Adult neurogenesis

Figure 1: Locations of adult mammalian neurogenesis

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).

## Contents

* 1 Neural Stem Cells
* 2 Maturation of New Neurons
* 2.1 Maturation of new neurons in the adult dentate gyrus
* 2.2 Maturation of new neurons in the adult olfactory bulb
* 2.3 Neuronal selection and survival
* 3 Regulation of Neurogenesis
* 4 Function of Neurogenesis
* 4.1 Hippocampus-dependent behavioral tasks
* 4.2 Olfactory bulb-dependent behavioral tasks
* 4.3 Computational impact of new neurons
* 5 Adult Neurogenesis in other Species
* 5.1 Birdsong system
* 5.2 Adult neurogenesis in Fish
* 6 References
* 7 Recommended reading
* 8 External links
* 9 See Also

## [edit] Neural Stem Cells

Figure 2: Dentate gyrus neurogenesis

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:

1. the subventricular zone of the lateral ventricles (SVZ) where NPCs generate cells that migrate into the olfactory bulb, and
2. the subgranular zone (SGZ) of the dentate gyrus (DG) where new granule cells become integrated into the local neuronal network ( Figure 1).

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).

## [edit] Maturation of New Neurons

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).

### [edit] Maturation of new neurons in the adult dentate gyrus

The process of adult hippocampal neurogenesis is entirely confined to the dentate gyrus. Local progenitor cells in the SGZ undergo neuronal differentiation, and may show a limited migration into the GCL. The speed of maturation is likely experience dependent, and varies between neurons. Approximate duration of a number of distinct post-mitotic developmental phases of newborn granule cells are listed here. Figure 3 shows a scematic of the anatomical phases of granule cell growth.

Figure 3: Maturation of newborn granule cells

1. Local GABA: (Less than 1 week old) Immature neurons have neurite outgrowth, but often not polarized towards molecular layer. Few or no synapses, but sensitive to locally diffuse GABA, which is depolarizing.
2. Synaptic GABA: (1 to 2 weeks old) Dendrites begin to extend into molecular layer (no spines) and axons can be observed in hilus. Synaptic GABA inputs can be observed, which is still excitatory. Glutamatergic inputs are not present. Immature action potentials can be observed when cells are directly stimulated.
3. Spine formation onset and axon outgrowth: (2 weeks old). By about 16 days neurons begin to develop spines in the molecular layer. GABA transitions to inhibitory around this time. By 17 days, new axons (mossy fibers) can be observed forming functional connections onto downstream hilar neurons and CA3 pyramidal cells.
4. Functionally immature neurons (~3 weeks to 2 months) Spine formation is gradual, with neurons progressively increasing their dendritic arborization and connections. Mossy fibers continue to mature, with boutons on CA3 neurons growing considerably by 28 days. Neurons still have unique physiological properties, including increased LTP, and different resistance, capacitance and resting potentials.
5. Fully mature neurons (> 2 months old). Newborn neurons eventually become physiologically indistinguishable from fully mature neurons.

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.

### [edit] Maturation of new neurons in the adult olfactory bulb

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.

1. Migration: (2-6 Days) Newborn cells migrate in chains along the rostral migratory stream (RMS), a structure maintained by specialized astrocytes. After the newborn neurons reach the middle of the OB they detach from the chains and migrate radially.
2. Neuronal Differentiation: (15-30 Days) After immature neurons reach the OB, they begin to differentiate into two different types of local interneurons. Over 95% differentiate into GABA-ergic granule neurons whereas the remainder become periglomerular neurons expressing either GABA and/or dopamine as neurotransmitter. Newborn granule cells can be distinguished into cells with dendrites that do not extend beyond the mitral cell layer and other cells that possess non-spiny dendrites reaching into the external plexiform layer.
3. Integration into network: (15 -30 Days) Newborn granule cells and periglomerular neurons become integrated into the OB circuitry and respond to olfactory stimuli.

### [edit] Neuronal selection and survival

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.

## [edit] Regulation of Neurogenesis

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.

## [edit] Function of Neurogenesis

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.

### [edit] Hippocampus-dependent behavioral tasks

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.

### [edit] Olfactory bulb-dependent behavioral tasks

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.

### [edit] Computational impact of new neurons

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.

* Increase of hippocampal memory capacity – several models predict network capacity will increase with neurogenesis, but Becker’s model (2005) explores the idea in a full hippocampal model. Becker predicts that the increase in possible sparse codes due to new neurons increases the quality of memory formation in downstream hippocampal regions.
* Reduction of interference between new and older memories – Wiskott and colleagues (2005) propose that the presence of new neurons helps the dentate gyrus network respond to changing inputs. Specifically, their model suggests that without neurogenesis, the hippocampal network will suffer from “catastrophic interference,” leaving the network unable to effectively encode new memories.
* Encoding time in memories – Aimone et al. (2006; 2009) suggest that the different physiological properties of immature neurons will bias the sparse coding function of the dentate gyrus, possibly providing a link between memory associations formed in the recurrent CA3 network.

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.

## [edit] Adult Neurogenesis in other Species

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.

### [edit] Birdsong system

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.

### [edit] Adult neurogenesis in Fish

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.

## [edit] References

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).

