Adult Neurogenesis: From Precursors to Network and Physiology

Physiol Rev 85: 523–569, 2005;doi:10.1152/physrev.00055.2003.Adult Neurogenesis: From Precursorsto Network and PhysiologyDJOHER NORA ABROUS, MURIEL KOEHL, AND MICHEL LE MOALLaboratoire de Physiopathologie des Comportements, Institut National de la Santéet de la Recherche Médicale, U588, Université de Bordeaux 2, Bordeaux, FranceI. Neurogenesis in the Adult Brain: a New Paradigm for Structure-Function Relationships 523II. From Newly Born Cells to Network 524A. Definitions 524B. In vivo evaluation of adult neurogenesis: methodological issues 525C. Integration of the newly born cells into neurogenic site networks 527D. Factors regulating adult neurogenesis 533III. The Anatomo-Functional Approach 539A. Environmental and physiological influences on neurogenesis 539B. Activation of the stress axis: acute and long-term effects on neurogenesis 543C. Aging and longitudinal observations 545D. Involvement of neurogenesis in pathologies 548IV. Conclusion 553Abrous, Djoher Nora, Muriel Koehl, and Michel Le Moal. Adult Neurogenesis: From Precursors to Network andPhysiology. Physiol Rev 85: 523–569, 2005; doi:10.1152/physrev.00055.2003.—The discovery that the adult mammalianbrain creates new neurons from pools of stemlike cells was a breakthrough in neuroscience. Interestingly, thisparticular new form of structural brain plasticity seems specific to discrete brain regions, and most investigationsconcern the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation (HF). Overall, twomain lines of research have emerged over the last two decades: the first aims to understand the fundamentalbiological properties of neural stemlike cells (and their progeny) and the integration of the newly born neurons intopreexisting networks, while the second focuses on understanding its relevance in brain functioning, which has beenmore extensively approached in the DG. Here, we propose an overview of the current knowledge on adultneurogenesis and its functional relevance for the adult brain. We first present an analysis of the methodologicalissues that have hampered progress in this field and describe the main neurogenic sites with their specificities. Wewill see that despite considerable progress, the levels of anatomic and functional integration of the newly bornneurons within the host circuitry have yet to be elucidated. Then the intracellular mechanisms controlling neuronalfate are presented briefly, along with the extrinsic factors that regulate adult neurogenesis. We will see that agrowing list of epigenetic factors that display a specificity of action depending on the neurogenic site underconsideration has been identified. Finally, we review the progress accomplished in implicating neurogenesis inhippocampal functioning under physiological conditions and in the development of hippocampal-related pathologiessuch as epilepsy, mood disorders, and addiction. This constitutes a necessary step in promoting the development oftherapeutic strategies.Downloaded from physrev.physiology.org on November 25, 2005I. NEUROGENESIS IN THE ADULT BRAIN: ANEW PARADIGM FOR STRUCTURE-FUNCTION RELATIONSHIPSDevelopmental biology teaches us that brain functioningrequires neurons of appropriate types to be generatedin appropriate places and numbers, and then tomigrate to their final positions and refine their synapticcontacts to a high degree of precision and avoid aberrantconnections. Finally, the brain must accommodategrowth of the organism and new behavioral or cognitivecapacities. For decades, neurobiologists have known thatneuronal network organization as well as individual performancesare altered by environmental events, experience,or internal signals such as hormones, aging, andvarious injuries (322).The adult brain faces two seemingly contradictorychallenges. On the one hand it must maintain behaviorwww.prv.org 0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society523

524 ABROUS, KOEHL, AND LE MOALand thus preserve the underlying circuitry, and on theother hand, it must allow circuits to adapt to environmentalchallenges. This dilemma between stability and plasticityis a subject of debate. It has been suggested that thestructural changes underlying plasticity exist at the levelsof dendritic spines, dendrites, and axons (28, 287, 297,383, 408). However, direct observation of dendrites andspines in the adult brain supports two divergent viewpoints, i.e., both long-term dendrite stability (192, 368)and experience-dependent synaptic plasticity (541). Datasuggest that dendritic spines are heterogeneous in shapeand structure and can be roughly divided in two groups:large spines that survive for months and even years andsmall spines that are motile, change form rapidly, andeither disappear or transform into large spines (for review,see Refs. 132, 216, 255). During long-term potentiation(LTP) of synaptic transmission, which is known toinvolve modifications in dendritic spine morphology (297,337, 586), small spines are both generated and eliminated(143, 338). Given the structure-stability-function relationships,it has been suggested that the small spines aregenerated during activity-dependent processes and acquisitionof memories, providing an inexhaustible source ofnew synapses, and that the large spines are the structuralbasis of memories in the long-term (255). For many authors,all these local and cellular phenomena have beenlabeled as neuroplasticity, a concept used to account forthe functional observations.In the search for structure-function relationships,great enthusiasm followed the discovery that embryonicneurons, for instance, dopaminergic neurons, could betransplanted into adult brains, survive and alleviate somepostlesion behavioral alterations. Although it generated aconsiderable amount of data, this approach has notproven very successful so far in living up to functional andtherapeutic hopes (157, 217). However, it has generated aconsiderable amount of data on the growth and the migrationof these neurons, and on their ability to makesynapse with the surrounding neurons of the host and toinfluence the activity of their target neurons. However,the turning point has been the demonstration that theadult mammalian brain is also capable of mitosis and thatthe generated cells differentiate into neurons that migrateto integrate circuitries. Interestingly, this particular newform of structural brain plasticity seems specific to discretebrain regions and most investigations concern thesubventricular zone (SVZ) and the dentate gyrus (DG)of the hippocampal formation (HF), although an interestingdebate developed in the wake of the propositionthat neurogenesis occurs in the neocortex of the adultprimate.In brief, the discovery of neurogenesis in the adultbrain confronted the persistent assumption that adultneurons did not undergo proliferation and that structurecould not be changed in this way. In the 1960s, Altman’sfirst observations of adult neurogenesis (11), followed bythe studies of Kaplan and Hinds (for a historical view, seeRef. 249), were followed by negative reactions and criticalpublications that did not confirm the existence of newbornneurons in adults (452). Ironically, at about the sameperiod, data were published on neurogenesis in birdsrelated to the appearance of seasonal song, a discoverythat gave rise to new thoughts on brain plasticity andadaptation (for review, see Ref, 410).Overall, two main lines of research have emergedsince the discovery that neurogenesis persists in discreteregions of the adult brain. The first aims to isolate neuralstem cells and understand their fundamental biologicalproperties, the ultimate objective being to manipulatethem and enhance repair and regeneration. The secondfocuses on understanding its functional relevance, especiallyin the DG. We will thus approach these two lines ofresearch in the following chapters. As we will see, it hasnow been unambiguously demonstrated that persistentneurogenesis occurs in the SVZ and DG of adult rodents.Most of our knowledge on the birth, proliferation, migration,and death of adult-born cells results from studiesperformed in the SVZ paradigm that easily allow the dissectionof the properties of the stem cells (and theirprogeny) and the integration of the newly born neuronsinto preexisting networks. Once the existence of the phenomenonhad been established, the important step was tounderstand what triggers and inhibits it, and how it isregulated. Identifying the functional roles of these adultbornneurons in the context of structure-function relationshipswill be the main focus of the review. The considerableevidence supporting the participation of thesenew neurons in brain functioning has been collected inthe DG, and their role in information storage and hippocampal-relatedpathology will be examined. On theassumption that the DG transforms entorhinal inputs tofacilitate storage in CA3, adult neurogenesis may allowthe DG to adapt to new flows of relevant informationwhile at the same time preserving it for the processing ofold memories. In more general terms, we will ask whetherneurogenesis acts on memory consolidation in a specificand functional manner or whether it prepares the HF forgeneral experiences and challenges.II. FROM NEWLY BORN CELLS TO NETWORKA. DefinitionsThe recent interest in adult neurogenesis studies hasled to a promiscuous use of the term stem cell and abroadening of its definition. However, based on theirfunctional properties, one can distinguish “stem” cellsfrom “progenitor or precursor” cells. Thus a stem cell iscurrently defined as an undifferentiated cell that exhibitsDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 525the ability to proliferate, to self-renew, and to differentiateinto multiple yet distinct lineages (356, 570). In the adultbrain, most stemlike cells are in a quiescent stage, exceptin the two neurogenic zones considered here, the SVZ andthe DG of the HF, where they have a very slow dividingturnover (a few weeks). In contrast, progenitor cells aremitotic cells with a faster dividing cell cycle that retainthe ability to proliferate and to give rise to terminallydifferentiated cells but are not capable of indefinite selfrenewal;they are more committed than stemlike cells,and their multipotentiality is still a matter of debate.Finally, when the cell type being studied is not clear, as isthe case in vivo, both stem and progenitor cells are referredto as precursor cells. For an overview of the characteristicsthat can be used to differentiate neural stemfrom progenitor cells, and of the controversies that stillpersist around definitions, we refer the reader to reviewsby Gage (160), Geuna et al. (167), and Seaberg and van derKooy (494).B. In Vivo Evaluation of Adult Neurogenesis:Methodological Issues1. Original studies: DNA synthesis staining andBrdU utilizationThe original studies on in vivo cell proliferation reliedon the use of [ 3 H]thymidine ([ 3 H]dT), which is incorporatedinto the cell during DNA synthesis, i.e., the Sphase of the cell cycle. Mitotically active cells are subsequentlyrevealed by autoradiography. More recently,BrdU, an analog of thymidine, has been used in lieu of[ 3 H]dT (412). These markers have comparable availabilitytimes and labeling efficiencies (411). Although [ 3 H]dTpresents the advantage of good stoichiometry (allowingdetermination of the number of mitotic events after labeling),BrdU revealed by immunohistochemistry is morefrequently used as the cost is lower, section processing isfaster, and stereological analysis is possible. In addition,BrdU is easier to combine with other cellular markers,which makes it possible to phenotype the newly borncells by double or triple immunohistochemistry.The original protocols used for BrdU labeling, establishedby Gage and colleagues (268, 267), consisted of adozen BrdU injections (50 mg · kg 1 · day 1 ip). Since thispioneering work, with the flurry of data, protocols havediversified. As we will see in section III, the number andthe doses of BrdU injections as well as the frequency ofadministration vary considerably from one experiment toanother depending on the area of interest (fewer injectionsare required for studying the SVZ compared with theDG), the species, the phenomena being examined (a decreaseor an increase in neurogenesis), and the subjecttype (young intact subjects, impaired or old individuals).To make the picture more complex, BrdU is sometimesadministered in mice via drinking water (1–1.5 mg/ml for2–4 wk) to minimize animal pain and distress (80, 332),with the disadvantage that individual daily intake is unknown.Following BrdU injections, the killing of the animal isadjusted depending on the step of neurogenesis that isbeing investigated: cell proliferation, cell determinationtoward a given phenotype, cell migration and differentiation,or cell death. In this way, to study proliferation,animals are killed following the last BrdU injection withina short time lapse ranging from a few hours to a few days.As early