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Gerd Kempermann

Publications and source records attributed to Gerd Kempermann.

At least 37 records · Page 2Linked to original sources
PubMed2005

Nestin-expressing cells divide and adopt a complex electrophysiologic phenotype after transient brain ischemia.

The intermediate filament nestin is upregulated in response to cerebral ischemia; the significance of this, however, is incompletely understood. Here, we used transgenic mice that express green fluorescent protein (GFP) under control of the nestin promotor to characterize the fate of nestin-expressing cells up to 8 weeks after 30 mins occlusion of the middle cerebral artery (MCAo) and reperfusion. The population of nestin-GFP+ cells increased in the ischemic lesion rim and core within 4 days, did not become TUNEL-positive, and was detectable up to 8 weeks in the lesion scar. Nestin-GFP+ cells proliferated in situ and underwent approximately one round of cell division. They were not recruited in large numbers from the subventricular zone (SVZ) as indicated by absence of colabeling with intracerebroventricularly injected dye DiI in the majority of nestin-GFP+ cells. Nestin-GFP+ cells expressed the chondroitin sulfate proteoglycan NG2 and nestin protein, but typically lacked mature astrocytic markers, that is, glial fibrillary acid protein (GFAP) or S100beta. Vice versa, the majority of GFAP+ cells lacked nestin-expression and surrounded the ischemic lesion by 4 days. Whole-cell patch-clamp recordings in acute brain slices from controls showed that only about half of nestin-GFP+ cells displayed complex membrane properties. In contrast, 4 days after the insult all nestin-GFP+ cells expressed these properties. We hypothesize that the change in physiologic properties induced by the ischemic insult is directed toward a specific function of nestin-expressing cells.

Animals↗
PubMed2004

Adult hippocampal neurogenesis and voluntary running activity: circadian and dose-dependent effects.

Running activity increases cell proliferation and neurogenesis in the dentate gyrus of adult mice. The present experiment was designed to investigate whether the effect of activity on adult neurogenesis is dependent on the time of day (circadian phase) and the amount of activity. Mice received restricted access to a running wheel (0, 1, or 3 hr) at one of three times of day: the middle of the light phase (i.e., when mice are normally inactive), dark onset (i.e., when mice begin their nocturnal activity), and the middle of the dark period (i.e., when mice are in the middle of their active period). Cell proliferation and net neurogenesis were assessed after incorporation of the thymidine analog bromodeoxyuridine (BrdU) and immunohistochemical detection of BrdU and neuronal markers. Running activity significantly increased cell proliferation, cell survival, and total number of new neurons only in animals with 3 hr of wheel access during the middle of the dark period. Although activity was positively correlated with increased neurogenesis at all time points, the effects were not statistically significant in animals with wheel access at the beginning of the dark period or during the middle of the light period. These data suggest that the influence of exercise on cell proliferation and neurogenesis is modulated by both circadian phase and the amount of daily exercise, thus providing new insight into the complex relationship between physiological and behavioral factors that can mediate adult neuroplasticity.

Animals↗
PubMed2004

Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice.

In adult hippocampal neurogenesis, new neurons appear to originate from a cell with astrocytic properties expressing glial fibrillary acidic protein (GFAP). Also, new astrocytes are generated in the adult dentate gyrus. Whereas the putative astrocyte-like progenitor cells are consistently S-100beta-negative, many new astrocytes are S-100beta-positive. Thus, it is unclear whether the GFAP-positive progenitor cells are astrocytes in a general sense or rather neural progenitor cells with certain astrocytic characteristics. We therefore investigated the development of GFAP-expressing cells in the context of adult hippocampal neurogenesis. Proliferating cells could be either GFAP-positive or doublecortin-positive (DCX), but never both, indicating two independent populations of dividing cells in the glial and neuronal lineages. Two distinct populations of cells with astroglial properties were detected-one expressing GFAP, the other co-expressing GFAP and S-100beta. We never found S-100beta-cells to be in S-phase. No overlap between neuronal and glial markers was seen at any time point. Thus, astrogenesis occurred in parallel and to some degree independent of adult neurogenesis. The uninterrupted GFAP expression in this lineage, and neuronal markers in the other lineage, argue against a late common precursor for neurogenesis and gliogenesis in the adult hippocampus. Very few newly generated microglia and no new oligodendrocytes were detected. Environmental enrichment and voluntary wheel running-two experimental paradigms with robust stimulatory effects on adult hippocampal neurogenesis-affected hippocampal astrogenesis differentially: Running, but not enrichment, strongly induced net astrogenesis (GFAP/S-100beta), but also GFAP-positive S-100beta-negative cells, which thus appear to be a transiently amplifiable intermediate population within the glial lineage.

