Adult neurogenesis is the process of generating new neurons which integrate into existing circuits after fetal and early postnatal development has ceased. In most mammalian species, adult neurogenesis only appears to occur in the olfactory bulb and the hippocampus. In addition there is a high level of adult neurogenesis in the olfactory epithelium (considered part of the peripheral nervous system) where olfactory receptor neurons are constantly replaced. The process appears more widespread but still limited in other vertebrate classes, having been described in select brain regions of certain birds, fish and reptiles. Furthermore, many invertebrates and vertebrates have neural regenerative capacities that involve neurogenesis (such as tail regeneration in salamanders).
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New neurons are generated throughout life from a population of dividing cells known as neural stem/progenitor cells (NPCs). Two criteria are typically used to define a cell as a stem cell:1) the potential of self-renewal and 2) the ability to give rise to multiple distinct cell types. NPCs isolated from the adult brain are classified as a ‘’multipotent’’ cell because they can differentiate into the the three main lineage cell types of the nervous system (neurons, astrocytes, and oligodendrocytes) when cultured in vitro. The evidence for multipotency of NPCs in vivo remains scant.
There are two neurogenic regions in the adult brain where under physiological conditions NPCs give rise to new neurons:
For those two regions several types of dividing progenitors were identified . The “type-1” cells (or ‘B’ cells in the SVZ) are similar to the radial glial cells observed during development, and have a morphology and physiology similar to mature astrocytes. Although they reside in the SGZ, they extend processes up into the molecular layer. Type-1 and B cells are relatively quiescent. In contrast “Type-2” cells (or ‘C’ cells in the SVZ),have a high proliferative activity but have a small roundish morphology. The current hypothesis is that Type-2 cells (or 'C' cells) give rise to Type-3 (or A cells) representing neuronally committed neuroblasts.
NPCs are not limited to neurogenic regions of the brain, rather their proliferation can be observed in most CNS regions, especially after injury. However, in these other regions it appears that neurogenesis is actively repressed by the local environment - NPCs from non-neurogenic regions have been observed to give rise to neurons when transplanted into the hippocampus. Some evidence indicates that this effect is mediated by the local astrocyte populations.
NPCs have historically been labeled in the brain by the addition of a proliferation marker, such as 3H-thymadine or bromodeoxyuridine (BrdU; Figure 2, bottom). Immunohistochemistry for BrdU can be combined with the detection of mature markers to identify the phenotype of the newborn cells. Recently, several molecular techniques for labeling adult-born cells have been developed, including transgenic mice with GFP driven by a stem cell gene's promoter (i.e., Nestin-GFP; Figure 2, top left) and retroviral labeling ( Figure 2, top right). BrdU labeling has been used to definitively show that new neurons are incorporated into the dentate gyrus and olfactory bulb of the adult human brain (Eriksson et al., 1998; Curtis et al., 2007).
Adult neurogenesis is unique from developmental neurogenesis because the new neurons must integrate into an established, functioning network. Much of the present knowledge about neuronal development in adult neurogenesis has been reviewed by Kempermann et al.(2004), Ming and Song (2005). Abrous et al. (2005), and Zhao et al.(2008).
Recent work using immediate early genes such as c-fos, Zif268, and Arc as putative markers of neuronal activity have shown that water maze training (Kee et al., 2007) or exposure to an enriched environment (Tashiro et al., 2007) during this maturation process will cause these neurons to be more responsive upon reexposure to the same condition several weeks later.
In contrast to adult neurogenesis in the dentate gyrus, cells that were born in the SVZ migrate a long distance into their target area, the olfactory bulb. This long migration gives olfactory neurogenesis a different timescale from DG neurogenesis.
One critical aspect of adult neurogenesis is the selection process. While large numbers of new neurons are born to the OB and DG, only a fraction of these cells survive. In the dentate gyrus, approximately half of the newborn neurons die within 2 weeks of birth, but this number is heavily regulated by various factors. In contrast to newborn DG neurons the selection process in the OB appears to be later in the development process, when young neurons with extended dendrites already covered with spines are susceptible to cell death.
The "rediscovery" of neurogenesis in the 1990's was due in large part to the observation that the levels of new neurons in the adult hippocampus are modulated by a range of factors, including stress (Gould et al., 1990), aging (Kuhn et al., 1996), environment (Kempermann et al., 1998), and activity (van Praag et al., 1999). Numerous drugs and behaviors have since been shown to affect the levels of new neurons in the brain. Modulation of neurogenesis typically occurs in one of two ways in vivo – either the modulator changes the levels of proliferation of NPCs, or the effect is on the survival of the new neurons. The most studied modulators have been summarized in the following tables. See Ming and Song (2005) and Abrous et al.(2005) for more details.