as 2 h after a single injection, mitotic figures canbe seen, and this time point has been proposed as a truemeasure of proliferation. However, in the case of senescentrats, multiple injections are required as cell proliferationand the frequency of labeled clusters are too low.Furthermore, when animals are killed within a short timeafter the last BrdU injection, newly born cells are small,irregular, and clustered (the clusters being more numerouswith multiple BrdU injections), which renders quantitativeanalysis challenging. For this reason, a washoutprotocol of a few days allowing cells to migrate is appliedin many experiments. Cell migration is followed by killingthe animals at different days (1–10 days) after BrdU injection,in which case it is necessary to limit the numberof BrdU injections (208). Survival of the newborn cells isusually studied by killing the animals after a long delay(several weeks) following BrdU administration, when thephenotype of the cells has been determined. Less frequently,retroviral tracing has also been used for “developmental”studies (81, 123, 439, 501). However, becauseretroviral infection is not controlled, labeling is quitevariable and is thus unsuitable for quantitative analysisbetween different experimental groups (556). Finally, inmost pharmacological and behavioral studies, the treatmentunder investigation is interrupted after BrdU pulses,and animals are killed after a “chase” period of severalweeks. It is important to be aware that in this case, theinfluence of the treatment on cell determination and cellsurvival is not addressed. To do so, the “treatment” shouldbe prolonged over the “chase” period time (for example,see Refs. 267, 335).2. Phenotyping cellsOne of the most important tasks is to phenotypecells, and markers specific to the dividing cells or thestate of maturation of newly born cells are available for invivo studies.A) PRECURSOR CELLS. So far, no marker that is exclusive tostemlike cells has been identified, which certainly reflectsthe divergence in opinion on the identity of the stemlikecell population. However, markers of stem-cell candidatesor simply dividing cells are now available and canbe divided into two categories depending on the purposeDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

526 ABROUS, KOEHL, AND LE MOALof the studies. The first category covers “universal” orgeneral molecular markers that are used to define thebiological characteristics of stemlike cells (for an extensivereview, see Ref. 440). Among these markers, the mostwidely used is nestin, which defines classes of intermediatefilament proteins; it was first described as the productof a gene whose expression distinguishes precursors frommore differentiated cells in the neural tube (156) and wasfound to be specifically expressed in neural progenitorcells (307). More recently, a family of molecular markershas been identified, which includes mouse-Musashi1(m-Msi1), a neural RNA-binding protein expressed predominantlyin proliferating neuronal and/or glial precursorcells but not in newly generated postmitotic neuronsand oligodendrocytes (246, 479).The second category of markers is more specificallyused in research aimed at uncovering the functional roleof adult neurogenesis and consists of antigens present incycling cells that are used as proliferative markers. Theyare often used in combination with BrdU, since incorporationof BrdU alone identifies cells undergoing DNAreplication but does not formally provide evidence thatthese cells are actually capable of division. They includeKi-67, a nuclear protein expressed in dividing cells for theentire duration of their mitotic activity, the expression ofwhich is neither linked to DNA repair nor to apoptoticprocesses (142, 259). Although less frequently used, proliferatingcell nuclear antigen (PCNA) allows assessmentof cell proliferation as well. It is an auxiliary protein ofDNA polymerase which is increasingly expressedthrough G 1 , peaks at the G 1 /S interface, and decreasesthrough G 2 (146, 162, 294). This marker has been usedsuccessfully to study cell proliferation and cell cyclelength in conjunction with BrdU cumulative labeling (39).Finally and much less used are P34cdc2, a key player inthe initiation of mitosis (415), and phosphorylated HistoneH3 (HH3) expression, which is confined to cells inthe G 2 and M phases of the cell cycle. In general, cells inthe G 2 phase exhibit punctuate HH 3 nuclear staining thatchanges to a more condensed pattern once they enter theM phase (214).B) IMMATURE NEURONS. The mammalian RNA-binding proteinHu, the homolog of the Drosophila neuron-specificRNA-binding protein Elav, is exclusively expressed inpostmitotic neurons (7, 479) and thus is frequently usedas an early neuronal marker (31, 414). Other markersinclude neuron-specific class III -tubulin (TuJ1), a cytoskeletalprotein expressed in all postmitotic neurons(360, 361), doublecortin (DCX), which encodes a microtubule-associatedprotein expressed in migrating neuroblasts(155, 168, 389), TOAD 64 (turned on after division,also called TUC-4, CRMP4, PUlip1), a cytoplasmic proteinexpressed transiently by postmitotic neurons (366), andthe polysialylated-neuronal cell adhesion molecule PSA-NCAM (277, 498). Another candidate for immature neuronalmarkers is the basic helix-loop-helix (bHLH) transcriptionfactor NeuroD, which seems to be expressedfrom a very early stage to the stage where new neuronsdevelop dendrites (496, 497). Some of these markers stainnonneuronal cells, and some of them (TOAD 64, PSA-NCAM, DCX) are present in the brain, for example, in thepiriform cortex, independently of neurogenesis (113, 389,392, 423, 498, 560), which makes the interpretation ofresults more difficult.C) MATURE NEURONS. The most frequently used specificmarkers for mature neurons are neuron specific enolase(NSE), neuronal specific nuclear protein (NeuN) (386),and microtubule-associated protein (MAP-2). However,the identification of the neuronal phenotype of newlygenerated cells using these markers is considered ambiguousas they also label other types of cells (189, 411, 453,454). An alternative approach consists in demonstratingthat adult-born cells do not express any marker for glialcells such as 2,3-cyclic nucleotide (CNP) for oligodendrocytes,and calcium binding proteins (S100, S100) orglial fibrillary acidic protein (GFAP) for astrocytes.3. Current identified pitfallsIn addition to the problem of neuronal identification,several methodological pitfalls have been identified. First,embryonic and postnatal injections of BrdU have beenreported to induce physical, morphological, and behavioralabnormalities (282, 495). Although only a few studieshave addressed the deleterious effects of BrdU injectionsin adulthood, a neurotoxic effect has been reported inaged rats, loss of body weight, and deterioration in thestate of the coat being induced by repeated administrationsof 150 mg · kg 1 · day 1 of BrdU for 5 days (130).Together with its early teratogenic effects, this suggeststhat incorporation of BrdU into mitotically active cellsmay inhibit cell formation and affect stemlike cell population.This raises the as yet unresolved problem thatBrdU may alter the functioning of the labeled cells. Second,changes in neurogenesis detected by variations inBrdU staining may be related to a modification in BrdUavailability through an alteration in blood flow or inblood-brain barrier permeability. To rule out such confoundingparameters, using endogenous markers of thecell cycle (Ki67, PCNA, HH 3 , and P34cdc2) and evaluatingchanges in different brain regions may be helpful. Forbehavioral studies, adequate control groups should beused to measure the involvement of a potential modificationof blood flow by exercise. Third, pharmacologicaltreatments or behavioral and environment-inducedchanges in neurogenesis may exert their effects by modifyingthe length of the cell cycle, the number of proliferatingcells, or both. However, in most “functional” studies,evaluating the cell cycle parameters is difficult if notimpossible, and one might question the relevance of thisDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 527“exercise.” Finally, BrdU or [ 3 H]dT labeling might producefalse negatives and positives. The most commonlyused dose of BrdU (50 mg/kg) labels only a fraction of theproliferating cells (75), which may result in an apparentabsence of effects of a given experimental setting on cellproliferation. However, multiple injections of this lowdose may overcome this problem. Furthermore, becausethe precursor cell population most certainly does notdivide synchronically, labeling all dividing cells with asingle injection of BrdU, whatever the dose, appears utopist.On the other hand, higher doses of BrdU associatedwith an enhanced sensitivity of immunohistochemicalmethods might lead to labeling apoptotic cells or nonproliferatingcells that synthesize DNA for repair (594), andthus to false positives. This problem is particularly relevantfor studies on lesions, epilepsy, or ischemia, where ahigh rate of cell death is observed. There are severalpossible ways to rule out BrdU labeling of nonproliferativecells: 1) observing mitotic figures a few hours afterBrdU or [ 3 H]dT application; 2) using other endogenouscell cycle markers; 3) using electronic microscopy; 4)analyzing a time course of BrdU labeling (95); 5) combiningBrdU with markers of cell death, although in this casefalse negative results due to the downregulation of markersby dying cells cannot be ruled out; 6) using retrovirallabeling (81, 123, 439, 501, 556), which is not devoid ofdisadvantages (the type of cells incorporating the virusmay not be fully controlled, and stereotaxic injection,known to cause injury, is required); and 7) visualizingneurogenic sites in nestin-promoter-GFP transgenic mice(577).4. SummaryThis last decade has been marked by tremendousadvances including the development of BrdU labelingmethods, the discovery of selective markers that differentiateneurons from glial cells, and the use of new molecularand genetic tools to follow the “development” ofthe newly born cells. As we will see in the followingsections, this technical progress has led to a lot of researchand data that have confirmed observations made inthe early 1960s and considered at that time by manyspecialists as nonconclusive. However, researchers arenow aware of problems and agree that proper interpretationsdepend on accepted rules: 1) [ 3 H]dT and BrdUlabeling are not sufficient to unambiguously differentiateold neurons from newborn cells, 2) the neuron-specificmarkers presently used must be complemented by appropriatecontrols to detect false positives and by electrophysiologicalrecordings to assert real neuronal phenotypes,and 3) the maturation and the integration of theadult-born neurons must be followed up.C. Integration of the Newly Born CellsInto Neurogenic Site Networks1. The SVZA) IDENTIFICATION OF THE STEMLIKE CELLS. The SVZ, locatedthroughout the lateral wall of the lateral ventricle, harborsthe largest population of proliferating cells in the adultbrain of rodents (12, 448, 511), monkeys (178, 179, 182,248, 286, 434), and humans (47, 144), and it has beenestimated that 30,000 cells are generated bilaterally dailyin the mouse SVZ (317). This region exhibits a rostrocaudalgradient of proliferative activity: proliferation ishigher in the dorsolateral corner of the rostral ventricleand falls caudally, moving from the striatum towards theHF (511). This gradient has been correlated with thecapability of the constitutively proliferative cells to divideand to form neurospheres (381, 493) and certainly reflectsthe existence of two populations of dividing cells, one ofquiescent stemlike cells and one of rapidly proliferatingprogenitor cells (381, 382). Four cell types have beendescribed in the SVZ: 1) ependymal ciliated cells (type E)facing the lumen of the ventricle, whose function is tocirculate the cerebrospinal fluid; 2) proliferating type Aneuroblasts, expressing PSA-NCAM, Tuj1, and Hu, andmigrating in “chains” toward the olfactory bulb (OB); 3)slowly proliferating type B cells expressing nestin andGFAP, and unsheathing migrating type A neuroblasts; and4) actively proliferating type C cells or “transit amplifyingprogenitors” expressing nestin, and forming clusters interspacedamong chains throughout the SVZ (15, 55, 122,124, 166, 220, 474).Although it has been proposed that the stemlike cellsmay be ependymal type E cells, which were shown todivide in vivo and to differentiate into neurons in the OB(242), this view has been challenged by van der Kooy andcolleagues (85) who have found that ependymal cellsgenerating spheres do not have the ability to self-renew orto produce neurons, and by Capela and Temple (79) whohave shown that ependymal cells do not form neurospheres.It is more likely that the type B cells represent astemlike cell type (123, 124). Indeed, after 1 wk of intracerebroventricular(icv) infusion of the antimitotic drugcytosine--D-arabinofuranoside (AraC), type C and type Acells are eliminated, whereas type B cells continue todivide. Between 1 and 2 days after treatment cessation,type C cells reappear, followed 2 days later by type Acells, suggesting that type B cells give rise to type C cells,which in turn generate neuroblasts (125). Furthermore,following the targeted introduction of a retrovirus intoGFAP-positive cells, which include type B cells, labeledcells migrate towards the OB where they give rise to newneurons (123). Thus the lineage progression B 3 C 3 Ahas been proposed (123, 124). However, Doetsch et al.(126) have also shown that after exposure to high concentrationsof EGF, the type C cells retain stemlike cellDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

