The neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for?

Several theories have proposed possible functions of adult neurogenesis in learning processes on a systems level, such as the avoidance of catastrophic interference and the encoding of temporal and contextual information, and in emotional behavior. Under the assumption of such functionality of new neurons, the question arises: what are the consequences of adult hippocampal neurogenesis beyond the temporally immediate computational benefit? What might provide the evolutionary advantage of maintaining neurogenesis in the dentate gyrus but almost nowhere else? I propose that over the course of life, activity-dependently regulated adult neurogenesis reveals its true significance in the retained ability for lasting and cumulative network adaptations. The hippocampal precursor cells that generate new neurons with their particular acute function represent a 'neurogenic reserve': the potential to remain flexible and plastic in hippocampal learning when the individual is exposed to novelty and complexity

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

Serotonin is required for exercise-induced adult hippocampal neurogenesis

Voluntary wheel running has long been known to induce precursor cell proliferation in adult hippocampal neurogenesis in rodents. However, mechanisms that couple activity with the promitotic effect are not yet fully understood. Using tryptophan hydroxylase (TPH) 2 deficient (Tph2-deficient) mice that lack brain serotonin, we explored the relationship between serotonin signaling and exercise-induced neurogenesis. Surprisingly, Tph2-deficient mice exhibit normal baseline hippocampal neurogenesis but impaired activity-induced proliferation. Our data demonstrate that the proproliferative effect of running requires the release of central serotonin in young-adult and aged mice. Lack of brain serotonin further results in alterations at the stage of Sox2-positive precursor cells, suggesting physiological adaptations to changes in serotonin supply to maintain homeostasis in the neurogenic niche. We conclude that serotonin plays a direct and acute regulatory role in activity-dependent hippocampal neurogenesis. The understanding of exercise-induced neurogenesis might offer preventive but also therapeutic opportunities in depression and age-related cognitive decline

Formacion de neuronas nuevas en el hipocampo adulto: neurogenesis [the new neuron formation in the adult hippocampus: neurogenesis]