Table of Dentate Gyrus Neurogenesis Regulators
Table of Olfactory Bulb Neurogenesis Regulators
Several neuro-psychiatric conditions have been associated with altered rates of neurogenesis in animal models, including Alzheimer’s disease, temporal-lobe epilepsy, ischemia, and depression. In each of these cases, it remains unclear whether perturbed neurogenesis is a symptom of the disorder or has a causal role. Aging also has a robust effect on neurogenesis, with levels of new neurons decreasing in later stages of life. The marked decrease occurs fairly early and neurogenesis is maintained at a very low level for most of the life span.
While the observation and characterization of neurogenesis has been robust, the role of adding new neurons on a region’s function has remained elusive in most cases. Nonetheless, because neurons are integrating into regions of relatively well described circuitry and function, several behavioral and computational ideas have been explored.
Several techniques to reduce adult neurogenesis have been used to look at the process’s effect on hippocampal function. These have included x-ray irradiation, anti-proliferative drugs (MAM) and molecular knock-downs. A range of hippocampus-dependent behaviors have been tested with mixed results (see Deng et al., 2010 for a review). Trace eyeblink conditioning was shown to be affected in MAM experiments, and contextual fear conditioning was impaired following irradiation and genetic ablation of adult neurogenesis. Morris Water Maze (MWM) testing has shown inconsistent results in several paradigms, with some experimenters seeing deficits in short-term retention, others in long-term retention, and others no discernable differences at all. Furthermore, set of behavioral studies have demonstrated that neurogenesis may have a role in the pattern separation function of the dentate gyrus (Clelland et al., 2009). Finally, a recent study has suggested that new neurons may be important in memory consolidation (Kitamura et al., 2009).
In addition to its presumed role in memory, the correlation of neurogenesis levels to stress has suggested a role in anxiety-related behaviors. For example, fluoxetine (the active compound in Prozac) is not effective as an anti-depressant in mice without adult neurogenesis due to irradiation.
The function of the olfactory pathway can be tested with a variety of behavioral tasks that test odor discrimination or odor learning. Using transgenic mice with reduced OB neurogenesis it could be shown that new OB neurons appear to be critically involved in odor discrimination. At the same time odor discrimination learning itself increases the survival of newborn OB neurons. The same effect on survival has been found using odor enrichment resulting in improved odor memory.
Because the dentate gyrus is the entry structure to the hippocampus, which has a substantial history of neural network modeling, several non-exclusive computational functions have been suggested for neurogenesis. These have arisen from both theoretical and computational modeling ventures. For a more detailed review of the theoretical functions of adult neurogenesis, see Aimone, Deng, and Gage; 2010.
Olfactory bulb neurogenesis has not been as extensively studied computationally, possibly because the olfactory bulb circuit does not have the history of modeling that the hippocampus has. Cecchi et al.’s (2001) theoretical study of OB neurogenesis suggests functional roles similar to those suggested for newborn neurons in the dentate gyrus. Cecchi’s results suggest that random incorporation of new neurons with activity-dependent survival will maximize the discrimination of odors presented to the network.
Higher levels of adult neurogenesis are observed in many non-mammalian species, many of which retain regenerative neurogenesis capabilities throughout life. Neurogenesis in the course of normal adult function has been best described in birds and fish.
Adult neurogenesis in birds has been most heavily characterized in the higher vocal center (HVC) area of the birdsong system, although it has been observed in other regions, including the avian hippocampus. Bird song neurogenesis is sometimes characterized by very high levels of seasonal variation – with more neurons appearing in months which have higher levels of song learning. For example, in the canary brain, there is a high level of seasonal cell death of RA projecting HVC neurons in males - in low-neurogenesis, non-learning periods, the HVC is a fraction of the size of learning seasons. Many of the underlying regulators of this process have been elucidated, including seasonal variations in testosterone.
Although this song system is not present in mammals, bird song neurogenesis is an active field of study because it is of the region’s clear role in a well-studied motor learning process. The specific role of new neurons in bird song learning still unclear, but it is interesting to note that the neurogenic cells in HVC have been implicated in sparse coding, just as dentate gyrus cells in the mammalian hippocampus.
Fish have many proliferative zones throughout the brain, which are thought to be able to provide neurons to almost any region of the brain (Zupanc, 2006). Consistent with other vertebrates, the olfactory bulb and dorsal telencephalon (the fish equivalent of the hippocampus) have robust neurogenesis, though most of the new neurons are found in the cerebellum. Because of this widespread proliferation, the overall rate of neurogenesis appears several orders of magnitude higher in fish than in rodents – with an estimate over about 0.2% of the total cells in the brain cells proliferating at any given time.
Below we include references from classic papers, key reviews summarizing the field,and recent studies which have not been reviewed elsewhere in detail (such as the computational modeling work).
Internal references
"Adult Neurogenesis" eds. Fred H Gage, Gerd Kempermann, Hongjun Song. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. 2007.
Hippocampus, Memory, Models of Hippocampus, Models of Olfactory System, Neurodegeneration, Neuronal Stem Cells Olfactory Bulb, Synaptic Turnover, Synaptogenesis