528 ABROUS, KOEHL, AND LE MOALproperties (126). In fact, there are opposing views onwhether neurospheres are derived from GFAP-positivecells (type B cells) or from fast proliferating type C cells(225, 380) (see Fig. 1).B) MIGRATION OF THE NEWLY BORN CELLS THROUGH THE ROSTRALMIGRATORY STREAM. The newly generated cells originatingfrom different levels of the SVZ migrate in chains rostrally,up to 5 mm in rodents and to 20 mm in monkeys, toreach the OB (122, 286, 317). This migration, which followsthe rostral migration stream (RMS) and requires 2–6days in rodents (220, 317, 325), involves PSA-NCAM (100,220, 418, 474, 540) and a chemorepulsion mechanismthrough Slit-Robo signaling (574). Although a role of theOB as a chemoattractant structure has been suggested, itsinvolvement in proliferation and guidance of the newlyborn cells still remains unclear. Indeed, whereas OB removal(275), transection of the olfactory peduncle (231),or unilateral nostril occlusion (96) does not prevent SVZprecursors from proliferating and migrating towards theOB, a transection through the RMS (9) or a removal of therostral OB (314) impedes neuroblast migration. It has thusbeen proposed that a diffusible attractant is secreted inspecific layers in the OB, including the glomerular layer(314).After reaching the middle of the OB, the newborncells detach from chains, migrate radially, and progressinto one of the overlying cell layers whereupon they undergoterminal differentiation. Neuroblast detachmentfrom chains is initiated by Reelin and tenascin, whereasradial migration depends on tenascin-R (198, 478).C) LIFE AND DEATH OF THE NEWLY BORN CELLS. Massive celldeath has been observed during the first 2 mo after a BrdUpulse (572). This elimination mechanism is prominent inthe OB compared with the RMS and the SVZ (39, 50, 439)and may maintain constant OB cell number by a continuouscell turnover, as was suggested during earlier development(419). The number of newly born cells that survive1 mo after a BrdU pulse (50 mg · kg 1 · day 1 of BrdUfor 4 consecutive days in 2-mo-old female wistar rats) hasbeen estimated to be 60,000 per granule cell layer in onestudy (50) and 120,000 in another (572). In the latter case,it was shown that 50% of the newly generated neurons(80,000 per granule cell layer and 800 per periglomerularlayer) that survived the initial period of cell deathsurvived for at least 19 mo (572), confirming earlier work(253). With the use of retroviral labeling of precursors inthe SVZ, it was confirmed that one-half of the labeled cellsdied shortly after their arrival in the OB (between 15 and45 days after neuronal birth) and that most dying cellswere mature, harboring dendritic arborization, and receivingconnections (439). It was further shown in thisstudy that survival of the newly generated granule cellsdepends on sensory input.D) DIFFERENTIATION OF THE NEWLY BORN CELLS IN THE OLFACTORYBULB. The newly born cells differentiate mainly into neuronsthat grow dendritic trees and differentiate into twotypes of intrabulbar interneurons. Most of the cells (75–99%) differentiate into GABA granule cells (GCs),whereas a smaller number (1–25%) differentiate into periglomerularcells expressing GABA and/or tyrosine hydroxylase(38, 81, 256, 326, 439, 475, 572). Several monthsafter their birth, 10,000 GABAergic granule neurons, 100periglomerular GABAergic neurons, and 60 new dopa-Downloaded from physrev.physiology.org on November 25, 2005FIG. 1. Neurogenesis in the subventricularzone (SVZ)/olfactory bulb (OB) system. Top panel:a sagittal view of a rodent brain showing the sites ofneurogenesis in the SVZ/OB system is given. Cellsproliferate mainly in the SVZ, migrate along therostral migratory stream (RMS) to reach the OB,where they migrate radially and undergo terminaldifferentiation. Bottom panel: a sequence of celltypes involved in neuronal lineage and specificmarkers allowing cell identification are presented.Markers appearing in bold are specific to each stage(see text for further details).Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

530 ABROUS, KOEHL, AND LE MOALThe clusters of dividing cells have been shown toinclude several cell types: neural precursors, committedneuroblasts, glial precursors, and endothelial precursors(angioblasts representing 37% of proliferative cells) thatare proximal to vessels (256, 363, 424). This suggests thatneurogenesis most probably occurs within the context ofvascular recruitment. Within this niche, endothelial cellsmay constitute a critical regulator for self-renewal ofstemlike cells (505) through the release of trophic factors(see sect. IID2C and Table 1).In the rodent DG, the vast majority of newly borncells are postmitotic and at least partially differentiatedbetween 3 and 7 days (111, 416), since during this periodBrdU-labeled cells express NeuroD (417). The cells thatdo not terminally differentiate die within 1 wk of theirgeneration, a process affecting 60% of the newborn cells(111, 204). In the macaque, a similar time course has beendemonstrated with an initial rise in BrdU-labeled cellsfollowed by a fall after 5 wk (182). Interestingly, the GCLharbors a much lower number of proliferating cells comparedwith the SVZ. Thus, in a study performed in 9- to10-wk-old rats, 9,000 newborn cells were found to begenerated per day (75). In a more recent study, only4,000 new cells, out of which 3,000 were found to benew neurons, were shown to be added daily in the DG of4-mo-old rats (456); this discrepancy in the number ofnewborn cells is certainly linked to the difference in theage of the animals used in the studies, as the productionof new neurons in the DG diminishes with age (see sect.IIIC1A). In the macaque, the number of newborn cells perday (200) represents 0.004% of one GCL (284).C) FATE OF THE NEWLY BORN CELLS. The newborn cells differentiatemainly into neurons in the GCL. In his originalFIG. 2. Neurogenesis in the hippocampalsystem. Top panel: a frontalview of a rodent brain showing the sitesof neurogenesis in the dentate gyrus(DG) of the hippocampal formation (HF)is given. The HF forms a trisynaptic network:multimodal inputs are transferredfrom neocortical regions to the DG viathe entorhinal cortex; information is thentransferred from the DG to CA3 throughthe mossy fibers, onward through theSchaffer collaterals to CA1 (and the subiculum)and then via the entorhinal cortexback out to the cortical associativeareas (16). Cells proliferate in the subgranularlayer (SGL) located at the interfacebetween the hilus and the granularlayer (GL), where they migrate and differentiateinto mature neurons. Bottompanel: a sequence of cell types involvedin neuronal development, along with specificmarkers allowing cell identification,is proposed [see text and recent reviewfrom Kempermann et al. (265) for furtherdetails].study using electron microscopy, Kaplan and co-workers(249–252) reported that the newborn cells exhibit theultrastructural characteristics of neurons. Then, theywere shown to express neuronal markers. During the first2 days after their birth, most BrdU-labeled cells expressnestin (95), then TuJ1 (75) or TOAD-64 (75, 536) in thefollowing 3 days, and DCX between 1 and 14 days aftertheir generation (65). DCX-BrdU-colabeled cells show featuresof progenitor cells as some of them coexpress Ki-67and are thus still able to divide (58, 154, 521). This rapidpostmitotic status of new cells has been confirmed withcalretinin, a calcium binding protein that is transientlyexpressed by postmitotic cells, the expression of which isobserved as early as 1 day after labeling dividing cells, apeak being reached after 1 wk (58). Although newly borncells express NeuN as early as 72 h after their generation(58, 193), only half of the BrdU-IR cells expressed NeuNover 3 wk (65). Using NSE, half of the newly born cellswere found to be neurons 2 wk after their birth (78).Calbindin is expressed later, by 3 wk after birth (180, 290,536, 537). A low percentage of adult-born cells differentiatesinto astrocytes (GFAP/S100), and rare are thosethat adopt a microglial or oligodendrocyte phenotype(521). It should be emphasized that even 4 mo after theirlabeling a nonnegligible proportion of BrdU-IR cells havean unknown phenotype. In monkeys, most newly generatedcells are claimed to be neurons as well since theyexpress TuJ1, TOAD-64, NeuN, NSE, and calbindin, andrarely markers of astrocytes (GFAP) or oligodendrocytes(CNP) (178, 182, 284). It was first thought that the newlyborn cells did not survive, thereby constituting a continuouslyrefreshed pool of neurons (189). However, it wasDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 531Extrinsic factors regulating in vivo cell proliferation and neurogenesis in the subventricularzone/olfactory bulb system and the dentate gyrus of the hippocampal formation under physiological conditionsTABLE 1.Subventricular Zone/Olfactory BulbDentate GyrusFactorsCellproliferation NeurogenesisNeuronaldifferentiationLong-termsurvivalCellproliferation NeurogenesisNeuronaldifferentiationLong-termsurvivalReference Nos.Hormones and peptidesCorticosteroneSuppression (adx) 0 m m 0 0 71, 74, 176, 465Cort. treatment n n 0 17, 71, 76, 212EstradiolEstrus cycle 0 mproE 0 n 536OVX 0 n 29, 536OVX acute 17-E m m then n 0 29, 422, 536OVX chronic 17-E 0 0 0 43517-E m (4h) 421Prolactin m m 0 506PACAP m m 362NeurosteroidsDHEA m m 0 0 254PregS m m m 349Allopreg n 349NeurotransmittersGlutamateEnt. Cx. lesion m 73NMDA activation n 73, 76NMDA blockade m m 46, 73, 76, 177, 390AMPA potentiation m 27mGluR II blockade m 581Serotonin5-HT depletion n n 29, 61Lesion graft m 63Reuptake inhibition 0 m m 0 0 10, 335, 4835-HT 1A blockade n 4515-HT 1A activation m m 0 m m 0 30, 4835-HT 1B blockade m 0 305-HT 1B activation m 05-HT 2A/2c blockade 0 n5-HT 2A/2c activation m 05-HT 2c blockade 0 05-HT 2c activation m m 0 0 0NorepinephrineDepletion 0 n n 0 0 292Reuptake inhibition m 335No donor m m m 587Growth or trophic factorsbFGF m m m 0 0 0 238, 240, 291EGF m n n 0 n n 291HB-EGF m m 0 m m 236, 238, 240TGF- m 98IGF-I m m (ovx) 0 or m (hpx) 0 1, 310, 435, 542BDNF m m 0 593CNTF m m m m 141VEGF m m 241Morphogenic factorsShh m m 0 0 295BMP n n n 311Noggin m m m 311Vitamins and retinoidsVitamin EDeficiency m n 86, 87Supplementation (tocopherol) n m m 83, 102Retinoic acid (chronictreatment)n n n n n 99Downloaded from physrev.physiology.org on November 25, 2005Adx, adrenalectomy; Cort, corticosterone; OVX, ovariectomy; 17-E, 17-estradiol; proE, proestrus; PregS, pregnenolone sulfate; Allopreg,allopregnanolone; Ent. Cx., entorhinal cortex; Hpx, hypophysiectomy; 0, no change; blank case, not determined; m, increase; n, decrease.Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