Animals↗
PubMed2004

Functional significance of adult neurogenesis.

'Function' is the key criterion for determining whether adult neurogenesis - be it endogenous, induced, or after transplantation - is successful and has truly generated new nerve cells. Function, however, is an elusive and problematic term. A satisfying statement of function will require evaluation on the three conceptual levels of cells, networks, and systems - and potentially even beyond, on the level of psychology. Neuronal development is a lengthy process, a fact that must be considered when judging causes and consequences in experiments that address function and function-dependent regulation of adult neurogenesis. Nevertheless, the information that has been obtained and published so far provides ample evidence that neurons generated in the adult can function and even suggests how they might contribute to cognitive processes.

Adult↗
PubMed2004

Milestones of neuronal development in the adult hippocampus.

Adult hippocampal neurogenesis originates from precursor cells in the adult dentate gyrus and results in new granule cell neurons. We propose a model of the development that takes place between these two fixed points and identify several developmental milestones. From a presumably bipotent radial-glia-like stem cell (type-1 cell) with astrocytic properties, development progresses over at least two stages of amplifying lineage-determined progenitor cells (type-2 and type-3 cells) to early postmitotic and to mature neurons. The selection process, during which new neurons are recruited into function, and other regulatory influences differentially affect the different stages of development.

Adult↗
PubMed2004

The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Animals↗
PubMed2004

Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus.

Steroid hormones are regulators of adult hippocampal neurogenesis and are central to hypotheses regarding adult neurogenesis in age-related and psychiatric disturbances associated with altered hippocampal plasticity--most notably dementias and major depression. Using immunohistochemistry, we examined the expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors during adult hippocampal neurogenesis. In young mice only 27% of dividing cells in the subgranular zone expressed GR, whereas 4 weeks after division 87% had become positive for GR and MR. GR was expressed by 50% of the radial glia-like type-1 and type-2a progenitor cells, whereas MR was expressed only by mature calbindin-positive granule cells. Doublecortin-positive neuronal progenitor cells (type-2b) and early postmitotic calretinin-positive neurons were devoid of GR and MR expression. Fifty per cent of the intermediate type-3 cells showed GR expression, possibly reflecting cells terminating maturation. Thus, all subpopulations of dividing precursor cells showed an identical receptor profile (50% GR, no MR), except for type-2b cells, which expressed neither receptor. There was also no overlap between calretinin and GR early postnatally (P8) or after physical activity or exposure to an enriched environment, both of which are potent neurogenic stimuli. In contrast, in old age calretinin-positive young neurons became GR and MR positive, suggesting increased steroid sensitivity. Age also increased the expression of GR in type-1 and type-2a precursor cells. Other intermediates were so rare in old age that they could not be studied. This course and variability of receptor expression in aging might help to explain differential vulnerability of adult neural precursor cells to corticoid-mediated influences.

Animals↗
PubMed2003

Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli.

To study how adult hippocampal neurogenesis might originate from the proliferation of stem or progenitor cells in vivo, we have used transgenic mice expressing green fluorescent protein (GFP) under the nestin promoter to identify these cells. Having described an astrocyte-like type 1 cell with low proliferative activity, a characteristic morphology, vascular end feet, and passive electrophysiological properties, we focused here on the large population of nestin-GFP-expressing type 2 cells, which lack all these features. Type 2 cells were highly proliferative and showed signs suggestive of their involvement in the neuronal lineage. They could be subclassified by the absence (type 2a) or presence (type 2b) of a coexpression of the early neuronal marker doublecortin. A third type of proliferating cells was doublecortin positive but nestin-GFP negative (type 3). We believe that type 2a, 2b, and 3 cells mirror a marker progression during earliest neuronal development. This view is supported by the increasing coexpression of the early granule cell-specific marker Prox-1. The low proliferative activity of type 1 cells showed little change over time or under "neurogenic interventions," such as a challenge by environmental complexity (ENR) or voluntary physical activity (RUN). However, RUN led to a significant increase of type 2 cells labeled with the proliferation marker bromodeoxyuridine (BrdU). ENR did not cause increased cell proliferation or an increased number of BrdU-labeled type 2 cells, but both ENR and RUN resulted in more newly generated cells lacking nestin-GFP immunoreactivity and expressing Prox-1. These findings allow us to break down what was broadly perceived as "proliferation" in earlier experiments into the relative contribution of several cell types, representing the earliest steps of neuronal development.

