Try out PMC Labs and tell us what you think. Learn More. 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 ificantly 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.
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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 3the 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. Because it has turned out that adult neurogenesis not only exists in the human hippocampus but even seems to be restricted to it see Spalding et al.
This is no reason to neglect research on adult neurogenesis in the olfactory system, which is a necessary part of any holistic view on adult neurogenesis, but reason enough to ask for the motifs behind this interest. There is a price to pay for this type of plasticity. Adult neurogenesis is a complex multistep process, not a simple event.
This review deals with the description of this process and the restriction points at which regulation occurs. Adult neurogenesis is brain development recapitulated in the adult and comprises a series of sequential developmental events that are all necessary for the generation of new neurons. In the original publications on adult neurogenesis, the precursor cell population, from which neurogenesis originates, could be identified only through the detection of their proliferative activity and the absence of morphological characteristics of mature neurons and later neuron-specific antigens, such as NeuN or calbindin Altman and Das ; Kaplan and Hinds ; Cameron et al.
The new neurons, in contrast, were identified by the presence of mature neuronal markers in cells that had been birthmarked with the thymidine or BrdU method see Kuhn et al.
The expression of polysialilated neural-cell-adhesion molecule PSA-NCAM with neurogenesis has been noted early but could not be clearly linked to either proliferation or the mature stage Seki and Arai ab. PSA-NCAM expression was the first indication of the developmental events that take place, filling the gaps between the start and endpoint of development. Today, we have quite detailed knowledge about the course of neuronal development in the adult hippocampus and, although many detailed questions are open, a clear overall picture has emerged Kempermann et al.
This is sometimes questionable because the process is not identical to the end result, the existence of mature new neurons, but it is also telling.
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A plasticity marker is widely considered as representative of the whole process and its result. Although there are justifications to exclude the dentate gyrus from the hippocampus, we believe that, from any functional perspective, this distinction is awkward. Arguably, the contribution of the dentate gyrus and the new neurons within it is critically important to overall hippocampal function.
The vote has, anyway, long been made by the scientific audience. We talk about adult hippocampal neurogenesis, when we mean neurogenesis in the adult dentate gyrus.
Adult hippocampal neurogenesis generates only one type of neuron: granule cells in the dentate gyrus. To date, there is no conclusive evidence that other neuronal cell types could be generated under physiological conditions, although some as-yet unconfirmed claims have been made Rietze et al.
Granule cells are the excitatory principal neurons of the dentate gyrus. They fire very sparsely and their activity is modulated by a large of interneurons in the dentate gyrus and hilus area. The precursor cells, from which adult neurogenesis originates, reside in a narrow band of tissue between the granule cell layer and the hilus, the so-called subgranular zone SGZ. The term was coined by the discoverer of adult hippocampal neurogenesis, Joseph Altman in The original description of adult neurogenesis in the rodent brain was published in by Joseph Altman and his colleague Gopal Das Altman and Das The SGZ contains the microenvironment that is permissive for neuronal development to occur.
According to one study, the niche is surrounded by a common basal membrane Mercier et al. The type 1 precursor cells, from which adult neurogenesis originates, have endfeet on the vasculature in the SGZ Filippov et al.
Local astrocytes play a key role in promoting neurogenesis. In vivo, the developing cells show a close spatial relationship with astrocytes Shapiro et al. Ex vivo, astrocytes and astrocyte-derived factors were potent inducers of neurogenesis from hippocampal precursor cells Song et al. In addition, there are commissural fibers from the contralateral side. Manipulations of all the different neurotransmitter and input systems, for example, by lesioning studies to the input structures or pharmacological intervention, have revealed a regulatory effect on adult neurogenesis, although the level of resolution is still too low to identify the relative specific contributions of the individual systems to the control of adult neurogenesis Bengzon et al.
Nevertheless, the role of interneurons is critical in more than one regard. Adult neurogenesis can be divided into four phases: a precursor cell phase, an early survival phase, a postmitotic maturation phase, and a late survival phase. Based on cell morphology and a set of marker proteins, six distinct milestones can be identified, which to date still somewhat overemphasize the precursor cell stages of adult neurogenesis Fig.
From a radial glia-like precursor cell, adult neurogenesis progresses over three identifiable progenitor stages associated with high proliferative activity to a postmitotic maturation phase and, finally, the existence of a new granule cell Brandt et al.
Although on the precursor cell stage and early after cell-cycle exit, large changes in cell s occur and the effects of development become more qualitative at later times.
Distinct steps of neuronal development
Developmental stages in the course of adult hippocampal neurogenesis see text for details. The precursor cell phase serves the expansion of the pool of cells that might differentiate into neurons. The early survival phase marks the exit from the cell cycle.
Most newborn cells are eliminated within days after they are born.
The postmitotic maturation phase is associated with the establishment of functional connections, the growth of axon and dendrites, and synaptogenesis. The late survival phase represents a period of fine-tuning.