532 ABROUS, KOEHL, AND LE MOALmore recently found that they do not have an ephemeralexistence and survive for at least 11 mo (263).Recently, it has been shown that beside glutamatergicgranule neurons, a small percentage of newly borncells (14%) differentiate into GABAergic basket cells(316). Furthermore, under specific circumstances (ischemiaor neonatal kainate administration), pyramidal cellsin Ammon’s horn are also generated (see also sect. IIID1B;Refs. 128, 399, 489). However, the progenitors responsiblefor the regenerating pyramidal neurons originate from theperiventricular region rather than from the SGZ (399).D) INTEGRATION OF THE NEWLY BORN CELLS. The newborn cellsintegrate the GCL 4–10 days after their generation. Asthey form dendrites, they receive synaptic contacts andextend axons into the CA3 region, suggesting that theymake synapses long before being fully mature (75, 204,252, 344, 517). Indeed, using virus-based transynaptic activityneuronal tracing (PVR GS518), the neurons generatedin the DG have been shown to be synaptically integratedinto the preexisting circuitry 4–8 wk after theirbirth (80), whereas they reach a mature morphology(soma size, total dendritic length, dendritic branching,and spine density) only 4 mo after their birth (513).E) FUNCTIONAL PROPERTIES OF THE NEWLY BORN CELLS. When stilllocated at the interface of the hilus, the newly born cellsexhibit electrophysiological properties characteristic ofimmature neurons: they are completely unaffected byGABA A receptor inhibition, and they exhibit paired-pulsefacilitation, have a lower threshold for induction of longtermpotentiation (LTP), and display robust LTP (564).With the use of nestin-promoter GFP transgenic mice,type I cells (putative B cells) were found to have low inputresistance values, whereas the type II cells (type D cells,expressing PSA-NCAM) exhibited higher input resistanceand voltage-dependent sodium currents (159). Recently,PSA-NCAM expressing cells have been shown to differfrom mature neurons in their passive (input resistance)and active membrane properties (such as calcium spikesthat boost fast sodium action potentials) and in theirenhanced ability to develop LTP (490). One month aftertheir birth, the “newborn” neurons, labeled by a retroviralvector expressing GFP, exhibit some electrophysiologicalproperties (input resistance, threshold potential for spikingand firing) similar to those of mature granule neurons(556). The stimulation of the perforant pathway, the mainexcitatory afference to the DG, elicits responses in “newborn”GFP-labeled cells, indicating that they receive functionalsynaptic inputs and are therefore functionally integratedinto the preexisting network. However, a depressionof synaptic currents is evoked in these cells followingthe paired-pulse stimulation of the perforant pathway,whereas a facilitation response is observed in maturecells, a discrepancy attributed to differences in presynapticrelease properties (556). The functionality of the adultborngranule cells has been further demonstrated byshowing, using c-fos, that 40% of 1-mo-old newborn granuleneurons were able to respond to various chemoconvulsants(232, 234). In contrast, following a more physiologicalform of hippocampal stimulation consisting in ahippocampal-dependent learning task, only 3% of cells areactivated (232). Finally, besides these functional excitatoryadult-born granule cells, it has been shown thatGABAergic newborn basket cells form functional inhibitorysynapses with the granule cells (316). This discoveryraises the question of the mechanisms and factors involvedin the production of excitatory granule neuronsversus inhibitory interneurons.3. The cortexAlthough very controversial, the existence of adultneurogenesis in the cortex deserves attention. Indeed,Altman and co-workers in the 1960s (11, 12, 14) andKaplan in the early 1980s (247–249) reported evidence forneurogenesis in the cortex of rats and cats. More recently,neurogenesis has been described in the rat anterior neocortex(182) and in the prefrontal, inferior temporal, andposterior parietal cortex of macaques (179, 182). Within 2wk after BrdU injection(s), the number of BrdU-labeledcells increased and then fell after 5 wk, indicating that alarge number of newly born cells died. The surviving cellswere assumed to be neurons since they extended axonslocally and expressed markers of immature (TOAD 64,TuJ1) and mature (38–52% of BrdU-NeuN cells) neuronsbut did not express GFAP or CNP. Although the site oforigin of the newly born neurons remains unclear, it hasbeen proposed that they may be generated into the SVZand migrate to neocortical areas through the white matteror may be recruited from local quiescent stemlike cells(179, 182, 284).In contrast to these data, other groups have reporteda complete absence of neurogenesis in the mouse (134,332) and monkey cortex (281, 453). Neurogenesis wasobserved in the neocortex of mice only following a targetedapoptotic degeneration of corticothalamic neurons(332), and in this case, endogenous neural precursorsmigrated and differentiated into neocortical neurons in alayer- and region-specific manner and reformed appropriatelong-distance corticothalamic connections; thus theyappeared to reconstruct the lesioned circuits. In the primateneocortex, although cell proliferation occurs, thenewly born cells do not seem to differentiate into neurons(285). These discrepancies may be due to differences inhousing conditions, the animals’ histories, and geneticbackground, and other technical considerations (survivaltimes, BrdU dosage and administration mode, immunohistochemistry.. .), but generally, the existence of thiscortical neurogenesis is still a matter of debate (411).Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 5334. SummaryFollowing a century of doubt and controversies,there is now a consensus that neurogenesis occurs in theadult brain in at least two regions, the SVZ and the DG. Inboth structures, stemlike cells proliferate, migrate, anddifferentiate mainly into granule neurons that will synthesizeGABA in the OB and glutamate in the DG. Althoughless studied, a small proportion of adult-born cells differentiateinto other types of interneurons (the periglomerularin the OB and the basket cells in the DG). Altogetherthis adult neurogenesis leads to the birth of 30,000 newneurons per day in the SVZ and between 3,000 and 9,000in the DG of young adult rats, depending on their age. Thereasons for which, 1) the SVZ and the DG harbor adultneurogenesis, 2) neurogenesis is curtailed in the DG comparedwith the OB, and 3) genesis rates are much lower inprimates, are currently unknown. Furthermore, becausethese structures do not grow in size, a homeostatic compensatoryequilibrium must be attained through an increasein cell death that must be equivalent to the initialaddition of neurons. This poorly understood phenomenon,in particular in the DG, deserves more attention forit is an important partner of neurogenesis. Finally, recentevidence indicates that the adult-born neurons of the OBand the DG are functional and thus play a physiologicalrole. Although these findings suggest a relevant contributionof these newly generated neurons to the bulbar orhippocampal function, further studies are needed to confirmthese reports and fully unravel their fundamentalconsequences on the animals’ behavior (see sect. III).D. Factors Regulating Adult NeurogenesisAlthough various factors that affect the division, migration,and differentiation of neural precursor cells havebeen isolated, the precise mechanisms that control neuronalfate in the adult nervous system remain largelyunknown. Both cell intrinsic programs and extracellular/environmental factors, which we will review below, are atplay.1. Intrinsic programs controlling neurogenesisTwo fundamental decisions are involved in order fora precursor cell to generate a neural cell. The first one isto decide whether to self-renew or to undergo mitoticarrest, and the second is to interpret mitotic arrest, usingcell autonomous cues that direct toward a particular fate.Much of our current understanding of these cell intrinsicprograms comes from work performed when neurogenesisis at its best, i.e., during development. However, it isimportant to emphasize that the rules that govern neuronalspecification during development may not be the samein the adult brain. Furthermore, since a description of thedetailed molecular mechanisms involved in cell proliferationand determination is beyond the scope of this review,we here propose only a brief overview of the intrinsicfactors involved, with a special mention whenevertheir involvement has been extended to the adult neurogeniczones.A) CONTROL OF CELL PROLIFERATION. Among the cell cyclefactors regulating cellular proliferation, Rb (retinoblastoma)and its related proteins (p107, p130), necdin, andthe E2F protein families are key players (for a review, seeRef. 580). Thus, during the G 1 phase, Rb predominates ina hypophosphorylated form that can bind to E2F, a positiveregulator of the cell cycle (403), thereby repressingits transcriptional activity and preventing the cells fromentering the S phase. In cycling cells, phosphorylated Rbaccumulated during the late G 1 phase releases E2F, thusallowing S phase entry. This phosphorylation depends onthe activation of cyclin-dependent kinases (CDK) actingsequentially. Early to mid-G 1 , cyclins of the D class (D1,D2, and D3) activate CDK4/CDK6, and in late G 1 , cyclin Eactivates CDK2, leading to hyperphosphorylation of theRb protein. Two families of CDK inhibitors (CDKIs) thatcan suppress cell proliferation by inhibiting Rb phosphorylationhave been identified (566): members of the inhibitorsof CDK4 family (INK4 family), including p15 Ink4b , p16 Ink4a ,p18 Ink4c , and p19 Ink4d , and members of the kinase inhibitoryprotein family (Cip/Kip family) such as p21 Waf1/Cip1 , p27 Kip1or p57 Kip2 (see Fig. 3).It is now clear that the Rb and E2F protein familiesare differentially expressed in proliferative and postmitoticcells of the adult brain. Thus, in the two neurogenicsites, the DG and the SVZ, Rb immunoreactivity is high inproliferating neuronal precursors and reduced during terminaldifferentiation (415), which implies that the transientincrease in the level of Rb is an important step in theinitiation of terminal mitosis in neuronal progenitors.Moreover, the Rb protein family was found to be essentialfor the development of a neural lineage and the exit fromthe cell cycle, whereas it does not seem to be involved inthe maintenance of postmitotic neurons (69, 89, 228, 299).The role of E2F1 as a key factor in regulating adultneurogenesis has been further emphasized in a recentstudy performed in mice lacking E2F1. These mice, whenadult, exhibit a lower level of cell proliferation and areduction in the number of neurons generated in adultneurogenic areas (94).The role of cell cycle regulators in the control ofneuron production has been studied as well. Transgenicmice that lack p27 Kip1 expression display a higher rate ofcell proliferation versus differentiation in the SVZ, leadingto an increased number of type C cells, a reduced numberof type A neuroblasts, and no change in the number oftype B cells (127). Finally, distinct functions for CDKinhibitors, either in the control of cell cycle exit anddifferentiation during neurogenesis (respectively, p27 Kip1Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

534 ABROUS, KOEHL, AND LE MOALand p19 Ink4d ) or in the maintenance of a quiescent state inneural progenitors (p18 Ink4c ) or neurons (p21 Cip1 ) inadults have been underlined (303).B) CONTROL OF CELL FATE. Data from developmental biologyhave clearly indicated that a core genetic programinvolving multiple bHLH transcription factors is requiredfor both neuronal differentiation and determination.These factors, deriving from proneural and neurogenicgenes, antagonistically control the switch from cell proliferationto neural differentiation: cascades of neuronalbHLH genes promote differentiation, whereas antineuronalbHLH genes repress them under the control of Notchand keep cells at a precursor stage (for recent generalreviews, see Refs. 358, 473).Two classes of proneural genes can be distinguished:the determination factors, such as Mash1 (mammalianachaete-scute homolog), Math1 (mammalian atonal homolog),and Ngns (Neurogenins) including Ngn2, expressedearly in mitotic neural precursor cells, and thedifferentiation factors, including NeuroD, NeuroD2, andMath2, expressed later in postmitotic cells (for reviews,see Refs. 49, 379). It was recently determined that theseproneural genes are downstream effectors of Pax6 (for areview, see Ref. 174), a transcription factor that promotesneurogenesis (210).These proneural genes are components of a cell-cellsignaling mechanism whereby a cell that becomes committedto a neural fate inhibits its neighbor from doinglikewise. This process of lateral inhibition, which restrictsthe domains of the proneural gene activity and involvesneurogenic genes, is mediated by the Notch pathway (forreviews, see Refs. 23, 32, 161, 244, 491, 567). Among theeffectors of Notch, three families of negative regulators ofFIG. 3. Schematic representation ofthe mammalian cell cycle. The cyclinD/cdk4–6 complex phosphorylates the Rbprotein leading to sequential phosphorylationby cyclinE/cdk2 and the release of freeE2F. Phosphorylation of Rb relieves transcriptionalrepression of genes involved inthe induction of S-phase entry. The abilityof the cyclin/cdk enzymes to phosphorylateRb is inhibited by cyclin-dependentkinase inhibitors (cdkis), the activation ofwhich thus suppresses cell proliferation.The basic helix-loop-helix (bHLH) proneuralgenes NeuroD, Mash1, and Ngn1 controlthe switch from cell proliferation toneural differentiation by activation of theKip/Cip Cdki family, thus preventing progressionthrough the G 1 -S phases. The HLHproteins Id1 and Id3 (inhibitor of differentiation)repress neuronal determination bydirect binding with proneural bHLH proteins,but also favor progression throughthe cell cycle via inhibition of the INK4 andKip/Cip Cdki families. Activating and inhibitinginfluences are represented by blue arrowsand red lines, respectively.the bHLH transcription factors are known: the HES, Id,and HES-related (HESR or HERP) families (226, 413,481, 545). These effectors repress neuronal determinationand differentiation in those cells not destined tobecome neuroblasts. Paralleling this regulation of neuronalproliferation by inhibiting neuronal fate, Notchwas also found to be involved in determining glial fate(186, 398, 467).Recent studies have highlighted that some of thesefactors, which are at play during development, may beinvolved in neuronal cell fate during adulthood. ThusNotch1 and Hes5 were found to be expressed at highlevels and with a similar pattern in both the adult SVZand DG, whereas numb and numblike, which negativelyregulate the Notch signal transduction, were not, suggestingan active Notch signal in the adult neurogeniczones (523). Similarly, the mRNA expression of severalbHLH factors was found to be present at various degreesin the adult HF, ranging from the restricted expressionof Mash1 within the proliferative SGZ, which is consistentwith its role in maintaining a precursor cell phenotype,to the widespread profile of Hes5 throughout theHF (140).In conclusion, despite the considerable advancesachieved recently with the development of moleculartools, the complex intrinsic machinery that controls andcoordinates proliferation and differentiation is still poorlyunderstood. As is the case for hematopoiesis, for whichmuch progress has been achieved, understanding thegene expression patterns of progenitor cells and theirprogeny will be a critical step in elucidating the mechanismsunderlying cell fate.Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 5352. Extrinsic factors regulating neurogenesisA) HORMONES AND NEUROSTEROIDS. I) Adrenal corticosteroids.Historically, corticosteroids were the first factorsto be studied for their influence on adult neurogenesis(354). Corticosteroids are released into the blood circulationfollowing the activation of the hypothalamo-pituitary-adrenal(HPA) axis, primarily by stress (351). Corticosterone,the main corticosteroid in rodents, regulatesits own secretion through negative feedback, by interactingwith two receptors (the mineralocorticoid MR, theglucocorticoid GR), present in the DG. Suppression ofcorticosterone secretion after bilateral adrenalectomy(adx) increases glial and neuronal births in the DG (71,176), whereas mitotic activity in the SVZ remains unchanged(465), suggesting a site-specific inhibitory influenceof corticosteroids. It was further shown that proliferationincreases within 24 h after adx and remains constantover the 6 subsequent days; the newly generatedcells survive for at least 4 wk in the absence of corticosterone,indicating that their survival is corticosteroneindependent (465). Cell death is also enhanced, but thepopulations of cells undergoing mitosis or apoptosis aredistinct: immature cells divide at the interface of the hilus,whereas more mature neurons, located at the interface ofthe molecular layer, die (72). These alterations are preventedby corticosterone replacement (176, 465). The respectiveroles of MR and GR on adrenalectomy-inducedstructural modifications have recently been examined(374). Treatment with a low dose of the MR agonist,aldosterone, prevents adrenalectomy-induced increase incell death, whereas a higher dose is necessary to normalizecell proliferation. Furthermore, treatment with a GRagonist, RU 28362, at doses that should fully occupy thisreceptor prevents both adrenalectomy-induced cell deathand birth. Thus the stimulation of both MR and GR mediatesthe effects of corticosterone on cell proliferationand protects mature cells from cell death.This inhibitory action of corticosterone on neurogenesishas also been found in other models: 1) acute corticosteroneadministration {2 40 mg/kg administered 1 hbefore a single [H 3 ]dT injection (71, 76); implantation of a200-mg corticosterone pellet followed by 1 200 mg/kgBrdU (17)}, 2) chronic corticosterone treatment [1 40mg/kg for 21 days; BrdU 10 50 mg/kg every 12 h on days17–21 (212)], 3) stress (see sect. IIIB1), and 4) interindividualdifferences in the activity of the HPA axis (305; seesect. IIIB2).The mechanisms by which corticosterone hamperscell proliferation remain unknown. In vitro, glucocorticoidsblock the G 1 phase of the cell cycle, notably throughrepression of cyclin D1, cyclin D2, Cdk4 and Cdk6, andinduction of the CDKIs p21 Cip1 and p27 Kip1 (438, 585, 592).However, it remains to be determined which of thesemechanisms is involved in vivo. Because only a smallminority of precursor cells express corticosteroid receptors(77), corticosterone may not act directly on proliferatingprecursors, although it cannot be excluded thatimmature forms of receptors that are not recognized bycurrent antibodies are involved. Corticosterone could acton neighboring glial or neuronal cells expressing corticosteroidreceptors, which could control the cell cycle byreleasing growth factors (515). Alternatively, corticosteronecould regulate proliferation indirectly by increasingglutamate release in the DG (520) (see sect. IID2B) astheeffects of adx or high levels of corticosterone can beblocked by NMDA receptor activation or inactivation,respectively (76). Corticosterone may also inhibit cellproliferation by dowregulating the production of insulinlikegrowth factor I (IGF-I) (585, 592).II) Gonadal hormones. The influence of female gonadalhormones has been investigated in the DG sinceestrogen replacement therapy seems to reduce the risk ofage-related cognitive impairments (213). Although cellproliferation in the GCL (and not the hilus) is higher infemale than in male rats, the newly born cells do notsurvive, which explains the lack of sex differences in thenumber of BrdU-IR cells 2 wk after labeling (536). Sexdependentproliferative activity involves the stimulatoryinfluence of estrogens, since the number of BrdU-labeledcells is highest during the proestrus phase of the estruscycle, when circulating levels of estrogens are highest(536), and acute administration of 17-estradiol reversesthe ovariectomy-induced decrease in cell birth (29, 536).In contrast, using TOAD-64 and calbindin as early and lateneuronal markers, it has been shown that estradiol doesnot alter neuronal differentiation (536).However, discrepant results have been reported followingchronic administration of estradiol to ovariectomizedadult female rats (435), spontaneous hypertensiverats (436), or adult wild meadow voles (163). Cell proliferationin the GCL (measured 24 h after a single intraperitonealinjection of [ 3 H]dT) is lower in female meadowvoles captured during the breeding season, when estradiollevels are high, compared with reproductively inactivefemales. A similar relationship has been confirmed inlaboratory-reared female meadow voles (421).These apparently contradictory results might be explainedby a complex regulatory mechanism. In fact, asingle administration of estradiol initially enhances(within 4 h) and subsequently suppresses (within 48 h)cell proliferation in the DG of ovariectomized female ratsor meadow voles (420, 421). The increase in cell proliferationis mediated by serotonin (29), whereas the decreaseis prevented by adx (422), suggesting an involvement ofcorticosterone. However, although corticosterone-inducedregulation of cell birth certainly involves NMDAreceptors, estradiol influences on cell proliferation arenot mediated by these receptors (420). Finally, estrogenmay act directly on estrogen receptors subtype (ER )Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

536 ABROUS, KOEHL, AND LE MOALpresent on hippocampal precursors (435) or throughIGF-I receptors (see sect. IID2C).III) Neurosteroids. Neurosteroids represent a subclassof steroids synthesized de novo in many regions ofthe brain, independently of peripheral sources (36). Theyare synthesized in the HF, by glial cells mainly, and influencehippocampal-mediated functions (349). Two principalfamilies can be distinguished according to their pharmacologicalproperties (333). In particular, dehydroxyepiandrosterone(DHEA) and pregnenolone sulfate(Preg-S) act as allosteric antagonists of the GABA A receptorswhile allopregnanolone (AlloP) is a positive modulatorof these receptors.Chronic treatment of young adult male rats withsubcutaneous pellets of DHEA (200 mg/pellet for 12 days)has been shown to stimulate hippocampal cell proliferationmeasured 24 h after BrdU injections (50 mg · kg 1 ·day 1 ) given on the last 4 days of the steroid treatment(254). After an additional 16 days of treatment, the newlyborn cells survive and express the neuronal marker NeuN.Interestingly, DHEA treatment is also able to reverse thesuppressive effect of corticosterone on neurogenesis, suggestingthat it may act as an antistress neurohormone.Recently, we have shown that icv infusion of Preg-S(2 12 nmol/7 l) increases cell proliferation in the DGof young adult rats within 24 h, whereas treatment withAlloP (2 6.3 nmol/7 l) decreases it (348). The newlygenerated cells survive for at least 1 mo and differentiatemainly into neurons (expressing NeuN). These actions ofPreg-S are mediated by GABA A receptors present on hippocampalprecursors, since icv administration of muscimol,a GABA A agonist, blocks Preg-S-induced cell proliferation.Furthermore, a direct action of Preg-S was suggestedas this compound stimulates in vitro theproliferation of spheres derived from the adult SVZ (348).Altogether, the reported effects of DHEA and Preg-Sare congruent with the observations that in vitro activationof GABA A receptors inhibits cortical cell proliferation,whereas GABA A receptors antagonists stimulate it(21, 318, 327).B) NEUROTRANSMITTERS AND NEUROREGULATORS. I) Glutamate.Destruction of the perforant pathway, the main glutamatergicafference to the DG arising from the entorhinalcortex, increases cell proliferation, thus indicating thatunder these experimental conditions glutamate exerts aninhibitory influence (73). As expected, blockade of NMDAsubtypes of glutamate receptors by injection of a noncompetitiveantagonist (MK801) increases cell genesis withina few hours in rats (1 mg/kg; Refs. 73, 76), tree shrews (1mg/kg; Ref. 177), gerbils (3 3 mg/kg; Ref. 46), andovariectomized adult female meadow voles (30 mg/kg;Ref. 420), and treatment with the competitive NMDA receptorantagonist CGP 37849 (5 mg/kg) increases bothcell proliferation and granule neurons density (73). Conversely,administration of NMDA (30 mg/kg) decreasescell proliferation in several species within hours (73, 76,420), which is congruent with the antiproliferative propertiesof glutamate on in vitro cortical cell proliferation(318). However, it should be mentioned that an inhibitoryinfluence of glutamate receptor blockade on neurogenesishas been reported in stroke-damaged brains (see sect.IIID1B). The newly born cells induced by the inactivationof NMDA receptors differentiate into neurons, expressingDCX, TOAD-64, NSE, or NeuN markers (73, 177, 390, 417).Furthermore, the MK-801-induced neurons are functionalas they respond to NMDA stimulation, measured by thephosphorylation of extracellular signal-regulated kinase(ERK), 29 days after their birth date (417). This indicatesthat newly born neurons acquire components for the intracellularsignal transduction cascade linking NMDA receptorsto phosphorylation of ERK (114).The mechanisms by which precursor proliferation isinhibited by glutamate in vivo through NMDA receptorsremain unknown, but they most probably do not involvecollateral deleterious effects as treatment with CGP 43487upregulates cell birth without inducing cell death or astrogliosis(390).Because glutamate also acts onto AMPA receptors,detected in neural progenitors (165), the influence ofpotentiators of AMPA receptors such as LY451646 hasbeen evaluated on hippocampal mitotic activity. Acuteadministration of LY451646 (0.025, 0.05, 0.125 mg/kg)does not influence the number of newly born cells observed24 h after BrdU pulse (4 75 mg/kg every 2 h).However, the median dose increases the number of cellsper cluster (64%) and the number of clusters (45%) (27).Furthermore, chronic treatment (21 days) with LY451646(0.05, 0.125, 0.500 mg/kg) enhances the number of proliferatingcells, of cells per cluster, and of clusters in adose-dependent manner (27).Altogether, these results suggest that glutamate exertsa complex influence on hippocampal cell proliferation,increasing it through activation of AMPA receptors,and inhibiting it through activation of NMDA receptors.Finally, the recent discovery that GABA and glutamate arecotransmitted at the mossy fibers synapses adds furthercomplexity to the respective role of each neurotransmitterin neurogenesis regulation (196).II) Serotonin. In the 1970s, it was proposed that earlyforming serotonin (5-HT) neurons act as humoral signalsgoverning neuronal development and neurogenesis in particular(26, 298). Since then, several approaches haveshown that serotonin upregulates cell proliferation in theadult DG and SVZ (see also sect. IIID2A). Inhibition of 5-HTsynthesis (by subchronic injections of PCPA for 6 days)and selective lesions of 5-HT neurons of the raphe decreasethe number of BrdU- and PSA-NCAM-IR cells in theDG and the SVZ (BrdU 50 mg/kg ip injected on the last 3days of PCPA treatment at 1–2h intervals and animalskilled 6 h after the last injection; Ref. 61). This