Animals↗
PubMed2003

Depressed new neurons--adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression.

In a novel theory, a failure of adult hippocampal neurogenesis has been proposed to provide the biological and cellular basis of major depression. The as yet unresolved function of the new hippocampal neurons will have to be in the center of any attempt to prove this hypothesis. Only knowledge of normal functional relevance of new neurons will allow an assessment of their potential role in disturbed hippocampal function in depression; however, major depression is not primarily a hippocampal disorder. We therefore propose that consideration of the neurogenesis hypothesis of depression be the most prominent aspect of a more general cellular plasticity hypothesis.

Adult↗
PubMed2003

Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes.

Based on the expression of glial fibrillary acidic protein (GFAP), a recent hypothesis considered stem or progenitor cells in the adult hippocampus to be a type of astrocyte. In a complementary approach, we used transgenic mice expressing green fluorescent protein (GFP) under the promoter for nestin, an intermediate filament present in progenitor cells, to demonstrate astrocytic features in nestin-GFP-positive cells. Morphologically, two subpopulations of nestin-GFP-positive cells were distinguishable; one had an elaborate tree of processes in the granule cell layer and expression of GFAP (but not of S100beta, another astrocytic marker). Electron microscopy revealed vascular end feet of nestin-positive cells, further supporting astrocytic differentiation. Electrophysiological examination of nestin-GFP-positive cells on acutely isolated hippocampal slices showed passive current characteristics of astrocytes in one subset of cells. Among the nestin-GFP-expressing cells with lacking astrocytic features, two cell types could be identified electrophysiologically: cells with delayed-rectifying potassium currents and a very small number of cells with sodium currents, potentially representing signs of the earliest steps of neuronal differentiation.

Age Factors↗
PubMed2003

Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice.

We here show that the early postmitotic stage of granule cell development during adult hippocampal neurogenesis is characterized by the transient expression of calretinin (CR). CR expression was detected as early as 1 day after labeling dividing cells with bromodeoxyuridine (BrdU), but not before. Staining for Ki-67 confirmed that no CR-expressing cells were in cell cycle. Early after BrdU, CR colocalized with immature neuronal marker doublecortin; and later with persisting neuronal marker NeuN. BrdU/CR-labeled cells were negative for GABA and GABAA1 receptor, but early on expressed granule cell marker Prox-1. After 6 weeks, no new neurons expressed CR, but all contained calbindin. Stimuli inducing adult neurogenesis have limited (enriched environment), strong (voluntary wheel running), and very strong effects on cell proliferation (kainate-induced seizures). In these models the induction of cell proliferation was paralleled by an increase of CR-positive cells, indicating the stimulus-dependent progression from cell division to a postmitotic stage.

Aging↗
PubMed2003

The nature and identification of quantitative trait loci: a community's view.

This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Animals↗
PubMed2003

Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis.

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.

Age Factors↗
PubMed2003

Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex.

We here report that voluntary wheel running led to a regional increase in the number of newly generated cortical microglia. We asked how adult cortical cell genesis would respond to environmental enrichment and physical activity, both stimuli that robustly induce adult hippocampal neurogenesis. After labeling proliferating cells with bromodeoxyuridine (BrdU) and immunohistochemical detection of BrdU, we found that both experimental paradigms did not result in general effects on cell proliferation and cell genesis in the neocortex. However, there were regionally and layer specific changes in the number of BrdU marked cells, both 1 day and 4 weeks after BrdU. Environmental enrichment led to a significant increase in the number of new astrocytes in layer 1 of the motor cortex. Voluntary wheel running, in contrast, caused an induction in the proliferation of microglia in superficial cortical layers of several brain regions. Under no condition was the number of new oligodendrocytes measurably enhanced. In contrast to the hippocampus, we did not find any new neurons in the cortex. The physiological 'activation' of microglia adds a new aspect to the question of microglial function in the healthy brain and of how adult brain cells can plastically react to physiological stimuli.

