Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain

Neurons and glia are generated throughout adulthood from proliferating cells in two regions of the rat brain, the subventricular zone (SVZ) and the hippocampus. This study shows that exogenous basic fibroblast growth factor (FGF-2) and epidermal growth factor (EGF) have differential and site-specific effects on progenitor cells in vivo. Both growth factors expanded the SVZ progenitor population after 2 weeks of intracerebroventricular administration, but only FGF-2 induced an increase in the number of newborn cells, most prominently neurons, in the olfactory bulb, the normal destination for neuronal progenitors migrating from the SVZ. EGF, on the other hand, reduced the total number of newborn neurons reaching the olfactory bulb and substantially enhanced the generation of astrocytes in the olfactory bulb. Moreover, EGF increased the number of newborn cells in the striatum either by migration of SVZ cells or by stimulation of local progenitor cells. No evidence of neuronal differentiation of newborn striatal cells was found by three-dimensional confocal analysis, although many of these newborn cells were associated closely with striatal neurons. The proliferation of hippocampal progenitors was not affected by either growth factor. However, EGF increased the number of newborn glia and reduced the number of newborn neurons, similar to the effects seen in the olfactory bulb. These findings may be useful for elucidating the in vivo role of growth factors in neurogenesis in the adult CNS and may aid development of neuronal replacement strategies after brain damage

Functional maturation of isolated neural progenitor cells from the adult rat hippocampus

Although neural progenitor cells (NPCs) may provide a source of new neurons to alleviate neural trauma, little is known about their electrical properties as they differentiate. We have previously shown that single NPCs from the adult rat hippocampus can be cloned in the presence of heparan sulphate chains purified from the hippocampus, and that these cells can be pushed into a proliferative phenotype with the mitogen FGF2 [Chipperfield, H., Bedi, K.S., Cool, S.M. & Nurcombe, V. (2002) Int. J. Dev. Biol., 46, 661-670]. In this study, the active and passive electrical properties of both undifferentiated and differentiated adult hippocampal NPCs, from 0 to 12 days in vitro as single-cell preparations, were investigated. Sparsely plated, undifferentiated NPCs had a resting membrane potential of approximate to -90 mV and were electrically inexcitable. In > 70%, ATP and benzoylbenzoyl-ATP evoked an inward current and membrane depolarization, whereas acetylcholine, noradrenaline, glutamate and GABA had no detectable effect. In Fura-2-loaded undifferentiated NPCs, ATP and benzoylbenzoyl-ATP evoked a transient increase in the intracellular free Ca2+ concentration, which was dependent on extracellular Ca2+ and was inhibited reversibly by pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS), a P2 receptor antagonist. After differentiation, NPC-derived neurons became electrically excitable, expressing voltage-dependent TTX-sensitive Na+ channels, low- and high-voltage-activated Ca2+ channels and delayed-rectifier K+ channels. Differentiated cells also possessed functional glutamate, GABA, glycine and purinergic (P2X) receptors. Appearance of voltage-dependent and ligand-gated ion channels appears to be an important early step in the differentiation of NPCs

Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord

The existence of multipotent progenitor populations in the adult forebrain has been widely studied. To extend this knowledge to the adult spinal cord we have examined the proliferation, distribution, and phenotypic fate of dividing cells in the adult rat spinal cord. Bromodeoxyuridine (BrdU) was used to label dividing cells in 13- to 14-week-old, intact Fischer rats. Single daily injections of BrdU were administered over a 12 d period. Animals were killed either 1 d or 4 weeks after the last injection of BrdU. We observed frequent cell division throughout the adult rodent spinal cord, particularly in white matter tracts (5-7% of all nuclei). The majority of BrdU-labeled cells colocalized with markers of immature glial cells. At 4 weeks, 10% of dividing cells expressed mature astrocyte and oligodendroglial markers. These data predict that 0.75% of all astrocytes and 0.82% of all oligodendrocytes are derived from a dividing population over a 4 week period. To determine the migratory nature of dividing cells, a single BrdU injection was given to animals that were killed 1 hr after the injection. In these tissues, the distribution and incidence of BrdU labeling matched those of the 4 week post injection (pi) groups, suggesting that proliferating cells divide in situ rather than migrate from the ependymal zone. These data suggest a higher level of cellular plasticity for the intact spinal cord than has previously been observed and that glial progenitors exist in the outer circumference of the spinal cord that can give rise to both astrocytes and oligodendrocytes

Human Adult Neurogenesis: Evidence and Remaining Questions

Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan

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

Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task

A number of reports have indicated that adult neurogenesis might be involved in hippocampal function. While increases in adult neurogenesis are paralleled by improvements on learning tasks and learning itself can promote the survival of newly generated neurons in the hippocampus, a causal link between learning processes and adult hippocampal neurogenesis is difficult to prove. Here, we addressed the related question of whether the baseline level of adult neurogenesis is predictive of performance on the water maze task as a test of hippocampal function. We used ten strains of recombinant inbred mice, based on C57BL/6, which are good learners and show high baseline levels of neurogenesis, and DBA/2, which are known to be poor learners and which exhibit low levels of adult neurogenesis. Two of these strains, BXD-2 and BXD-8, showed a 26-fold difference in the number of newly generated neurons per hippocampus. Over all strains, including the parental strains, there was a significant correlation between the number of new neurons generated in the dentate gyrus and parameters describing the acquisition of the water maze task (slope of the learning curves). Similar results were seen when the parental strains were not included in the analysis. There was no correlation between adult hippocampal neurogenesis and probe trial performance, performance on the rotarod, overall locomotor activity, and baseline serum corticosterone levels. This result supports the hypothesis that adult neurogenesis is involved in specific aspects of hippocampal function, particularly the acquisition of new information

Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus

AbstractNew neurons are continuously born in the dentate gyrus of the adult mouse hippocampus, and regulation of adult neurogenesis is influenced by both genetic and environmental determinants. Mice of the 129/SvJ strain have significantly less hippocampal neurogenesis than other inbred mouse strains [1] and do not perform well in learning tasks. Here, the impact of environmental stimuli on brain plasticity during adulthood of 129/SvJ mice was studied using ‘enriched environments’ where mice receive complex inanimate and social stimulation [2,3]. In contrast to our earlier reports on mice of the C57BL/6 strain – which are competent in learning tasks and in which environmental stimulation did not influence cell proliferation [4,5] – environmentally stimulated 129/SvJ mice were found to have twice as many proliferating cells in the dentate gyrus compared with mice in standard housing. Environmental stimulation fostered the survival of newborn cells in 129/SvJ mice; this effect had also been seen in C57BL/6 mice. Phenotypic analysis of the surviving cells revealed that environmental stimulation resulted in 67% more new neurons. In combination with our earlier results, these data indicate a differential impact of inheritable traits on the environmental regulation of adult hippocampal neurogenesis. In addition, we observed behavioral changes in environmentally stimulated 129/SvJ mice

More hippocampal neurons in adult mice living in an enriched environment

Neurogenesis occurs in the dentate gyrus of the hippocampus throughout the life of a rodent, but the function of these new neurons and the mechanisms that regulate their birth are unknown. Here we show that significantly more new neurons exist in the dentate gyrus of mice exposed to an enriched environment compared with littermates housed in standard cages. We also show, using unbiased stereology, that the enriched mice have a larger hippocampal granule cell layer and 15 per cent more granule cell neurons in the dentate gyrus