upregula-Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 537tion of hippocampal cell proliferation depends on serotoninas it is reversed by intrahippocampal grafts of embryonic5-HT neurons (63). Partial lesions of 5-HT rapheneurons lead, after an initial deprivation of hippocampal5-HT fibers, to a spontaneous reinnervation of this structureby 5-HT fibers. At this time, the fall of mitotic activity(and PSA-NCAM expression) is reversed (62). These actionsof serotonin are mediated by 5-HT 1A receptors inboth the DG and the SVZ (30, 451) while 5-HT 2A and5-HT2Creceptors are selectively involved in the regulationof cell proliferation in the DG and SVZ, respectively (30).Finally, 4 wk after chronic treatment with 5-HT 1A or5-HT2Aagonists (daily injection of 8-OH-DPAT or RO600175 for 15 days, 75 mg/kg of BrdU injected twice onthe last 8 days of the treatment), the newly born cells in theDG and/or the OB express NeuN (30).III) Nitric oxide. Nitric oxide (NO), a free radicalmolecule synthesized from L-arginine by NO synthase,serves as a neurotransmitter in the brain (8). In the SVZ ofadult mice, neuronal precursors have been found to bewithin the sphere of influence of a NO source and toexpress NO synthase at the sites of terminal differentiation(377). Administration of DETA/NONOate, a NO donor,to young adult rats significantly increases both cellproliferation and migration in the SVZ and the DG (587).C) TROPHIC FACTORS. Many trophic factors have beenshown to have mitogenic actions in the adult brain neurogenicregions. Thus the proliferative effects of basicfibroblast growth factor (bFGF or FGF-2) have beenclearly demonstrated for the SVZ. Chronic administrationof bFGF intracerebroventrically (360 ng/day for 14 days,50mg·kg 1 · day 1 of BrdU being injected during the last12 days of the treatment; Ref. 291) or intranasally (5 0.2g/day at 5-min intervals for 1 wk concurrent with 2 50mg · kg 1 · day 1 of BrdU at 8-h intervals; Ref. 240)increases the number of mitotic nuclei in the SVZ within24 h. This leads to an increased number of newly bornneurons (expressing DCX in the SVZ; Ref. 240) that reachthe OB where they express NeuN (4 wk after their birth;Ref. 291). In contrast, in the DG, a lack of effect (291) ora small but nonsignificant increase in cell birth (25%,following 3 days icv infusion of 10 g/ml) was reported(238). Consistently, in mice lacking bFGF, basal hippocampalneurogenesis is “normal,” suggesting that otherfactors may maintain low levels of precursor proliferationunder resting conditions (582). However, overexpressionof bFGF by gene transfer in wild-type and bFGF-deficientmice upregulates DG cell proliferation, which indicatesthat a robust and constant bFGF expression is a necessarycondition for increasing cell birth in this structure(582).Epidermal growth factor (EGF; 350 ng/day for 14days, 50 mg · kg 1 · day 1 of BrdU being injected duringthe last 12 days of the treatment; Ref. 291) and heparinbindingEGF (HB-EGF; 3 days icv infusion of 10 g/mlconcurrent with 2 50 mg · kg 1 · day 1 of BrdU at 8-hintervals; Refs. 236, 238) stimulate cell birth in the SVZ (1and 7 days after growth factor infusion, respectively)certainly via EGF receptors (381, 416, 502). However,these two factors probably have distinct actions, sinceHB-EGF increases the number of BrdU-IR cells expressingDCX or NeuroD in the SVZ as well as the number ofnewly generated cells reaching the OB (236, 240), whereasEGF reduces the number of newly born neurons reachingthe OB (291). In the DG, HB-EGF (236, 238) but not EGF(291) increases cell proliferation by interacting mostprobably with EGF receptors expressed by the dividingcells (416). The adult-born cells express the neuronalmarker NeuroD (236).Transforming growth factor (TGF)- is required forSVZ precursor proliferation. Indeed, icv administration ofTGF- (400 ng/day for 6 days) induces a dramatic increasein precursor proliferation (98), whereas TGF- null miceshow a decrease in proliferating cells in the SVZ, and inthe total number of newly born cells within their target,the OB (543). No data on the influence of TGF- onhippocampal precursors are yet available.IGF-I is a growth-promoting peptide hormone that isproduced in the CNS by neurons and glial cells (20) andexhibits neurotrophic properties in adulthood (405). Itsinfluence on neurogenesis has been examined in hypophysiectomizedrats presenting low levels of circulatingIGF-I (1). Thus peripheral administration of IGF-I(1.25 mg · kg 1 · day 1 ) induces an increase of cell proliferationin the dentate GCL and the hilus after 6 days.Long-term treatment (0.39 mg · kg 1 · day 1 for 20 days)increases both BrdU-labeled cell number and their differentiationinto neurons as measured by the percentage ofBrdU-IR cells expressing calbindin. In contrast, an IGF-Iinducedincrease in cell proliferation in nonhypophysiectomizedrats is not associated with an enhancement oftheir differentiation potential toward a neuronal fate(542). In vitro experiments (2) strongly suggest that IGF-Iregulates cell proliferation in vivo by acting directly onIGF-I receptors expressed by newly born cells (542), buta recent study has also shown that estrogen receptors arenecessary for the induction of in vivo hippocampal cellproliferation by IGF-I (435).Brain-derived neurotrophic factor (BDNF) is a memberof a family of related neurotrophic proteins, the functionof which is to prevent neurons from dying duringdevelopment. Chronic icv infusion of BDNF (0.012 l/dayfor 12 days) increased BrdU-labeled cells in the SVZ andin the GCL of the OB (593). The newly born cells expressedTuJ1 or MAP2. Survival (169, 276) and/or differentiation(6, 22) of the neuronal precursors and theirprogeny rather than proliferation seem to be influencedby BDNF. Concerning the DG, it has been shown thatheterozygous BDNF knockout mice exhibit reduced proliferationand survival of BrdU-labeled cells (301), sug-Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

538 ABROUS, KOEHL, AND LE MOALgesting a role for BDNF as a positive regulator of bothproliferation and survival. However, repeated, but notsingle, administration of a compound that stimulates endogenousBDNF, riluzole, increases cell birth (3-fold) butnot cell survival. Most of the newly generated cells (90%)differentiate into granule neurons (expressing NeuN)(257). This effect is blocked by icv administration ofBDNF-specific antibodies, suggesting that an increase inBDNF is necessary for the promoting effect of riluzole onprecursor proliferation. Altogether these data show thatBDNF plays an important role in the maintenance of basalneurogenesis, a conclusion similar to that obtained followinga developmental loss of function of this gene(312).Vascular endothelial growth factor (VEGF) is ahypoxia-induced angiogenic protein that exhibits neurotrophicand neuroprotective properties (359). Given thatneurogenesis occurs in close proximity to blood vesselsand that clusters of dividing cells contain endothelialprecursors (see sect. IIC2B), VEGF may constitute the linkbetween neurogenesis and angiogenesis. This is supportedby the observation that icv administration of VEGF(0.24 g/day for 3 days concurrent with 2 50 mg · kg 1· day 1 BrdU) stimulates cell proliferation in the rodentSVZ and SGZ by 7 days after treatment onset (241). At thattime, the newly born cells express DCX and NeuN markers.The neuroproliferative effect of VEGF is associatedwith an upregulation of cyclin D1, Cyclin E and cdc25, andan increase in the nuclear expression of E2F1, E2F2, andE2F3 (591), which is consistent with a regulation of theG 1 /S phase transition of the cell cycle.D) MORPHOGENIC FACTORS. Sonic hedgehog (Shh), an importantmorphogen in development, is a signaling glycoproteinthat acts through Patched 1-Smoothened (Ptc1-Smo) receptor complex to trigger various events duringCNS development, including determination of ventralneural phenotypes, induction of oligodendrocyte precursors,proliferation of specific neuron progenitor populations,and modulation of growth cone movements (for areview, see Ref. 346). In a comprehensive study, Lai andco-workers (295) investigated the role of Shh in the adultbrain and showed that it increased proliferation of culturedadult rat hippocampal progenitors in a dose- andtime-dependent fashion. In vivo, the exogenous administrationof Shh and the inhibition of its signaling increasedand reduced cell proliferation, respectively. Finally, thepresence of the Shh receptor Patched in the DG andAmmon’s horn in the HF, and the high levels of expressionof Shh in structures that project towards the DGsupport the assumption that Shh could be an endogenouspositive regulator of cell proliferation in the adult DG(295).Another group of early neural morphogens, the bonemorphogenic proteins (BMPs), belongs to the TGF- superfamily,which includes TGF-, activins, and the relativesnamed growth/differentiating factors (GDF). Theseglycoproteins play a crucial role in bone remodeling andin the regulation of dorsoventral patterning of the neuraltube and cell fate during embryonic development. Furthermore,several BMPs, including BMP4, are involved inrepression of the oligodendroglial lineage and generationof the astroglial lineage during brain maturation (190).Similarly, in the adult SVZ, BMPs (BMP2, BMP4, BMP7)inhibit neurogenesis and direct astroglial differentiation,whereas their antagonist Noggin promotes neurogenesis(311). It has been proposed that Noggin produced by thetype E cells antagonizes the type B cells expressing BMP(311). Furthermore, BMP2, BMP4, and BMP7 have beenfound to activate a promoter of the gene for the HLHfactor Id1, which is known to inhibit the function ofneurogenic transcription factors such as Mash1 and neurogenin.Thus the switch from neuronal to astrocyte faterealized by BMPs certainly involves HLH proteins (578).These findings were extended to the HF. Indeed, a novelsecretory factor, neurogenesin-1 (Ng1), released by hippocampalastrocytes and dentate granule cells adjacent toprogenitor cells, was found to promote neuronal fate inthe adult HF through antagonism of BMPs, which alter thefate of neural stemlike cells from neurogenesis to astrogliogenesisby upregulating the expression of the negativeHLH factors Id1, Id3, and Hes5 (548).E) REGULATION BY GLIAL CELLS. Regulation of adult neurogenesisby glial cells has been emphasized (500). Astrocytes,which play an important role as sensors of changesin their extracellular microenvironment, could regulateneurogenesis by secreting local signals (514). These signals,unknown so far, may be ionic fluxes, neurosteroids,cytokines, growth factors, and glutamate metabolites (48,243, 245, 296, 486, 516, 579, 595). The observation thatsome proliferating cells in the DG express a receptor forS100, a small acidic calcium binding neurotrophic proteinreleased by astrocytes, reinforces the putative contributionof glial cells in the regulation of adult neurogenesis(339).F) REGULATION BY CELL DEATH. An equilibrium between neurogenesisand cell death probably ensures a homeostaticbalance in the adult brain. This hypothesis, based on theobservation that the neurogenic structures do not grow insize, implies that cell death provides a stimulus for increasedneurogenesis, a hypothesis reinforced by severallines of argument: 1) during development, there is a balancebetween the birth and death of granule cells (183); 2)mechanical lesions, aspiration, and transection stimulateneuronal precursor proliferation in the GCL and/or theSVZ (180, 242, 531, 546, 568); 3) proliferation in the SVZ isupregulated under inflammatory conditions (70); 4) adrenalectomy,limbic seizures, and ischemia enhance bothcell death and cell birth; and 5) the apoptotic degenerationof corticothalamic neurons (by means of targetedphotolysis) induces endogenous neural precursors to dif-Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 539ferentiate into mature neurons in regions of the cortexundergoing targeted neuronal death (332). The inductionof neurogenesis in these regions of the adult neocortexthat do not normally undergo any neurogenesis (332) mayresult from the removal of a normal inhibitory influenceor the loss of a secreted stimulatory factor produced bythe dying cells.G) SUMMARY. Adult neurogenesis within each neurogenicsite is regulated differently by a growing list of“epigenetic factors” [to which should be added prolactin(506), norepinephrine (35, 292), the pituitary adenylatecyclase-activating polypeptide (PACAP) (362), ciliary neurotrophicfactor (141), retinoic acid (99), and vitamin E(83, 86, 87); see Table 1 for a complete summary]. Althoughmost of these factors modulate cell proliferationthrough unknown mechanisms, a regulation of Cyclin D1and p27 Kip1 expressions may constitute a common pathway(438).The specificities of each neurogenic site may be relatedto differences in the intrinsic properties of the dividingcells (for example, their intrinsic ability to senseneural activity; Ref. 114) and/or in their microenvironment,which corresponds to the summation of local neurogenicsignals expressed or synthesized “locally” byhealthy neighboring cells or by dying cells. These signalsmay also be synthesized “peripherally” and released inneurogenic sites by neuronal afferences or by blood vessels.In this context, the role of the cerebral vasculaturehas gained importance as adult neurogenesis occurswithin an “angiogenic niche,” and an alteration in thevascular microenvironment, or its ability to respond tochanges in metabolic demands, may be responsible for adisruption in neurogenesis (371, 372, 460).III. THE ANATOMO-FUNCTIONAL APPROACHComplementary to the neuroanatomic studies thatrevealed some key biological properties of adult neuralstemlike cells, the integration of the adult newborn neuronsinto preexisting networks has prompted the fundamentalquestion of their functional relevance. So far, moststudies have focused on the role of adult neurogenesis inhippocampal functioning. Parsimoniously, this region, includedin the limbic-cognitive system, is part of an integratednetwork involved in learning and memory, attentionalprocesses, motivational states, and emotion (68,135, 136, 227, 352, 484). As pointed out by Hampton et al.