Abstract
A half century of studying the neurogenesis of the adult brain has produced much evidence for an endogenous conversion of neural stem cells. Yet the idea receives increasing criticism, in addition to the many positive comments. Does neurogenesis proceed at a rate sufficiently high for its functional significance? Are new cells capable of integrating into proper brain regions in order to perform a reparative role? How long do new neurons persist in the integration sites, and how significant is their role in the neuronal circuit structure? An organizing function is hypothesized for endogenous adult brain neurogenesis on the basis of current information. One of the main arguments for the hypothesis is the multiplicity of key physiological processes functionally associated with the involvement of new neurons and glial cells: learning, memory, adaptive behavior, protective stress responses, reproductive function, changes in the state of mind, injuries, ischemic and neurodegenerative disorders, etc. The adjustable reprogramming of neuronal precursors and the reparative role of new cells are analyzed. The organizing role of neurogenesis is considered a justified complex process that is important for the function of the adult brain.
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Addington, C.P., Roussas, A., Dutta, D., et al., Endogenous repair signaling after brain injury and complementary bioengineering approaches to enhance neural regeneration, Biomark Insights, 2015, vol. 10, suppl. 1, pp. 43–60.
Aimone, J.B., Wiles, J., and Gage, F.H., Computational influence of adult neurogenesis on memory encoding, Neuron, 2009, vol. 61, no. 2, pp. 187–202.
Appleby, P.A. and Wiskott, L., Additive neurogenesis as a strategy for avoiding interference in a sparsely-coding dentate gyrus, Network, 2009, vol. 20, no. 3, pp. 137–161.
Avram, S., Borcan, F., Avram, L.C., et al., QSAR approaches applied to antidepressants induced neurogenesis— in vivo and in silico applications, Mini-Rev. Med. Chem., 2015, vol. 16, pp. 230–240.
Benner, E.J., Luciano, D., Jo, R., et al., Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4, Nature, 2013, vol. 497, pp. 369–373.
Bennett, L., Yang, M., Enikolopov, G., and Iacovitti, L., Circumventricular organs: a novel site of neural stem cells in the adult brain, Mol. Cell. Neurosci., 2009, vol. 41, no. 3, pp. 337–347.
Boldrini, M., Underwood, M.D., Hen, R., et al., Antidepressants increase neural progenitor cells in the human hippocampus, Neuropsychopharmacology, 2009, vol. 34, pp. 2376–2389.
Brezun, J.M. and Daszuta, A., Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats, Neuroscience, 1999, vol. 89, pp. 999–1002.
Butti, E., Bacigaluppi, M., Rossi, S., et al., Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity, Brain, 2012, vol. 135, part 11, pp. 3320–3335.
Cameron, H.A. and McKay, R.D., Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus, J. Comp. Neurol., 2001, vol. 435, no. 4, pp. 406–417.
Cheyne, J.E., Grant, L., Butler-Munro, C., et al., Synaptic integration of newly generated neurons in rat dissociated hippocampal cultures, Mol. Cell Neurosci., 2011, vol. 47, no. 3, pp. 203–214.
Clelland, C.D., Choi, M., Romberg, C., et al., A functional role for adult hippocampal neurogenesis in spatial pattern separation, Science, 2009, vol. 325, pp. 210–213.
Colucci-D’Amato, L., Bonavita, V., and di Porzio, U., The end of the central dogma of neurobiology: stem cells and neurogenesis in adult CNS, Neurol. Sci., 2006, vol. 27, no. 4, pp. 266–270.
Couillard-Despres, S. and Aigner, L., In vivo imaging of adult neurogenesis, Eur. J. Neurosci., 2011, vol. 33, pp. 1037–1044.
David, D.J., Samuels, B.A., Rainer, Q., et al., Neurogenesis- dependent and-independent effects of fluoxetine in an animal model of anxiety/depression, Neuron, 2009, vol. 62, pp. 479–493.
Deng, W., Aimone, J.B., and Gage, F.H., New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci., 2010, vol. 11, no. 5, pp. 339–350.
