Turku Centre for Biotechnology, ÅboAkademi University and University of Turku, Turku, Finland



Adult neurogenesis, a concept emergent in the late 1990s, is the generation of new neurons in the adult brain. This process occurs thank to cells who have this proliferative feature, named as Neural Stem Cells (NSCs). Neural Stem Cells (NSCs) are primary progenitors who can generate the two neural types (neurons and glia). Classically it was assumed that NSCs are only present in the embryo, but today it is extensively known that are also present in the postnatal and adult brain, although the majority were found in embryo stage.

According with Merkle et al. 2006, these cells are characterized by the following features: 1. They come from glial cells, 2. They are related linearly between adult and embryonic cells (since they are transformed from neuroepithelial cells to radial glia, and then they show astroglial cells characteristics), and 3. These cells are divided essentially asymmetrically leading to another intermediate progenitor (IPC) as a parent, and sometimes divided symmetrically, to increase the progeny (Ortega Martinez and Trejo, 2015). Meanwhile, intermediate progenitors (IPCs) are always divided symmetrically to amplify the number of progeny dividing (Merket et al., 2006). These symmetric divisions are an important determinant of the brain size, so those species with larger brains have a larger pool of intermediate progenitors (Marshall et al., 2005).

These cells, in adults, are mainly found at the subventricular zone (SVZ), adjacent to the lateral ventricles and at the dentate gyrus (DG) of the hippocampus, known like subgranular zone (SGZ) the ‘imaginary line’ below granular zone of DG where these cells are found (see Fig. 1). However, there are evidences of the existence of these cells elsewhere in the adult brain, including the cortex (Feliciano et al., 2012) or the hypothalamus (Lee et al., 2012). These precursor cells are quiescent (usually non-dividing) that can be divided into different stimuli. When this happens, there are two possibilities; A) their division generates intermediate progenitor cells (IPC), which then gives rise to neurons; B) whereas if they come from astroglial progenitors, the result will be the generation of glial. The process of formation of neurons through intermediate progenitors is a longer process, as there are different types of intermediate progenitors known as 2a, 2ab, 2b and type 3 according to their stage of development and expressing markers, whereas astroglial progenitors have comparatively a lower proliferative capacity. However, intermediate progenitors send numerous processes before being symmetrically divided, motivated by local sensing factors (Noctor et al., 2004).

The NSCs don’t only come from the nervous system but can be derived from embryonic stem cells (ES cells) or reprogrammed fibroblasts (Wernig et al., 2008). Different kinds of neural progenitor/stem cells basis have been established on their characteristics. There are two different populations known like: neural stem cells which show glial characteristics (Radial Glia Cells, RGLs), and intermediate progenitors (IPC). The latter are also divided into other types (2a, 2ab, 2b, 3). The classification of these cells and the markers used to identify them has created much controversy among scientists. However, there is a large consensus that the astrocytic NSC have many features, such as the expression of glial fibrilar acidic protein (GFAP), which has made us change our perception of glia (Merkle et al., 2006). Other studies (Kempermann et al., 2003) support the interpretation that radial astrocytes have a role as primary progenitors.


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Ainge, J.A., Tamosiunaite, M., Woergoetter, F., Dudchenko, P.A., 2007. Hippocampal Ca1 place cells encode intended destination on a maze with multiple choice points. J. Neurosci., 27, 9769-79.

Amaral, D.G., 1978. A golgi study of cell types in the hilar region of the hippocampus in the rat. J. Comp. Neurol., 182, 851-914.

Amaral, D.G., Ishizuka, N., Claiborne, B., 1990. Neurons, numbers and the hippocampal network. Prog. Brain. Res., 83, 1-11.

Appleby, P.A., Kempermann, G., Wiskott, L., 2011. The role of additive neurogenesis and synaptic plasticity in a hippocampal memory model with grid-cell like input. PLoS. Comput. Biol., 7, e1001063.

Bekinschtein, P., Oomen, C.A., Saksida, L.M., Bussey, T.J., 2011. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory and pattern separation: BDNF as a critical variable? Semin. Cell. Dev. Biol., 22, 536-542.

Blackstad, T.W., 1956. Commissural connections of the hippocampal region in the rat, with special reference to their mode of termination. J. Comp. Neurol., 105, 417-537.

Bruel-Jungerman, E., Rampon, C., Laroche, S., 2007. Adult hippocampal neurogenesis, synaptic plasticity and memory: Facts and hypotheses. Rev. Neurosci., 18, 93-114.

Bryans, W.A., 1959. Mitotic activity in the brain of the adult white rat. Anat. Rec., 133, 65-71.

Burghardt, N.S., Park, E.H., Hen, R., Fenton, A.A., 2012. Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus, 22, 1795-808.

Cassel, J.C., Cassel, S., Galani, R., Kelche, C., Will, B., Jarrard, L., 1998. Fimbria-Fornix vs selective hippocampal lesions in rats: Effects on locomotor activity and spatial learning and memory. Neurobiol. Learn. Mem., 69, 22-45.