(201), current theories of hippocampal function wrestlewith two major conceptual issues: whether the structureencodes spatial, nonspatial, or both types of information(139) and whether the information encoded is episodic orsemantic. Recent evidence infers that hippocampal neuronalnetworks could support the cognitive mechanismsof declarative memory by encoding features of experiences.Indeed, declarative memory involves a record ofeveryday experiences, which includes information aboutthe content of that experience and the spatial and temporalcontext in which it occurred (episodic memory), woventogether into the framework of the individual’s knowledge(semantic memory) (135). According to the memoryspace model of declarative memory, the HF plays a criticalrole in 1) representing experiences as a series ofevents and places and 2) linking memories together byidentifying common features into a network that supportsinferential expression. This said, the role of the HF inlong-term memory is in dispute as the “standard theory”assumes that the HF becomes dispensable after the conversionof short-term memory into long-lasting memory,whereas the “multiple trace theory” makes the assertionthat the HF is involved in the storage and retrieval ofepisodic memory regardless of the age of memory (394).Although current advances do not yet allow the attributionof a specific role for newborn neurons in thisconceptual framework, in the following sections we willreview the progress achieved in implicating neurogenesisin both hippocampal functioning under physiological conditionsand the apparition of hippocampal-related pathologies,which are mainly studied in preclinical animal models.Operationally, two approaches have been considered:the first consists of relating changes in hippocampal neurogenesisto changes in the ability to perform hippocampal-relatedtasks, and the second consists of studying theinfluence of hippocampal-related tasks on neurogenesis.A. Environmental and Physiological Influenceson Neurogenesis1. Experience in enriched environments,neurogenesis, and learningA) OLD PROBLEM, NEW DATA. Rosenzweig and co-workers(470–472) were the first to introduce the concept of anenriched situation, i.e., a complex environment enrichedin sensorial stimulations, social experiences, and physicaland cognitive exercises (555). This concept has given riseto a wealth of studies showing that exposure to suchenvironments, which are considered as enriched for standardlaboratory conditions, modifies brain functioning,learning, problem-solving ability, brain chemistry, andseveral structural aspects of brain organization. The consequenceof environment enrichment on hippocampalneurogenesis was originally studied in “juvenile” femaleC57Bl/6J mice. Exposure to an enriched environment between3 and 13 wk of age was found to increase survivalof newly born cells (measured 4 wk after daily injectionsof 50 mg BrdU for 12 consecutive days from days 28 to 40of enrichment), whereas cell proliferation (measured 1day after the BrdU pulses) remained unchanged in theGCL and in the hilus (267). Similar results have beenDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

540 ABROUS, KOEHL, AND LE MOALobtained with adult female rats (after injecting BrdU 50mg·kg 1 · day 1 on days 26–30 of enrichment) (407).These first reports led Kempermann and Gage (262) tofurther investigate the impact of environmental enrichmenton mice, and it was later shown that cell proliferationin the GCL was increased only when mice were killed3 mo after their removal from the enriched environment(262). In addition, a comparison of different strains ofmice showed that enriched experience affects hippocampalneurogenesis differently according to genetic background:as reported above, it increases cell survival butnot cell proliferation in C57BL/6 mice (267) which have ahigh baseline level of neurogenesis (268), whereas it increasescell proliferation in 129/SvJ mice (261) whichhave low levels of neurogenesis (268). This interestingfinding indicates that environment has a differential impactdepending on inheritable traits, an effect still unexplained.Finally, in most experiments, enrichment led toan improvement in spatial memory in the water maze, alearning task that requires the subjects to learn multipleextra-maze visual cues, allowing them to build a dynamicspatial representation of their surroundings to navigate toa platform hidden underneath the water surface (378).However, whether these genetic variations of neurogenesishave a functional significance in spatial memory remainsunknown (266).B) MECHANISMS INVOLVED IN ENRICHMENT-INDUCED NEUROGENESIS.Exposure to an enriched environment is known to influencebrain chemistry, in particular neurotransmitters andtrophic factors, which may underlie its action on neurogenesis(151, 370, 442, 471, 555, 584). In addition to thesefactors, several components of this environment may beinvolved in the regulation of neurogenesis.Thus the effects of an enriched environment on neurogenesisand spatial memory may be related to an enhancementof motor exercise rather than learning. Toexamine this hypothesis, female mice were housed with arunning wheel, injected with BrdU (50 mg · kg 1 · day 1for the first 12 days) and killed 1 or 30 days after the lastBrdU injection. In these conditions, cell proliferation andcell survival in the GCL, and performances in spatiallearning tasks were enhanced, suggesting that “physicalactivity” is an important mediator of enrichment-inducedneurogenesis (553, 554). Further studies proposed thatthe stimulatory effects of running are mediated by VEGF(148), blood-borne IGF-I (542), NMDA receptor 1-subunit,and BDNF production (278).In their early studies, Rosenzweig and Bennett (471)suggested that environmental changes or novelty were amajor factor in the effects of enrichment on brain andbehavior (471), which suggests that it could be a relevantfactor involved in enrichment-induced neurogenesis aswell. The observation that exposure to enriched conditionsfor an extended period of 6 mo does not add furtherbenefit certainly lends weight to this hypothesis (262).The social environment may also contribute to enrichment-inducedneurogenesis. This hypothesis has beentested in rats reared for 4 wk in isolation and injected withBrdU (2 50 mg · kg 1 · day 1 ) on the last 3 days of therearing treatment. Compared with grouped-reared rats,isolation decreases hippocampal cell proliferation within24 h, the number of newly born cells surviving over anadditional period of 4 wk of isolation, and the percentageof newly born cells expressing TOAD-64. Interestingly,the isolation-induced decrease in cell proliferation is reversedby a subsequent 4 wk of group housing (BrdUbeing injected on the last 3 days of the rearing period; Ref.320). Together, these results indicate that social environmentis a highly relevant factor underlying the anatomicaleffects of an enriched environment.2. Reciprocal relation between learningand neurogenesisA) LEARNING INFLUENCES SEVERAL ASPECTS OF NEUROGENESIS. Theeffect of learning on survival of newly born cells has beenexamined in the water maze and in eyeblink conditioningusing a trace protocol (175). In this latter test, whichrequires an intact HF (385, 512), animals have to associatean auditory tone (conditioned stimulus) with a cornealairpuff or electrical stimulation (unconditioned stimulus)that is temporally separated by a trace interval (350). Inboth learning tasks, rats are tested 1 wk after a singleBrdU injection (200 mg/kg). The number of BrdU-labeledcells is enhanced by learning immediately or 1 wk afterthe end of training, an effect accompanied by a decreasein cell death. In associative learning, the performance ofindividual rats positively predicts the life span of 1-wk-oldBrdU-labeled cells, i.e., rats exhibiting the best behavioralscores possessed more newborn cells; this also suggeststhat learning (and not training) is a sufficient condition toincrease the survival of adult-born cells (309). This learning-inducedincrease in cell survival was maintained 2 moafter acquisition of associative learning (309). The observedenhancement of cell survival is specific to learningbecause neurogenesis remains unchanged in rats exposedto unpaired conditions in eyeblink conditioning or in ratsproducing the same amount of motor responses in thewater maze. Furthermore, learning-induced upregulationof neurogenesis may be specifically attributed to hippocampalfunctioning as delay-eyeblink conditioning,classically attributed to the cerebellum, and training on acued test in the water maze, a hippocampal-independenttype of learning, do not modify neurogenesis (508).Although these experiments indicate an enhancingeffect of learning in the water maze on cell survival,contradictions exist concerning cell proliferation. Whenanimals are injected daily for the entire testing period (50mg · kg 1 · day 1 for 12 days; Ref. 554) or the very last dayof testing (200 mg/kg; Ref. 175), the number of BrdU-Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 541labeled cells remains unchanged. However, when animalsare injected at the end of the learning phase (50 mg ·kg 1 · day 1 for 3 days), when an asymptotic level ofperformance is reached, then the number of newly bornneurons in the GCL of the DG increases (306). To reconcilethese data, we hypothesized that different phases ofthe learning process have distinct actions on cell proliferation.To test this hypothesis rats were injected withBrdU (50 mg · kg 1 · day 1 ) either during the initial phase(4 days, Fig. 4, A and E), characterized by a fast and largeimprovement in performance, or during the late phase (4days, Fig. 4C), when an asymptotic level of performanceFIG. 4. Learning can increase or decrease the production of newborncells. The aim of these experiments was to distinguish the effectsof the early phase () of learning (characterized by a rapid and largeimprovement in performance) and of the late phase of learning (whenasymptotic levels of performance are reached) on neurogenesis. To thisend, bromodeoxyuridine (BrdU; solid bars) was injected during the early (A, E) or the late (C) of learning and animals were killed (arrows)after partial learning (A, at the end of the early ) or when the task hadbeen mastered (C and E, at the end of the late ). The early of learningdid not modify the number of cells generated during this period (B). Thelate of learning increased the number of newly born cells generatedduring this period (D), whereas it decreased the number of newly borncells produced during the early (F). C, control group; L, learning group.**P 0.001 compared with control group. [Modified from Döbrössy etal. (121).]was reached. We found that the early phase of learningdoes not modify proliferation (Fig. 4A), whereas the lateone does (121). Indeed, the number of newly born cellsincreased contingently with the late phase of learning(Fig. 4B), and these new cells differentiated into neuronsthat persisted in the DG for at least 5 wk after the animalshad acquired the task. In contrast, the late phase of learninginduced a decrease in the number of newly born cellsproduced during the early phase (Fig. 4C).Most importantly, the extent of BrdU cell loss wasinversely related to learning performances: rats with thehighest and lowest cell loss have the best and worstperformances, respectively. This decline in adult-borncells most probably mirrors cell death, since learninginduces an increase in numbers of pyknotic cells (129)and tunnel-positive cells (18). The observations that learningin the water maze increases the expression of proteinsinvolved in apoptosis (82) and that intrahippocampal administrationof anticaspases, which blocks cell death,impairs long-term but not short-term spatial memory(106), strengthen the hypothesis that cell death is animportant component of hippocampal learning.The mechanisms by which cell survival and proliferationare regulated during learning are so far unknown. Anonspecific effect of training or exercise on blood flow tothe brain that may increase BrdU availability is unlikely,since neurogenesis is unchanged in control “swimmers”(121, 175). Trophic factors known to support the viabilityand function of many types of neurons are likely mediatorsof learning-dependent changes in the HF. Indeed,hippocampal bFGF and BDNF are increased during tasklearning and decreased once an asymptotic performanceis reached (171, 271).B) A BLOCKADE OF NEUROGENESIS DISTURBS LEARNING. The participationof neurogenesis in memory formation has beenmore directly tested by using the DNA methylating agentmethylazoxymethanol (MAM; 5 mg/kg for 14 days concurrentwith 75 mg · kg 1 · day 1 of BrdU on days 10–12-14).This treatment decreases the number of adult-born cellsby 80% and alters trace conditioning, whereas delay conditioning,neuronal responsiveness (presynaptic neurotransmitterrelease and excitability), and synaptic plasticityare not disrupted (509). Three weeks after treatmentcessation, the replenishment of immature neurons is associatedwith a recovery to acquire the trace conditionedresponse. Altogether, these results suggest that newlyborn cells are necessary for the formation of trace memories.Because MAM treatment for 6 days only is unable toaffect trace conditioning, adult-born cells may not be“functional” until 1–2 wk after birth. Although it has beenshown that newborn cells extend their axons in the CA3subfield within 4–10 days after birth (204), a basic temporalstudy following their functional maturation (bymeans of electrophysiological properties or c-fos expression)is still lacking.Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

