ABSTRACT: When does adult hippocampal neurogenesis begin? We describe the development of the neurogenic niche in the subgranular zone (SGZ) of the hippocampal dentate gyrus. We did so from the perspective of the situation in the adult. Ontogeny of the dentate gyrus is complex and results in an ectopic neurogenic niche that lifelong generates new granule cells. Neurogenesis during the fetal and early postnatal periods builds the dentate gyrus and gives way to activity-dependent "adult" neurogenesis. We used markers most relevant to adult neurogenesis research to describe this transition: Nestin, Sox2, BLBP, GFAP, Tbr2, Doublecortin (DCX), NeuroD1 and Prox1. We found that massive changes and a local condensation of proliferating precursor cells occurs between postnatal day 7 (P7), near the peak in proliferation, and P14. Before and around P7, the spatial distribution of cells and the co-localization of markers were distinct from the situation in the adult. Unlike the adult SGZ, the marker pair Nestin/Sox2 and the radial glial marker BLBP were not overlapping during embryonic development, presumably indicating different types of radial glia-like cells. Before P7 GFAP-positive cells in the hilus lacked the radial orientation that is characteristic of the adult type-1 cells. DCX, which is concentrated in type-2b and type-3 progenitor cells and early postmitotic neurons in the adult, showed diffuse expression before P7. Intermediate progenitor cell marker Tbr2 became restricted to the SGZ but was found in the granule cell layer (GCL) and hilus before. Lineage markers NeuroD1 and Prox1 confirmed this pattern. We conclude that the neurogenic niche of adult neurogenesis is in place well before true adulthood. This might indicate that consistent with the hypothesized function of adult neurogenesis in activity-dependent plasticity, the early transition from postnatal neurogenesis to adult neurogenesis coincides with the time, when the young mice start to become active themselves.
    Preview · Article · May 2015 · Frontiers in Neuroanatomy
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    ABSTRACT: Matrix-metalloproteinase and photosensitive peptide units are combined with heparin and poly(ethylene glycol) into a light-sensitive multicomponent hydrogel material. Localized degradation of the hydrogel matrix allows the creation of defined spatial constraints and adhesive patterning for cells grown in culture. Using this matrix system, it is demonstrated that the degree of confinement determines the fate of neural precursor cells in vitro.
    Full-text · Article · Mar 2015 · Advanced Healthcare Materials
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    ABSTRACT: CyclinD2 knockout mice show decreased levels of endogenous dentate neurogenesis. We investigated whether transplanted dentate progenitor cells from wild-type mice respond in vivo to an enriched environment and whether they improve deficient dentate neurogenesis through a neurotrophic effect. Adult CyclinD2 knockout mice were transplanted with passaged adult progenitor cells and kept in an enriched environment or under standard housing conditions in isolation. After one week, animals living in an enriched environment underwent water maze testing. Progenitor cells grown on a Laminin/Poly-D-Lysine monolayer expressed SOX2 and Nestin and could be differentiated in vitro into neurons and astrocytes. After transplantation into the dentate gyrus, cells preferentially survived along the Laminin-rich ependymal lining of the basal cistern or basal membrane of capillaries. A subpopulation of transplanted cells migrated into the interstitial space of the hippocampus and was not associated with Laminin. Environmental enrichment led to a significant increase in the survival of transplanted progenitor cells on Laminin in the dentate gyrus after two weeks. However, animals did not show an enhanced performance in the Morris water maze, and transplantation failed to exert a neurotrophic effect on endogenous neurogenesis after two weeks. A major limitation of the study however is the short-term period of investigation, which may have been insufficient to capture functional effects. In conclusion, initial survival of transplanted neural progenitor cells was dependent on the presence of Laminin and was significantly enhanced by environmental enrichment. Further studies are needed to address whether an enriched environment continues to promote graft survival over longer periods of time.
    No preview · Article · Jan 2015 · Cell Transplantation
  • Gerd Kempermann
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    ABSTRACT: In this brief chapter, the question is discussed whether acutely stimulating adult hippocampal neurogenesis would indeed be a meaningful medical intervention. This is generally assumed. However, the degree to which new neurons are lastingly integrated into the neuronal network is not only a matter of the acute availability of a pool of precursor cells and immature neurons but also (and more importantly) specific survival of the newborn cells. Under normal conditions, only a small percentage of new cells terminally differentiate into new granule cells. Across the lifespan, a sufficiently large pool of recruitable cells must be maintained, rather than focusing on achieving acute peaks of proliferation, because these new cells can only build upon what is already present. Consequently, maintaining youthful levels of precursor cell activity in the dentate gyrus is a prerequisite for lifelong, cellular plasticity.