Characteristic electrophysiological patterns allow the asment of functional states to the morphologically distinguishable steps of development. One central question in research on adult hippocampal neurogenesis is how far it is similar to or distinct from embryonic and early postnatal neurogenesis in the dentate gyrus. The dentate gyrus develops in three distinctive waves of development, of which adult neurogenesis is the last Altman and Bayer ab.
The bulk of dentate gyrus neurons is produced at around P7. From a functional perspective, Laplagne et al. On the other hand, quality and quantity of extrinsic stimuli and memory contents that pass the dentate gyrus will be dramatically different between postnatal and adult periods.
Also, the speed of maturation might differ Overstreet-Wadiche et al. Such cell types do not actually constitute distinct populations of cells but rather reflect milestones of a developmental process. Adult hippocampal neurogenesis originates from a population of precursor cells with glial properties. A subset of these shows morphological and antigenic characteristics of radial glia.
Their cell body is found in the SGZ and the process extends into the molecular layer. Not all radial elements show the same marker expression and some markers for radial glia during embryonic development are absent.
The astrocytic nature of hippocampal precursor cells was first shown by Seri, Alvarez-Buylla, and colleagueswhen they suppressed cell division by application of a cytostatic drug and found that the first cells that reappeared were proliferative astrocyte-like cells with radial morphology. The second line of evidence came from experiments in which the receptor for an avian virus was expressed under the promoter of glial fibrillary acidic protein GFAP or nestin, so that astrocyte-like or nestin-expressing cells could specifically be infected by an otherwise inert virus. Transduced cells generated new neurons in vivo, demonstrating the developmental potential in vivo Seri et al.
Ex vivo, hippocampal precursor cells were first isolated by Ray et al. In culture, the precursor cells show s of stemness self-renewal and multipotency Palmer et al. A similar discussion arose in vivo, in which two studies asked whether the radial glia-like type 1 cells are capable of both asymmetric and symmetric divisions.
Encinas and colleagues presented a model in which the potential of the precursor cells is fixed and the precursor cell population becomes exhausted with advancing age Encinas et al. This finding was contrasted by a study by Bonaguidi et al. Both studies might be correct, but show different aspects of the same issue.
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If adequately stimulated, the precursor cells might switch their program and allow the long-term maintenance of the precursor cell pool, which is lost in the case of inactivity. This idea is plausible in the context of other aspects of the activity-dependent regulation of adult neurogenesis but remains to be tested Kempermann a. With that caveat in mind, the radial glia-like type 1 cells of the hippocampus give rise to intermediate progenitor cells, type 2 cells.
These show a high proliferative activity. A subset of these cells still expresses glial markers but lack the characteristic morphology of radial cells type 2a. On the level of type 2 cells that, together with type 1 cells, express intermediate filament nestin, first indications of neuronal lineage choice appear.
These markers comprise, among others, transcription factors NeuroD1 and Prox1. This cellular phenotype has been called a type 2b cell Steiner et al.
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Of these, Prox1 is specific to granule cell development. Manipulation of Prox1 abolishes adult neurogenesis at this stage Karalay et al. Type 2 cells are also characterized by their expression of Eomes Tbr2a transcription factor that, during embryonic cortical development, identifies the basal progenitor cells, which maintain self-renewing properties and can differentiate into neurons Hodge et al. Tbr2 appears to suppress Sox2 and is critical for the transition from stem cells to intermediate progenitor cells Hodge et al. A point-by-point comparison between adult neurogenesis and fetal and early postnatal neurogenesis in the dentate gyrus is still lacking, but many transcription factors involved in embryonic cortical and hippocampal development are also involved in adult hippocampal neurogenesis Li and Pleasure ; Hodge et al.
Insight into the transcriptional control of the initiation of neuronal differentiation is scarce. From the available data, however, it is obvious that if a fate choice decision is made at all, it must occur on the level of the type 2a cells. All later cells express NeuroD1 and Prox1 and there is no overlap between NeuroD1 and Prox1 and astrocytic markers at any time point.
Tailless Tlx is a key candidate for a transcription factor involved in controlling the transition between glial and neuronal phenotypes of the precursor cells Shi et al. Beckervordersandforth et al.
On the level of type 2 cells, the developing cells also receive first synaptic input, which is GABAergic Tozuka et al. A more recent study, however, suggests that type 1 cells also express GABA A receptors throughout and AMPA receptors only in their processes with no ionotropic glutamate receptors Renzel et al.
Although type 1 cells can respond to extrinsic stimuli by increasing cell proliferation Huttmann et al. The radial cells represent the largely quiescent compartment, and the control of quiescence is also under the control of GABA that comes from the local parvalbumin-expressing interneurons basket cells Song et al. Type 2 cells respond to physiological stimuli, such as voluntary wheel running Kronenberg et al.
Among the neuronal lineage markers first appearing at the type 2b stage is DCX.