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Adult Neurogenesis in the Mammalian Central Nervous System

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Adult Neurogenesis in the Mammalian Central Nervous System AR245-NE28-09 ARI 20 May 2005 7:51 Adult Neurogenesis in the Mammalian Central Nervous System Guo-li Ming and Hongjun Song Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; email: [email protected], [email protected] Annu. Rev. Neurosci. Key Words 2005. 28:223–50 neural stem cell, progenitor, development, regeneration, plasticity doi: 10.1146/ annurev.neuro.28.051804.101459 Abstract Copyright c 2005 by Annual Reviews. All rights Forty years since the initial discovery of neurogenesis in the postnatal reserved rat hippocampus, investigators have now firmly established that ac- First published online as a tive neurogenesis from neural progenitors continues throughout life Annu. Rev. Neurosci. 2005.28:223-250. Downloaded from www.annualreviews.org Access provided by University of Pennsylvania on 04/27/17. For personal use only. Review in Advance on in discrete regions of the central nervous systems (CNS) of all mam- March 17, 2005 mals, including humans. Significant progress has been made over 0147-006X/05/0721- the past few years in understanding the developmental process and 0223$20.00 regulation of adult neurogenesis, including proliferation, fate speci- fication, neuronal maturation, targeting, and synaptic integration of the newborn neurons. The function of this evolutionarily conserved phenomenon, however, remains elusive in mammals. Adult neuro- genesis represents a striking example of structural plasticity in the mature CNS environment. Advances in our understanding of adult neurogenesis will not only shed light on the basic principles of adult plasticity, but also may lead to strategies for cell replacement therapy after injury or degenerative neurological diseases. 223 AR245-NE28-09 ARI 20 May 2005 7:51 2004). In most mammals, active neurogenesis Contents occurs throughout life in the subventricular zone (SVZ) of the lateral ventricle and in INTRODUCTION................. 224 the subgranular zone (SGZ) of the dentate HISTORIC OVERVIEW ........... 225 gyrus in the hippocampus. Neurogenesis METHODOLOGIES FOR outside these two regions appears to be ex- INVESTIGATION OF ADULT tremely limited, or nonexistent, in the intact NEUROGENESIS .............. 226 adult mammalian CNS. After pathological Analysis of Endogenous Adult stimulation, such as brain insults, adult Neurogenesis In Vivo.......... 226 neurogenesis appears to occur in regions Analysis of Adult Neurogenesis otherwise considered to be nonneurogenic. In Vitro and Ex Vivo........... 229 Our understanding of adult neurogenesis in NEUROGENESIS IN THE mammals has progressed significantly over INTACT ADULT the past decade, and we now know a great MAMMALIAN CNS............. 231 deal more about the biology of this biological The Adult Neural Stem Cell, Its phenomenon, from the identity and location Proliferation, and Neuronal of adult neural stem cells, and proliferation Fate Specification ............. 231 and fate specification of neural progenitors, Neuronal Migration and Nerve to migration, nerve guidance, neuronal mat- Guidance ..................... 234 uration, and synaptic integration of newborn Neuronal Maturation, Synapse neurons in the adult CNS environment Formation, and Plasticity . .... 235 (Alvarez-Buylla & Lim 2004, Gage 2000, MODULATION OF Goh et al. 2003, Kempermann & Gage 1999, ENDOGENOUS ADULT Lie et al. 2004). We have also gained signif- NEUROGENESIS .............. 236 icant knowledge of how adult neurogenesis ADULT NEUROGENESIS is regulated in the normal and abnormal UNDER PATHOLOGICAL CNS (Duman et al. 2001, Fuchs & Gould STIMULATIONS ............... 239 2000, Kempermann 2002). Advances in our Ischemic Brain Injury ............. 239 understanding of adult neurogenesis have Seizures.......................... 239 been facilitated by the isolation and in vitro Radiation Injury .................. 240 analysis of multipotent neural progenitors Degenerative Neurological derived from the adult CNS (Gottlieb 2002). Diseases ...................... 240 The demonstration of active adult neurogen- POTENTIAL FUNCTIONS OF esis also opens possibilities to repair the adult ADULT NEUROGENESIS . 241 CNS after injury or degenerative neurolog- PERSPECTIVE .................... 242 Annu. Rev. Neurosci. 