Colucci-D'Amato, L., Bonavita, V., di Porzio, U., 2006. The end of the central dogma of neurobiology: Stem cells and neurogenesis in adult cns. Neurol. Sci., 27, 266-70.

Deng, W., Aimone, J.B., Gage, F.H., 2010. New neurons and new memories: How does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci., 11, 339-50.

Ekstrom, A.D., Kahana, M.J., Caplan, J.B., Fields, T.A., Isham, E.A., Newman, E.L., Fried, I., 2003. Cellular networks underlying human spatial navigation. Nature, 425, 184-8.

Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., Gage, F.H., 1998. Neurogenesis in the adult human hippocampus. Nat. Med., 4, 1313-7.

Fanselow, M.S., Dong, H.W., 2010. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron, 65, 7-19.

Feliciano, D.M., Bordey, A., 2013. Newborn cortical neurons: Only for neonates? Trend. Neurosci., 36, 51-61.

Foster, D.J., Wilson, M.A., 2006. Reverse replay of behavioural sequences in hippocampal place cells during the awake state. Nature, 440, 680-3.

Gilbert, P.E., Kesner, R.P., 2006. The role of the dorsal Ca3 hippocampal subregion in spatial working memory and pattern separation. Behav. Brain. Res., 169, 142-9.

Gould, E., 2007. How widespread is adult neurogenesis in mammals? Nat. Rev. Neurosci., 8, 481-8.

Granger, R., Wiebe, S.P., Taketani, M., Lynch, G., 1996. Distinct memory circuits composing the hippocampal region. Hippocampus, 6, 567-78.

Gross, C.G., 2000. Neurogenesis in the adult brain: Death of a dogma. Nat. Rev. Neurosci., 1, 67-73.

His, W., 1904. Die Entwicklung Des Menschlichen Gehirns.

Hunsaker, M.R., Kesner, R.P., 2008. Evaluating the differential roles of the dorsal dentate gyrus, dorsal ca3, and dorsal Ca1 during a temporal ordering for spatial locations task. Hippocampus, 18, 955-64.

Hunsaker, M.R., Kesner, R.P., 2013. The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory. Neurosci. Biobehav. Rev., 37, 36-58.

Hunsaker, M.R., Rosenberg, J.S., Kesner, R.P., 2008. The role of the dentate gyrus, Ca3a, B, and Ca3c for detecting spatial and environmental novelty. Hippocampus, 18, 1064-73.

Jung, M.W., McNaughton, B.L., 1993. Spatial selectivity of unit activity in the hippocampal granular layer. Hippocampus, 3, 165-82.

Kempermann G., Jessberger, S., 2003. Adult-born hippocampal neurons mature into activity-dependent responsiveness. Europ. J. Neurosci., 18, 2707-12.

Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M., Gage, F.H., 2003. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Dev., 130, 391-9.

Kesner, R.P., Lee, I., Gilbert, P., 2004. A behavioral assessment of hippocampal function based on a subregional analysis. Rev. Neurosci., 15, 333-51.

Kesner, R.P., Rolls, E.T., 2001. Role of long-term synaptic modification in short-term memory. Hippocampus, 11, 240-50.

Lee, D.A., Blackshaw, S., 2012. Functional implications of hypothalamic neurogenesis in the adult mammalian brain. Int. J. Dev. Neurosci., 30, 615-21.

Lee, I., Kesner, R.P., 2002. Differential contribution of Nmda receptors in hippocampal subregions to spatial working memory. Nat. Neurosci., 5, 162-8.

Lee, I., Kesner, R.P., 2003. Differential roles of dorsal hippocampal subregions in spatial working memory with short versus intermediate delay. Behav. Neurosci., 117, 1044-53.

Leutgeb, J.K., Leutgeb, S., Moser, M.B., Moser, E.I., 2007. Pattern separation in the dentate gyrus and ca3 of the hippocampus. Sci., 315, 961-6.

Maguire, E.A., Gadian, D.G., Johnsrude, I.S., Good, C.D., Ashburner, J., Frackowiak, R.S., Frith, C.D., 2000. Navigation-related structural change in the hippocampi of taxi drivers. Proc. Nat. Acad. Sci. USA, 97, 4398-403.

Marr, D., 1971. Simple memory: A theory for archicortex. Philos. Trans. R SocLond. B Biol. Sci., 262, 23-81.

Marshall, C.A., Novitch, B.G., Goldman, J.E.I., 2005. Olig2 directs astrocyte and oligodendrocyte formation in postnatal subventricular zone cells. J. Neurosci., 25, 7289-98.

Merkle, F.T., Alvarez-Buylla, A., 2006. Neural stem cells in mammalian development. Curr. Opin. Cell. Biol., 18, 704-9.

Ming, G.L., Song, H., 2011. Adult neurogenesis in the mammalian brain: Significant answers and significant questions. Neuron., 70, 687-702.

Mizumori, S.J., Perez, G.M., Alvarado, M.C., Barnes, C.A., McNaughton, B.L., 1990. Reversible inactivation of the medial septum differentially affects two forms of learning in rats. Brain. Res., 528, 12-20.