New neuron formation in the adult brain was an interesting finding that extended the knowledge about brain plasticity. In 1966 Joseph Altman reported the incorporation of tritiated thymidine to neural cell DNA. This finding indicated the proliferation event in the adult brain. After twenty years of this finding, new information was generated that confirmed the new neuron formation in the adulthood. In this review, we will mention different aspects of the new neuron formation process called neurogenesis, as well as some of the factors that modulate such process, citing the information already known about the neuronal development stages that take place for the new neuron formation in the hippocampus. Finally, we will review some evidence about the neurogenic process in depression and in neurodegenerative diseases, as well as the possible role of the new neurons when they are integrated into the neuronal network. In the adult brain there are two regions where new neuron formation process takes place: the olfactory bulb and the hippocampus. New neurons are derived from neural stem cells, which reside in the subventricular zone of the lateral ventricles and in the subgranular zone of the dentate gyrus. Neural stem cells may proliferate and generate the rapid amplifying progenitor and neuroblast populations. These populations will migrate and differentiate in neurons to finally be integrated into the neuronal network. In the adult brain, neural stem cells have radial glial features expressing specific markers as the glial fibrilar acidic protein (GFAP), as well as the un-differentiated cell marker nestin. This characteristic makes suitable neural stem cells identification. Thus, the new neurons can be identified by both the specific marker expression and by electrophysiological properties. The different cell development stages during the neurogenic process have been characterized in the subventricular zone as well as in the subgranular zone of the dentate gyrus. In addition to the radial-glia features, neural stem cells show a slowly dividing ratio and once the neural stem cells divide by asymmetric division a rapid amplifying progenitor population is generated. In the hippocampus, phenotype analysis had allowed cell classification in three different types according to the kind of protein marker expression. These progenitors are generated during the expansion phase by symmetric cell division. Type 2a and 2b present short neuritic processes parallel to the granular cell layer and the Type 3 present longer processes integrated into the granular cell layer. During this step, where the migration and cell fate decision take place, the cells express different markers as the microtubule associated protein doublecortin, the homeobox gene related to the drosophila gene prospero Prox-1 and the neuron-specific nuclear protein Neu-N. Once the cells exit the cell cycle, immature neurons are generated showing longer dendritic processes crossing the granular cell layer. These immature neurons will fully differentiate to be integrated into the neuronal network. At this final stage the cells are fully differentiated and the new neurons express specific markers as the calcium binding protein calbindin and their electrophysiological properties are similar to the old neurons. Neurogenesis is a complex process that is modulated and regulated by different factors. One of these is the niche which is formed by the neural stem cells, astrocytes and endothelial cells. Adult neural stem cells proliferate and differentiate depending on the cellular and molecular composition of the niche. The three components work in synchrony in both neurogenic areas with active proliferation. The role of the niche is the maintenance of the stem cells pool. The astrocytes modulate the proliferation of the neural stem cell and of the rapid amplifying cell population, as well as the migration of these cells by the action of the secreting factors. The niche also plays a key role in maintaining the astrocytic and the endothelial cell populations. Besides the niche, other factors are involved in the neurogenic process, such as the neurotransmitters (GABA, glutamate, serotonin, dopamine), hormones (prolactin, growth hormone), growth factors (FGF, EGF) and neurotrophins (BDNF, NT3). All of them modulate different steps of the process. Some other factors that influence the new neuron formation include the physical activity, enrichment environment and social interaction. It has been shown that physical activity increases the number of surviving newborn cells when rodents have free access to the running wheel. Another positive regulator of the neurogenic process is the enrichment environment. The influence of this factor on the new neuron formation was demonstrated when the animals were maintained in a cage with tunnels and toys. In addition, when the rodents were forced to learn a particular task, more new neurons were found in the dentate gyrus. Additionally, the social interaction has a positive influence on the new neuron formation. Even when neurogenesis is positively regulated by the afore mentioned factors, different conditions and factors have a negative influence on this process. It is known that psychological stress affects in a negative manner the neurogenic process. The stress decreases the proliferation of progenitor cells in the dentate gyrus. This negative effect involves glucocorticoids whose increased levels inhibit the new neuron formation. Also, an exogenous administered corticosterone suppresses the new neuron formation. Another negative factor on neurogenesis related to glucocorticoids, is the sleep deprivation, which impairs the neurogenic process by increasing corticosterone levels causing a reduction in cell proliferation. Also, the abuse drugs cause a negative effect in the new neuron formation. It is known that chronic alcoholism negatively impact eurogenesis as well as cocaine, drug that impairs the proliferation dynamics in the dentate gyrus. Psychiatric disorders, such as depression, have been associated with an impaired neurogenesis, which is reverted by antidepressant drugs. In contrast to the effects of stress, an antidepressant pharmacologic treatment increases the new neuron formation. The antidepressant effect is dependent on chronic treatment, consistent with the time course of the therapeutic action of these compounds. Recently, it has been shown that fluoxetine increases symmetric divisions of early progenitor cells and that these cells called or named neuronal progenitors targeted by fluoxetine in the adult brain. This report describes one mechanism for antidepressant; however, the mechanisms by which antidepressant drugs act is not known at all and can be complex. Nevertheless, it has been reported that antidepressants induce an increase in serotonin or norephinephrine levels which activate the corresponding receptors and their downstream signaling pathways. One of these signaling pathways is the cAMP-CREB cascade. This second messenger is upregulated in the hippocampus together with the activity of the cAMP-dependent protein kinase. On the same pathway, the cAMP response element binding protein (CREB) shows an increase in function and expression. In patients with neurodegeneration, a defect in the neurogenesis process has been described. In Alzheimer’s disease, cell proliferation and the potential regenerative factors levels are diminished. However, several studies have revealed an increase in the expression of the neurogenic marker doublecortin. Recently, it has been reported the presence of proliferative cells in presenile Alzheimer hippocampus without indications for altered dentate gyrus. In addition to this finding, the influence of the enrichment environment on the new neuron formation has been explored. In these studies, it was shown that rodents housed under enrichment conditions had an increased neurotrophin 3 (NT-3) and brain derived neurotrophic factor, as well as an increased hippocampal neurogenesis accomplished with the improvement in the water maze performance. In another study, described by Lazarov in 2005, the enrichment environment leads a reduction in the levels of cerebral beta-amyloid and an increase in the genes associated with learning-memory, neurogenesis and cell survival pathways. In amyotrophic lateral sclerosis that is characterized by motor neuron degeneration the new neuron formation is impaired. By using mutant mice for the superoxide dismutase-1 enzyme, an enzyme that is altered in amyotrophic lateral sclerosis and with the precursor cells isolated from the subventricular zone of the this mutants there is a reduction in the incorporation of the DNA synthesis marker bromodeoxyuridine(BrdU), and in the response to mitogen stimulation, in presymptomatic and symptomatic mice, respectively. Evidence obtained so far strongly suggest that neural stem cells manipulation can be a good possibility to induce the neuron replacement in the treatment of neurodegenerative and psychiatric illnesses. However it is necessary to go deeply in the mechanisms and signaling pathways involved in the neurogenesis processes

Adult-Generated Hippocampal Neurons Allow the Flexible Use of Spatially Precise Learning Strategies

Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning

Temporal and spatial dynamics of brain structure changes during extensive learning

The current view regarding human long-term memory as an active process of encoding and retrieval includes a highly specific learning-induced functional plasticity in a network of multiple memory systems. Voxel-based morphometry was used to detect possible structural brain changes associated with learning. Magnetic resonance images were obtained at three different time points while medical students learned for their medical examination. During the learning period, the gray matter increased significantly in the posterior and lateral parietal cortex bilaterally. These structural changes did not change significantly toward the third scan during the semester break 3 months after the exam. The posterior hippocampus showed a different pattern over time: the initial increase in gray matter during the learning period was even more pronounced toward the third time point. These results indicate that the acquisition of a great amount of highly abstract information may be related to a particular pattern of structural gray matter changes in particular brain areas

Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival

Neural precursor cells contribute to adult neurogenesis and to limited attempts of brain repair after injury. Here we report that in a murine experimental glioblastoma model, endogenous neural precursors migrate from the subventricular zone toward the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting red fluorescent protein-labeled G261 cells into the caudate-putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). Fourteen days after inoculation, the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early noncommitted and committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. 5-bromo-2-deoxyuridine labeling and dye tracing experiments revealed that the tumor-associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone, the neural precursors showed extensive tropism for glioblastomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient; this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioblastoma cells with neural precursors improved the survival time of old mice to a level similar to that in young mice. Coculture experiments showed that neural precursors suppressed the rapid increase in tumor cell number, which is characteristic of glioblastoma, and induced glioblastoma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells; the presence of precursor cells is antitumorigenic; and this cellular interaction decreases with aging

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