    No preview · Chapter · Jan 2015
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    ABSTRACT: Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12months of age, cell proliferation and survival of newborn neurons was reduced in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6months, hippocampal neurogenesis was altered in CADASIL mice independently of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell-autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Neurobiology of Disease
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    ABSTRACT: Exercise stimulates cellular brain plasticity by extending the pool of proliferating neural precursor cells in the adult hippocampus. This effect has been investigated extensively, but the most immediate cellular effect induced by exercise that results in this acute increase in the number of cycling cells remained unclear. In the developing brain as well as adult pathological models, cell cycle alterations have a major influence on the balance between proliferative and neurogenic divisions. In this study we investigated whether this might also apply to the acute physiological pro-neurogenic stimulus of physical exercise in adulthood. Do changes in cell cycle precede the measurable increase in proliferation? After 5 days of voluntary wheel running, however, we measured only a very small, statistically not significant acceleration in cell cycle, which could not quantitatively explain the observed increase in proliferating cells after exercise. Thus, at this acute stage, changes at the level of cell cycle control is not the primary causal mechanism for the expansion of the precursor cell population, although with time after the stimulus changes in cell cycle of the entire population of labeled cells might be the result of the expanded pool of cells that have progressed to the advanced neurogenic stages with shorter cell cycle length.
    Full-text · Article · Oct 2014 · Frontiers in Neuroscience
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    Nambirajan Govindarajan · Gerd Kempermann
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    ABSTRACT: In May this year, Stockholm hosted a Keystone Symposium on Adult Neurogenesis, attracting scientists from around the world despite the lack of customary snow. The symposium offered an extraordinary program, covering diverse topics that ranged from the neural stem cell lineage and regulation of neurogenesis to functional aspects of neurogenesis in homeostasis and disease, and even computational modeling. This Meeting Review describes some of the exciting presentations and emerging themes from the symposium, which reveal how much this young field has matured.
    Preview · Article · Oct 2014 · Development
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    ABSTRACT: CD4 + T cells provide a neuro-immunological link in the regulation of adult hippocampal neurogenesis, but the exact mechanisms underlying enhanced neural precursor cell proliferation and the relative contribution of different T helper (Th) cell subsets have remained unclear. Here, we explored the proneurogenic potential of interleukin 17-producing T helper (Th17) cells, a developmentally and functionally distinct Th cell subset that is a key mediator of autoimmune neurodegeneration. We found that base-line proliferation of hippocampal precursor cells in a T cell-deficient mouse model of impaired hippocampal neurogenesis can be restored upon adoptive transfer with homogeneous Th17 populations enriched for myelin-reactive T cell receptors. In these experiments, enhanced proliferation was independent of direct interactions of infiltrating Th17 cells with precursor cells or neighboring cells in the hippocampal neurogenic niche. Complementary studies in immunocompetent mice identified several receptors for Th17 cell-derived cytokines with mRNA expression in hippocampal precursor cells and dentate gyrus tissue, suggesting that Th17 cell activity in peripheral lymphoid tissues might promote hippocampal neurogenesis through secreted cytokines.
    Full-text · Article · Jul 2014 · F1000 Research

Publication Stats

24k Citations
1,196.96 Total Impact Points

Institutions

  • 2010-2015
    • Deutsches Zentrum für Neurodegenerative Erkrankungen
      Bonn, North Rhine-Westphalia, Germany
  • 2008-2015
    • Technische Universität Dresden
      • Center for Regenerative Therapies Dresden
      Dresden, Saxony, Germany
  • 2007-2015
    • Center for Regenerative Therapies, Dresden
      Dresden, Saxony, Germany
  • 2001-2010
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
  • 2002-2009
    • Charité Universitätsmedizin Berlin
      • Department of Neurology with Chair in Experimental Neurology/BNIC
      Berlín, Berlin, Germany
  • 2002-2005
    • Humboldt-Universität zu Berlin
      • Institute for Theoretical Biology (ITB)
      Berlín, Berlin, Germany
  • 1999-2002
    • Universität Regensburg
      • Department of Neurology
      Ratisbon, Bavaria, Germany
  • 1997-1999
    • Salk Institute
      • Laboratory of Genetics
      La Jolla, California, United States
  • 1998
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States