2005.28:223-250. Downloaded from www.annualreviews.org Access provided by University of Pennsylvania on 04/27/17. For personal use only. ical diseases using cell replacement therapy in the near future (Lindvall et al. 2004, Rossi & Cattaneo 2002). In this review on Adult neural stem INTRODUCTION adult neurogenesis in the mammalian CNS cells: a type of Neurogenesis, a process of generating func- systems, we start with milestone discoveries unspecified tionally integrated neurons from progenitor and methodologies in the field of adult neu- precursor cells that has the capacity to cells, was traditionally believed to occur only rogenesis. We then summarize the current proliferate in during embryonic stages in the mammalian understanding of adult neurogenesis and generating more of CNS (Ramon y Cajal 1913). Only recently finish with a discussion of potential functions itself and to make has it become generally accepted that new of mammalian adult neurogenesis. Interested new neurons, neurons are indeed added in discrete regions readers may consult several recent compre- astrocytes, and oligodendrocytes of the adult mammalian CNS (Gross 2000, hensive reviews on this topic (Alvarez-Buylla Kempermann & Gage 1999, Lie et al. & Lim 2004, Goh et al. 2003, Kempermann 224 Ming · Song AR245-NE28-09 ARI 20 May 2005 7:51 & Gage 1999, Lie et al. 2004, Lindvall et al. 2004, Parent 2003, Rossi & Cattaneo 2002). The predominant repair mechanisms in the adult CNS were traditionally thought to be very limited and restricted to a postmitotic state, such as sprouting of axon terminals and HISTORIC OVERVIEW synaptic reorganization. The recent demonstration of func- In addition to proving the neuron doctrine tional neurogenesis and isolation of multipotent neural stem using the Golgi technique, Santiago Ramon cells from the adult mammalian CNS, including that of hu- y Cajal (1913) also concluded that neurons mans, has important implications for the development of new are generated exclusively during the prenatal strategies for the treatment of injury and neurodegenerative phase of development. Although suggestions diseases in the adult CNS. First, stem cells with the potential regarding the existence of dividing cells to give rise to new neurons appear to reside in many different in the postnatal CNS were raised (Allen regions of the adult CNS. These findings raise the possibility 1912, Hamilton 1901), it was impossible, that endogenous neural stem cells can be mobilized for the using methods of the time, to trace the fate replacement of dying neurons in neurodegenerative diseases. of those rare dividing cells and to prove Indeed, recent reports have provided evidence that in some in- that the newborn cells were in fact neurons jury models limited neuronal replacement occurs in the CNS. rather than glia (Ramon y Cajal 1913). Since Second, the complete process of neuronal development can be then, “no new neurons after birth” became a recapitulated in certain areas of the adult CNS, resulting in in- central dogma in neuroscience for almost a tegration of functional new neurons into the existing circuits. century (Gross 2000). In the late 1950s, a new Exploration of the underlying mechanisms of adult neuroge- method was developed to label dividing cells nesis may lead to strategies to support functional neuronal with [H3]-thymidine, which incorporates replacements in other areas with either endogenous progen- into the replicating DNA during the S-phase itors or neuronal progeny of stem cells from other sources, of the cell cycle and can be detected with such as embryonic stem cells. autoradiography (Sidman et al. 1959). The generation of new neurons was first reported using this technique in three-day old mouse (Nottebohm 2004). Adult neural stem cells, brains (Smart 1961). Soon after, Altman and the sources of new neurons, were first isolated colleagues published a series of papers report- from the adult CNS of rodents (Reynolds & 3 Neurogenesis: a ing [H ]-thymidine evidence for new neurons Weiss 1992) and later from humans (Kukekov process of generating in various regions of adult rats, including the et al. 1999). The field was revolutionized functional neurons dentate gyrus of the hippocampus (Altman by the introduction of bromodeoxyuridine from progenitor & Das 1965), neocortex (Altman 1966) and (BrdU), a synthetic thymidine analogue, as cells, including olfactory bulb (Altman 1969). However, another S-phase marker of the cell cycle proliferation and neuronal fate little attention was given to these studies, (Gratzner 1982). Because BrdU can be de- specification of Annu. Rev. Neurosci. 2005.28:223-250. Downloaded from www.annualreviews.org Access provided by University of Pennsylvania on 04/27/17. For personal use only. perhaps because they were considered to lack tected by immunocytochemistry for pheno- neural progenitors, functional relevance. The issue of adult neu- typic analysis and stereological quantification, and maturation and rogenesis was revisited in the late 1970s when this approach remains the most commonly functional Kaplan & Hinds (1977) demonstrated that used technique in the field. Before the end integration of neuronal progeny newborn neurons in the hippocampus sur- of the twentieth century,
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