Animals↗
PubMed2003

Adult-born hippocampal neurons mature into activity-dependent responsiveness.

The mammalian hippocampus is a highly plastic brain structure in which new neurons are generated throughout adulthood. Do these new neurons qualitatively and quantitatively participate in the activity-dependent gene expression after challenging the hippocampus in a learning task? Adult mice were injected with bromodeoxyuridine (BrdU) to label dividing cells and indeed, individual BrdU-labelled new neurons expressed the immediate early gene protein (IEGp) c-fos during the acquisition phase of the Morris water maze task to the same extend as older granule cells. To assess the responsiveness of all new neurons we also analysed the expression patterns of three IEGps (c-fos, zif268 and Homer1A) after kainic acid (KA)- or pentylenetetrazol (PTZ)-induced seizures. We found that after a maturation period of between 2 and 5 weeks a comparable ratio of adult-generated granule cells participated in IEGp-expression as in the population of older granule cells. Thus, new neurons appear quantitatively integrated into hippocampal circuits, suggestive of a relevant contribution to hippocampal function.

Animals↗
PubMed2003

Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice.

New neurons are continually generated in the adult hippocampus, but the important question, whether adult neurogenesis is transient or leads to the lasting presence of new neurons, has not yet been answered. Dividing cells were labeled with bromodeoxyuridine (BrdU) and were investigated by means of immunofluorescence and confocal microscopy at several time-points 1 day to 11 months thereafter. BrdU-labeled neurons remained stable in number and in their relative position in the granule cell layer over at least 11 months. This finding implies that the addition of new neurons is not transient and that their final number and localization are determined early. By contrast, expression of immature markers beta-III-tubulin and doublecortin in BrdU-labeled cells, peaked early after division and was not detectable after 4 weeks. In transgenic mice expressing enhanced green fluorescent protein under the nestin promoter none of the BrdU/nestin-positive cells early after division expressed the mature marker NeuN, confirming that no dividing neurons were detected. These new data suggest that new neurons are recruited early from the pool of proliferating progenitor cells and lead to a lasting effect of adult neurogenesis.

Animals↗
PubMed2002

Genetic influence on phenotypic differentiation in adult hippocampal neurogenesis.

Regulation of adult hippocampal neurogenesis has different regulatory levels, including cell proliferation, survival and differentiation. Cell proliferation and survival are differentially influenced by inheritable traits and the genetic background determines which regulatory levels of adult hippocampal neurogenesis are preferentially involved in a neurogenic response to environmental stimuli. We here compared baseline adult neurogenesis in wild-derived strain Mus spretus and three inbred laboratory strains: A/J, C3H/HeJ and DBA/2J. Proliferation of was similar in the four strains, with the extremes being A/J, which had about 2100+/-570 (mean+/-S.D.) labeled newborn cells per dentate gyrus (after 6 days of bromodeoxyuridine injections), and DBA/2J, which had approximately 1400+/-260. C3H/HeJ had approximately 1500+/-600 and M. spretus had 1550+/-270. Survival of new cells after 4 weeks was 19% in A/J and DBA/2J, and 21% in M. spretus, but 37% in C3H/HeJ. Survival in C3H/HeJ was significantly different from DBA/2. Phenotypic analysis revealed that DBA/2J produced significantly fewer new neurons than A/J and C3H/HeJ (47% vs. 63% and 67%) but significantly more new astrocytes than A/J and C3H/HeJ (28% vs. 9% and 11%). In absolute terms there were 370+/-120 new neurons in C3H/HeJ, 250+/-60 in A/J, 130+/-50 in DBA/2J, and 190+/-130 in M. spretus. Our results indicate that regulation of adult hippocampal neurogenesis affects the level of phenotypic differentiation. At the present time it cannot be determined whether this regulation occurs by influencing cell fate decisions or by promoting selective survival.

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