Deshpande, A., Bergami, M., Ghanem, A., et al., Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb, Proc. Natl. Acad. Sci. U.S.A., 2013, vol. 110, pp. 1152–1161.
Dranovsky, A. and Leonardo, E.D., Is there a role for young hippocampal neurons in adaptation to stress? Behav. Brain Res., 2012, vol. 227, no. 2, pp. 371–375.
Eisch, A.J., Cameron, H.A., Encinas, J.M., et al., Adult neurogenesis, mental health, and mental illness: hope or hype? J. Neurosci., 2008, vol. 28, no. 46, pp. 11785–11791.
Enikolopov, G., Overstreet-Wadiche, L., and Ge, S., Viral and transgenic reporters and genetic analysis of adult neurogenesis, Cold Spring Harbor Perspect. Biol., 2015, vol. 7, no. 8, pp. a018804. doi 10.1101/cshperspect.a018804
Gage, F.H. and Temple, S., Neural stem cells: generating and regenerating the brain, Neuron, 2013, vol. 80, no. 3, pp. 588–601.
Gao, X., Enikolopov, G., and Chen, J., Moderate traumatic brain injury promotes proliferation of quiescent neural progenitors in the adult hippocampus, Exp. Neurol., 2009, vol. 219, no. 2, pp. 516–523.
Ge, S., Yang, C.H., Hsu, K.S., et al., A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain, Neuron, 2007, vol. 54, no. 4, pp. 559–566.
Giachino, C. and Taylor, V., Notching up neural stem cell homogeneity in homeostasis and disease, Front. Neurosci., 2014, vol. 8, p. 32. doi 10.3389/fnins.2014.00032
Gomazkov, O.A., Signaling molecules as regulators of neurogenesis in the adult brain, Neurochem. J., 2013, vol. 7, no. 4, pp. 241–255.
Gomazkov, O.A., Transformation of neural stem cells and reparative processes in the brain, Zh. Nevropatol. Psikhiatr. im. S.S. Korsakova, 2014, vol. 114, no. 8, pp. 4–12.
Gould, E., How widespread is adult neurogenesis in mammals? Nat. Rev. Neurosci., 2007, vol. 8, no. 6, pp. 481–488.
Ho, N.F., Hooker, J.M., Sahay, A., et al., In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise, Mol. Psychiatry, 2013, vol. 18, no. 4, pp. 404–416.
Hoffman, E., Pickavance, L., Thippeswamy, T., et al., The male sex pheromone darcin stimulates hippocampal neurogenesis and cell proliferation in the subventricular zone in female mice, Front. Behav. Neurosci., 2015, vol. 9, p. 106. doi 10.3389/fnbeh.2015.00106
Hsiao, Y.H., Hung, H.C., Chen, S.H., and Gean, P.W., Social interaction rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF dependent hippocampal neurogenesis, J. Neurosci., 2014, vol. 34, no. 49, pp. 16207–16219.
Imayoshi, I., Sakamoto, M., Ohtsuka, T., et al., Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain, Nat. Neurosci., 2008, vol. 11, pp. 1153–1161.
Jessberger, S., Clark, R.E., Broadbent, N.J., et al., Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats, Learn. Mem., 2009, vol. 16, pp. 147–154.
Karow, M., Sanchez, R., Schichor, C., et al., Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells, Cell Stem Cell, 2012, vol. 11, pp. 471–476.
Kazanis, I., Gorenkova, N., Zhao, J.W., et al., The late response of rat subependymal zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche, Exp. Neurol., 2013, vol. 248, pp. 387–397.
Kitamura, T. and Inokuchi, K., Role of adult neurogenesis in hippocampal-cortical memory consolidation, Mol. Brain, 2014, vol. 7, pp. 13. doi 10.1186/1756-6606-7-13
Kobayashi, M., Nakatani, T., Koda, T., et al., Absence of BRINP1 in mice causes increase of hippocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders, Mol. Brain, 2014, vol. 7, p. 12. doi 10.1186/1756-6606-7-12
Kojima, T., Hirota, Y., Ema, M., et al., Subventricular zonederived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum, Stem Cells, 2010, vol. 28, pp. 545–554.