Moser, E.I., Kropff, E., Moser, M.B., 2008. Place cells, grid cells, and the brain's spatial representation system.  Ann. Rev. Neurosci., 31, 69-89.

Ninkovic, J., Mori, T., Gotz, M., 2007. Distinct modes of neuron addition in adult mouse neurogenesis. J. Neurosci., 27, 10906-11.

Noctor, S.C., Martinez-Cerdeno, V., Ivic, L., Kriegstein, A.R., 2004. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci., 7, 136-44.

Nottebohm, F., 1989. From bird song to neurogenesis. Sci. Am., 260, 74-9.

O'Reilly, R.C., McClelland, J.L., 1994. Hippocampal conjunctive encoding, storage, and recall: Avoiding a trade-off. Hippocampus, 4, 661-82.

Ortega-Martinez, S., 2015. A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front. Mol. Neurosci., 8(46).

Ortega-Martinez, S., 2015. Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: The double neurogenic niche hypothesis. Behav. Brain. Res., 281, 309-317.

Ortega-Martínez, S., Trejo, J.L., 2015. The postnatal origin of adult neural stem cells and the effects of glucocorticoids during their genesis. Behav. Brain. Res., 279, 166-176.

Pastalkova, E., Itskov, V., Amarasingham, A., Buzsaki, G., 2008. Internally generated cell assembly sequences in the rat hippocampus. Sci., 321, 1322-7.

Rolls, E.T., Kesner, R.P., 2006. A computational theory of hippocampal function, and empirical tests of the theory. Prog. Neurobiol., 79, 1-48.

Sahay, A., Scobie, K.N., Hill, A.S., O’Carroll, C.M., Kheirbek, M.A., Burghardt, N.S., 2011. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature, 472, 466-470

Sahay, A., Wilson, D.A., Hen, R., 2011. Pattern separation: A common function for new neurons in hippocampus and olfactory bulb. Neuron., 70, 582-8.

Saxe, M.D., Battaglia, F., Wang, J.W., Malleret, G., David, D.G., Monckton, J.E., Garcia, A.D., Sofroniew, M.V.,  Kandel, E.R., Santarelli, L., Hen, R., Drew, M.R., 2006. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Nat. Acad. Sci. USA, 103, 17501-6.

Scoville, W.B., Milner, B., 2000. Loss of recent memory after bilateral hippocampal lesions. 1957. J. Neuropsychiat. Clin. Neurosci., 12, 103-13.

Snyder, J.S., Kee, N., Wojtowicz, J.M., 2001. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol., 85, 2423-31.

Song, H., Stevens, C.F., Gage, F.H., 2002. Astroglia induce neurogenesis from adult neural stem cells. Nature, 417, 39-44.

Squire, L.R., 1992. Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychol. Rev., 99, 195-231.

Ueba, T., Zhao, X., Christie, B.R., Barkho, B., McConnell, M.J., Nakashima, K., Lein, Eadie, B.D., Willhoite, A.R., Muotri, A.R., Summers, R.G., Chun, J., Lee, K.F., Gage, F.H., 2003. Mice lacking methyl-cpg binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Nat. Acad. Sci. USA, 100, 6777-82.

Van Praag, H., Kempermann, G., Gage, F.H., 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci., 2, 266-70.

Van Praag, H., Schinder, A.F., Christie, B.R., Toni, N., Palmer, T.D., Gage, F.H., 2002. Functional neurogenesis in the adult hippocampus. Nature, 415, 1030-4.

Weisz, V.I., Argibay, P.F., 2012. Neurogenesis interferes with the retrieval of remote memories: Forgetting in neurocomputational terms. Cognition, 125(1), 13-25.

Wernig, M., Zhao, J.P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F., Broccoli, V., Constantine-Paton, M., Isacson, O., Jaenisch, R., 2008. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with parkinson's disease. Proc. Nat. Acad. Sci. USA, 105, 5856-61.

Wiebe, S.P., Staubli, U.V., Ambros-Ingerson, J., 1997. Short-term reverberant memory model of hippocampal field ca3. Hippocampus, 7, 656-65.

Witter, M.P., 1993. Organization of the entorhinal-hippocampal system: A review of current anatomical data. Hippocampus, 3, 33-44.

Yassa, M.A., Reagh, Z.M., 2013. Competitive trace theory: A role for the hippocampus in contextual linterference during retrieval. Front. Behav. Neurosci., 7, 107.

Young, J.Z., Nakashiba, T., McHugh, T.J., Buhl, D.L., Tonegawa, S., 2008. Transgenic inhibition of synaptic transmission reveals role of Ca3 output in hippocampal learning. Science (New York, NY), 319, 1260-64.

Zhang, C.L., Zou, Y., He, W., Gage, F.H., Evans, R.M., 2008. A role for adult Tlx-positive neural stem cells in learning and behaviour. Nature, 451, 1004-7.

Zhao, C., Teng, E.M., Summers, R.G., Ming, G.L., Gage, F.H., 2006. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci., 26, 3-11.