* Abrous DN, Koehl M, and Le Moal, M – “Adult Neurogenesis: From Precursors to Network and Physiology” Physiological Reviews; 85: 523-569; 2005
* Aimone JB, Wiles J, and Gage FH – “Potential Role for Adult Neurogenesis in the Encoding of Time in New Memories” Nature Neuroscience; 9: 723-727; 2006.
* Aimone JB, Wiles J, and Gage FH - "Computational Influence of Adult Neurogenesis on Memory Encoding" Neuron; 61: 187-202; 2009
* Aimone JB, Deng W, and Gage FH - "Adult Neurogenesis: Integrating Theories and Separating Functions" Trends in Cognitive Sciences; 14: 325-337; 2010.
* Altman J and Das GC - "Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats" Journal of Comparative Neurology; 124(3): 319-335; 1965.
* Becker S – “A Computational Principal for Hippocampal Learning and Neurogenesis” Hippocampus; 15:722-738; 2005
* Cecchi GA, Retreanu LT, Alvarez-Buylla A, Magnasco MO – “Unsupervised Learning and Adaptation in a Model of Adult Neurogenesis” Journal of Computational Neuroscience; 11:175-182; 2001
* Carleton A, Petreanu LT, Lansford R, Alvarez-Buylla A, and Lledo PM - "Becoming a new neuron in the adult olfactory bulb" Nature Neuroscience; 6(5): 507-518
* Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C, Holtas S, van Roon-Mom WMC, Bjork-Eriksson T, Nordborg C, Frisen J, Dragunow M, Faull RLM, and Eriksson PS - "Human Neuroblasts Migrate tot he Olfactory Bulb via a Lateral Ventricular Extension" Science; 315: 1243-1249; 2007
* Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH and Bussey TJ - "A functional role for adult hippocampal neurogenesis in spatial pattern separation." Science 325(5937): 210-213; 2009
* Deng W, Aimone JB, and Gage FH - "New Neurons and New Memories: How Does Adult Neurogenesis Affect Learning and Memory?" Nature Reviews Neuroscience; 11: 339-350; 2010
* Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, and Gage FH - "Neurogenesis in the adult human hippocampus" Nature Medicine; 4(11): 1313-1317; 1998
* Gould E, Woolley CS and McEwen BS - "Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus" Neuroscience; 37(2): 367-375; 1990.
* Kaplan MS and Hinds JW - "Neurogenesis in the adult rat: electron microscopic analysis of light radiographs" Science; 197(4308): 1092-1094; 1977
* Kee N, Teixeira CM, Wang AH, and Frankland PW - "Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus." Nature Neuroscience; 10(3): 355-362; 2007
* Kempermann G, Kuhn HG, and Gage FH - "More hippocampal neurons in adult mice living in an enriched environment" Nature; 386(6624): 493-495; 1997
* Kempermann G, Jessberger S, Steiner B, and Kronenberg G - "Milestones of neuronal development in the adult hippocampus" Trends in Neurosciences; 27(8):447-452; 2004
* Kitamura T, Yoshito S, Noriko T, Akiko M, Yosuke N, Hiroshi A, Mariko S, Hiroyuki S, and Kaoru I - "Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory" Cell 139(4): 814-827; 2009
* Kuhn HG, Dickinson-Anson H, and Gage FH - "Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor population" Journal of Neuroscience; 16(6): 2027-2033; 1996
* Lie DC, Song H, Colamarino SA, Ming GL, and Gage FH - "Neurogenesis in the adult brain: new strategies for central nervous system diseases" Annual Reviews of Pharmacology and Toxicology; 44: 399-421; 2004
* Lledo PM, Alonso M, and Grubb MS - "Adult neurogenesis and functional plasticity in neuronal circuits" Nature Reviews Neurosciences; 7(3): 179-193; 2006
* Ming GL and Song H – “Adult neurogenesis in the mammalian central nervous system” Annual Review of Neuroscience; 28:223-250; 2005
* Nottebohm F, “Neuronal replacement in the adult brain” Brain Research Bulletin; 57: 737-749; 2002
* Tashiro A, Makino H, and Gage FH - "Experience-Specific Functional Modification of the Dentate Gyrus through Adult Neurogenesis: A Critical Period during an Immature Stage" Journal of Neuroscience; 27(12):3252-3259; 2007
* Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, and Schinder AF - "Neurons born in the adult dentate gyrus form functional synapses with target cells" Nature Neuroscience; 2008
* van Praag H, Kempermann G, and Gage FH - "Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus" Nature Neuroscience; 2(3): 266-270; 1999
* van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, and Gage FH - "Functional neurogenesis in the adult hippocampus" Nature; 415:1030-1034; 2002.
* Wiskott L, Rasch MJ, and Kempermann G – “A Functional Hypothesis for Adult Hippocampal Neurogenesis: Avoidance of Catastrophic Interference in the Dentate Gyrus” Hippocampus; 16:329-343; 2006
* Zhao C, Deng W, Gage FH - "Mechanisms and functional implications of adult neurogenesis" Cell; 132(4):645-60; 2008
* Zupanc GKH – “Neurogenesis and neuronal regeneration in the adult fish brain” Journal of Comparative Physiology A; 192: 649-670; 2006

Internal references

* Valentino Braitenberg (2007) Brain. Scholarpedia, 2(11):2918.
* Eugene Roberts (2007) Gamma-aminobutyric acid. Scholarpedia, 2(10):3356.

## [edit] Recommended reading

"Adult Neurogenesis" eds. Fred H Gage, Gerd Kempermann, Hongjun Song. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. 2007.

## [edit] External links

* James B. Aimone's website
* Sebastian Jessberger's website
* Fred H. Gage's website

## [edit] See Also

Hippocampus, Memory, Models of Hippocampus, Models of Olfactory System, Neurodegeneration, Neuronal Stem Cells Olfactory Bulb, Synaptic Turnover, Synaptogenesis