Kokaia, Z., Martino, G., Schwartz, M., and Lindvall, O., Crosstalk between neural stem cells and immune cells: the key to better brain repair? Nat. Neurosci., 2012, vol. 15, pp. 1078–1087.
Kokoeva, M.V., Yin, H., and Flier, J.S., Neurogenesis in the hypothalamus of adult mice: potential role in energy balance, Science, 2005, vol. 310, no. 5748, pp. 679–683.
Kuvacheva, N.V., Morgun, A.V., Komleva, Yu.K., et al., Effect of enriched environment on the early stages of the development of progenitor cells of the brain in young and aging rats, Sib. Med. Zh. (Irkutsk), 2013, vol. 120, no. 5, pp. 47–51.
Lazic, S.E., Fuss, J., and Gass, P., Quantifying the behavioural relevance of hippocampal neurogenesis, PLoS One, 2014, vol. 9, no. 11, p. e113855. doi 10.1371/journal.pone.0113855
Lieberwirth, C. and Wang, Z., The social environment and neurogenesis in the adult Mammalian brain, Front. Hum. Neurosci., 2012, vol. 6, p. 118. doi 10.3389/fnhum.2012.00118
Lieberwirth, C., Liu, Y., Jia, X., and Wang, Z., Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles, Horm. Behav., 2012, vol. 62, no. 4, pp. 357–366.
Liu, A., Jain, N., Vyas, A., and Lim, L.W., Ventromedial prefrontal cortex stimulation enhances memory and hippocampal neurogenesis in the middle-aged rats, Elife, 2015, vol. 4. doi 10.7554/eLife.04803
Lu, Z., Elliott, M.R., Chen, Y., et al., Phagocytic activity of neuronal progenitors regulates adult neurogenesis, Nat. Cell. Biol., 2011, vol. 13, pp. 1076–1083.
Lucassen, P.J., Stumpel, M.W., Wang, Q., and Aronica, E., Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients, Neuropharmacology, 2010, vol. 58, no. 6, pp. 940–949.
Martino, G., Butti, E., and Bacigaluppi, M., Neurogenesis or non-neurogenesis: that is the question, J. Clin. Invest., 2014, vol. 124, no. 3, pp. 970–973.
Malberg, J.E., Eisch, A.J., Nestler, E.J., and Duman, R.S., Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus, J. Neurosci., 2000, vol. 20, pp. 9104–9110.
Martí-Fàbregas J., Romaguera-Ros M., Gómez-Pinedo U., et al., Proliferation in the human ipsilateral subventricular zone after ischemic stroke, Neurology, 2010, vol. 74, pp. 357–365.
Martino, G., Butti, E., and Bacigaluppi, M., Neurogenesis or non-neurogenesis: that is the question, J. Clin. Invest., 2014, vol. 124, no. 3, pp. 970–973.
Massa, F., Koehl, M., Wiesner, T., et al., Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity, Proc. Natl. Acad. Sci. U.S.A., 2011, vol. 108, pp. 6644–6649.
Mosher, K.I., Andres, R.H., Fukuhara, T., et al., Neural progenitor cells regulate microglia functions and activity, Nat. Neurosci., 2012, vol. 15, pp. 1485–1487.
Nait-Oumesmar, B., Decker, L., Lachapelle, F., et al., Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination, Eur. J. Neurosci., 1999, vol. 11, pp. 4357–4366.
Obernier, K., Tong, C.K., and Alvarez-Buylla, A., Restricted nature of adult neural stem cells: re-evaluation of their potential for brain repair, Front Neurosci., 2014, vol. 8, p. 162. doi 10.3389/fnins.2014.00162
Osman, A.M., Porritt, M.J., Nilsson, M., and Kuhn, H.G., Long-term stimulation of neural progenitor cell migration after cortical ischemia in mice, Stroke, 2011, vol. 42, pp. 3559–3565.
Pan, Y.W., Storm, D.R., and Xia, Z., Role of adult neurogenesis in hippocampus-dependent memory, contextual fear extinction and remote contextual memory: new insights from ERK5 MAP kinase, Neurobiol. Learn. Mem., 2013, vol. 105, pp. 81–92.
Peretto, P. and Bonfanti, L., Adult neurogenesis 20 years later: physiological function vs. brain repair, Front. Neurosci., 2015, vol. 9, p. 71. doi 10.3389/fnins.2015.00071
Picard-Riera, N., Decker, L., Delarasse, C., et al., Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice, Proc. Natl. Acad. Sci. U.S.A., 2002, vol. 99, pp. 13211–13216.
Rojczyk-Golebiewska, E., Palasz, A., and Wiaderkiewicz, R., Hypothalamic subependymal niche: a novel site of the adult neurogenesis, Cell. Mol. Neurobiol., 2014, vol. 34, pp. 631–642.
Sabelström, H., Stenudd, M., Reu, P., et al., Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice, Science, 2013, vol. 342, pp. 637–640.
Sanin, V., Heeß, C., Kretzschmar, H., and Schüller, U., Recruitment of neural precursor cells from circumventricular organs of patients with cerebral ischaemia, Neuropathol. Appl. Neurobiol., 2013, vol. 39, no. 5, pp. 510–518.
Santarelli, L., Saxe, M., Gross, C., et al., Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science, 2003, vol. 301, no. 5634, pp. 805–809.
Shingo, T., Gregg, C., Enwere, E., et al., Pregnancy stimulated neurogenesis in the adult female forebrain mediated by prolactin, Science, 2003, vol. 299, pp. 117–120.
Sierra, A., Encinas, J.M., Deudero, J.J., et al., Microglia shape adult hippocampal neurogenesis through apoptosiscoupled phagocytosis, Cell. Stem. Cell, 2010, pp. 483–495.
Smagin, D.A., Park, J.H., Michurina, T.V., et al., Altered hippocampal neurogenesis and amygdalar neuronal activity in adult mice with repeated experience of aggression, Front. Neurosci., 2015, vol. 9, p. 443.
Snyder, J.S. and Cameron, H.A., Could adult hippocampal neurogenesis be relevant for human behavior? Behav. Brain Res., 2012, vol. 227, pp. 384–390.
Snyder, J.S., Soumier, A., Brewer, M., et al., Adult hippocampal neurogenesis buffers stress responses and depressive behavior, Nature, 2011, vol. 476, no. 7361, pp. 458–461.
Soloviova, O.A., Proshin, A.T., Storozheva, Z.I., and Sherstnev, V.V., Neurogenesis enhancer Ro 25-6981 facilitates repeated spatial learning in adult rats, Bull. Exp. Biol. Med., 2012, vol. 153, no. 5, pp. 764–766.
Spalding, K.L., Bergmann, O., Alkass, K., et al., Dynamics of hippocampal neurogenesis in adult humans, Cell, 2013, vol. 153, no. 6, pp. 1219–1227.
Sullivan, R., Duncan, K., Dailey, T., et al., A possible new focus for stroke treatment—migrating stem cells, Expert. Opin. Biol. Ther., 2015, vol. 15, no. 7, pp. 949–958.
Sun, X., Zhang, Q.W., Xu, M., et al., New striatal neurons form projections to substantia nigra in adult rat brain after stroke, Neurobiol. Dis., 2012, vol. 45, no. 1, pp. 601–609.
Surget, A., Tanti, A., Leonardo, E.D., et al., Antidepressants recruit new neurons to improve stress response regulation, Mol. Psychiatry, 2011, vol. 16, no. 12, pp. 1177–1188.
Tajiri, N., Duncan, K., Antoine, A., et al., Stem cell-paved biobridge facilitates neural repair in traumatic brain injury, Front. Syst. Neurosci., 2014, vol. 8, p. 116. doi 10.3389/fnsys.2014.00116
Tiraboschi, E., Tardito, D., Kasahara, J., et al., Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades, Neuropsychopharmacology, 2004, vol. 29, no. 10, pp. 1831–1840.
Tishkina, A.O., Stepanichev, M.Yu., Aniol, V.A., et al., Microglial functions in a healthy brain, Usp. Fiziol. Nauk, 2014, vol. 45, no. 4, pp. 3–18.
Trueman, R.C., Klein, A., Lindgren, H.S., et al., Repair of the CNS using endogenous and transplanted neural stem cells, Curr. Top. Behav. Neurosci., 2013, vol. 15, pp. 357–398.
Turnley, A.M., Basrai, H.S., and Christie, K.J., Is integration and survival of newborn neurons the bottleneck for effective neural repair by endogenous neural precursor cells? Front. Neurosci., 2014, vol. 8, p. 29. doi 10.3389/fnins.2014.00029
Wabik, A. and Jones, P.H., Switching roles: the functional plasticity of adult tissue stem cells, EMBO. J., 2015, vol. 34, no. 9, pp. 1164–1179.
Wang, C., Liu, F., Liu, Y.-Y., et al., Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain, Cell Res., 2011, vol. 21, no. 11, pp. 1534–1550.
Wang, H.D., Dunnavant, F.D., Jarman, T., and Deutch, A.Y., Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat, Neuropsychopharmacology, 2004, vol. 29, pp. 1230–1238.
Wang, W., Lu, S., Li, T., et al., Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function, J. Neurosci., 2015, vol. 35, no. 20, pp. 7833–7849.
Wang, X., Mao, X., Xie, L., et al., Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice, PLoS One, 2012, vol. 7, no. 6, p. e38932. doi 10.1371/journal.pone.0038932
Wu, M.V., Sahay, A., Duman, R.S., and Hen, R., Functional differentiation of adult-born neurons along the septotemporal axis of the dentate gyrus, Cold. Spring. Harb. Perspect. Biol., 2015, vol. 7, p. a018978. doi 10.1101/cshperspect.a018978
Wu, M.V., Shamy, J.L., Bedi, G., et al., Impact of social status and antidepressant treatment on neurogenesis in the baboon hippocampus, Neuropsychopharmacology, 2014, vol. 39, no. 8, pp. 1861–1871.
Yamaguchi, M. and Mori, K., Critical periods in adult neurogenesis and possible clinical utilization of new neurons, Front. Neurosci., 2014, vol. 8, pp. 177–183.
Yang, J., Shi, Q.D., Yang, Y.B., et al., Vasoactive intestinal peptide administration after stroke in rats enhances neurogenesis and improves neurological function, Brain Res., 2015. doi 10.1016/j.brainres.2015.09.001
Yarygin, K.N. and Yarygin, V.N., Neurogenesis in the central nervous system and prospects of regenerative neurology, Zh. Nevropatol. Psikhiatr. im. S.S. Korsakova, 2012, vol. 112, no. 1, pp. 4–13.
Yu, T.S., Zhang, G., Liebl, D.J., and Kernie, S.G., Traumatic brain injury-induced hippocampal neurogenesis requires activation of early nestin-expressing progenitors, J. Neurosci., 2008, vol. 28, pp. 12901–12912.
Zhang, R.L., Zhang, Z.G., and Chopp, M., Ischemic stroke and neurogenesis in the subventricular zone, Neuropharmacology, 2008, vol. 55, pp. 345–352.
Zhang, Z.G. and Chopp, M., Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic, Lancet. Neurol., 2009, vol. 8, pp. 491–500.
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Original Russian Text © O.A. Gomazkov, 2016, published in Uspekhi Sovremennoi Biologii, 2016, Vol. 136, No. 3, pp. 227–246.
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Gomazkov, O.A. Neurogenesis as an organizing function of the adult brain: Is there enough evidence?. Biol Bull Rev 6, 457–472 (2016). https://doi.org/10.1134/S2079086416060013
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DOI: https://doi.org/10.1134/S2079086416060013