542 ABROUS, KOEHL, AND LE MOALRecently, it has been reported that the formation ofspatial memories may not be associated with neurogenesis.Indeed, the blockade of cell proliferation by the same14-day MAM treatment as described above does not alterspatial learning in the water maze or contextual conditioningin fear conditioning (510). In our opinion, this lackof effect is due to the residual newly born cells thatcontinue to be generated under MAM (700/day for 3BrdU injections), indicating that learning can occur with avery small percentage of new neurons. This assumption isbased on the observation that some aged rats are able toacquire spatial navigation learning despite a very lownumber of newly born cells [200/day for 5 BrdU injections;see sect. IIIC2, Fig. 6 (130)].An emerging strategy to clarify the role of neurogenesisin learning consists of using ionizing-irradiationknown to induce cognitive impairments in animals (37, 66,119, 184) and in humans (372). X-irradiations (0–15 Gy)decrease the number of BrdU-labeled cells in a dosedependentmanner (following a 60 mg/kg injection ofBrdU 1 h before death) and the number of cells expressingp34 cdc2 or Ki-67 in the adult DG (369, 433, 532). Twomonths after irradiation, the production of adult-bornneurons (expressing NeuN) is significantly reduced certainlyas a consequence of an altered neurogenic microenvironment(369, 372). The reduction in hippocampalmitotic activity is accompanied 1 wk postirradiation bybehavioral deficits in a hippocampal-dependent task ofspatial short-term memory (place-recognition). In contrast,performances in the water maze remain unaffected2 wk postirradiation, a time by which proliferative activityhas resumed, albeit at a low level (75 nascent cells dailyin the dorsal DG; Ref. 330).3. DiscussionData accumulated in the past decade suggest that thebirth of new cells is a necessary condition for the acquisitionof memory traces (see also data on prenatal stressand aging). However, a higher reduction in cell genesisseems to be required for the appearance of deficits inlearning spatial cues than in trace conditioning, a differencewhich may be related to task difficulty (508). Furthermore,hippocampal-dependent behaviors influencecell proliferation, cell survival, and cell death. The questionof how adult neurogenesis participates in memoryprocessing (i.e., encoding, consolidation, retrieval) is asFIG. 5. Influence of the different phases oflearning on neurogenesis. The early phase () oflearning increases the survival of cells that predateexposure to the task (175). These cells could beinvolved in the encoding of memory traces, allowingtask acquisition (see sect. IIIA3A). Since thelearning-induced increase in cell survival is longlasting(309), the surviving adult-born neuronscould participate in the long-term storage of informationand to recall remote memories. Two distinctprocesses take place after completion of the latephase of learning (121; see Fig. 4 and sect. IIIA3, Band C): 1) death of the cells born during the earlyphase of learning, which may be involved in memorytrace consolidation. This cell death phenomenoncould constitute a trimming mechanism thatsuppresses old unnecessary neurons and/or the immatureneurons that are too old or have not establishedlearning-related synaptic connections. 2)There is an increase in the number of cells generatedcontingently with the late phase training.Given that the learning-induced increase in cell proliferationis long-lasting, these newly born cellscould be involved in a resetting process renderingthe DG available for the acquisition of new memories(forgetting and flexibility).Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 543yet unresolved. Although speculative, the followingframework is proposed (Fig. 5).A) DO ADULT-BORN NEURONS PRODUCED BEFORE LEARNING HAVE AROLE IN MEMORY PROCESSING? Since survival of the newly borncells whose birth predates the beginning of learning isincreased during the learning task (175), the encoding ofmemory traces may be processed in these adult-bornneurons. According to the “use it or lose it” principle, thecells that survived and integrated into the granule cells/mossy fiber system could function as postsynaptic detectorsof correlated afferent activity and thereby update thebearing map, which is constructed in the DG from directionalcues (229). After processing, which relies on patternseparation properties (270), episodic memories arestored temporally by virtue of the CA3 auto-associativesystem (468). The adult-born neurons could also be involvedin temporal pattern completion: if a degraded versionof a stimulus is presented after learning, the representedfeature can be recalled from this incomplete inputinformation.The role of adult-born neurons in long-term storageand retrieval of remote memories is still elusive as therole of the HF and the DG is still a matter of debate. Oneview stipulates that the HF has a limited storage capacityas 1-mo-old memories do not require the HF, memorytraces being transferred within cortical areas where theyare consolidated and permanently stored (19, 56, 273, 274,342, 573). In relation to this apparent time-limited role ofthe HF, it was originally thought that after encoding andconversion of short-term memory into long-lasting memory,the adult-born neurons were eliminated (189). However,adult-born neurons that have been recruited bylearning survive for several weeks (121, 309) and thusoutlive the time required for cortical transfer. This timewindowis, in our opinion, hardly reconcilable with the“consolidation transfer hypothesis.” Furthermore, if oneconsiders that adult-born neurons are integrated into theDG, which is no longer necessary for maintaining thememory traces, they may have adopted another, as yetundetermined, role (508).However, the view that the HF becomes dispensableafter the conversion of short-term memory into longlastingmemory is disputed, as it is supposed to be involved,together with neocortical areas, in the storage andthe retrieval of remote memories (387, 388, 393–395). Inparticular, the HF seems important in the recall of old,detailed, episodic memories that are context dependent(469, 527). This scenario is consistent with the long-termsurvival of adult-born neurons (121, 309), which could actas binding detector cells capable of memorizing bindingsbetween items (503) or could store a memory index, i.e.,an index of neocortical areas that are activated by experientialevents and contain no intrinsic meaning in termsof representation of external events (538). In these cases,adult-born neurons most probably do not store the memorytraces themselves but may play a critical role inlinking representations of distinct experience, and longtermstorage of spatial representations could be achievedby synaptogenesis occurring within this CA3 (455). Alternatively,adult-born neurons could store the contextualinformation regarding the episode (the so-called contextualtrace; Ref. 394).B) A ROLE OF CELL DEATH IN STABILIZATION? A surprising phenomenonis that the death of old and/or newly bornneurons also plays an important role in enabling hippocampallearning. This may constitute a trimming mechanismreplacing the unnecessary old neurons and/or theimmature neurons that have not established learning-relatedsynaptic connections with freshly minted ones. Thismay serve the function of increasing the signal-to-noiseratio, thus consolidating the memory trace. This phenomenon,which on one hand is consistent with the “use it orlose it” principle and on the other hand goes against theclassic assumption in learning-induced structural plasticitythat “more is better,” recalls the regressive eventsobserved during development (450).C) IS LEARNING-INDUCED CELL PROLIFERATION INVOLVED IN MEMORYCLEARANCE OR FLEXIBILITY? Learning-induced cell proliferationis not correlated with learning performances, suggestingthat these newly born cells do not directly sustain ongoinglearning and may rather be involved in future behaviors.This phenomenon may represent a resetting process ensuringthat the hippocampal system is available to processnew memories. This hypothesis is strengthened by theobservation that presenilin-1 knockout mice that presentnormal basal neurogenesis exhibit a reduction in enrichment-inducedcell proliferation and better retrieval ofcontextual fear memory traces compared with controlmice (153). Thus a deficiency in the upregulation of cellproliferation induced by the late phase of learning mayprevent memory clearance, thereby impairing forgettingprocesses and disabling hippocampal functions. It is alsopossible that this alteration in cell proliferation alters theinferential use of past memories in a novel situation (flexibility)and thus leads to rigidity and perseverance.B. Activation of the Stress Axis: Acuteand Long-Term Effects on NeurogenesisExposure to stressful events prepares animals to engagein fight or flight responses, and a role of the HF inthese defensive behaviors has been proposed (52, 205).Moreover, as stressful events have deleterious effects onhippocampal integrity (351, 352, 484), the influence ofdifferent types of stress on hippocampal neurogenesis hasbeen studied.1. Effects of stress on neurogenesisIn most studies, a decrease in cell proliferation hasbeen observed after stressful events, but this effect ap-Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

544 ABROUS, KOEHL, AND LE MOALpears highly dependent on the nature and the timing ofstress.In male but not female rats, exposure to the odor ofa predator [trimethyl thiazoline (TMT), the major componentof fox feces] downregulates the number of proliferatingcells estimated 2 h, 24 h, and 1 wk after a singleBrdU injection (100–200 mg/kg) (149, 537). However, thiseffect is transient as TMT-induced downregulation ofBrdU cell numbers disappears 3 wk after labeling whendividing cells express NeuN or NSE (149). Likewise, inmale tree shrews (Tupaia belangeri), a single exposure toan unknown congener, which results in the establishmentof a dominant/subordinate relationship, brings down thenumber of dividing cells (labeled by one injection ofBrdU, 75 mg/kg) in the DG of the subordinate within 2 h(177). In the marmoset (Callithrix jacchus) however, asingle exposure to a resident-intruder model of stressreduces the number of newly born cells (2 h after 1 75mg/kg BrdU) in the DG of the intruder (181). Repeated (3or 6 wk) but not acute (2 or 6 h) restrain stress decreasescell proliferation duration-dependently in the SGZ of rats(2 h after 1 200 mg BrdU/kg; Ref. 441). In contrast, theacute stress of cold immobilization and a forced swimreduce cell proliferation (1 day after a 1 200 mg/kgBrdU injection before the stress) in the DG and not theSGZ, an effect that is normalized within 1 day (209).Chronic, unpredictable stress exerted over 3 wk reducesmitotic activity in the SGZ (and not the DG) as estimatedby KI-67 staining. At this time point, another batch ofanimals was injected with BrdU (1 200 mg/kg), and 3wk later, the effect of chronic stress on the survival ofBrdU-labeled cells was examined. Because the BrdU cellnumber was unchanged, it was concluded that cell survivalis not influenced by stress. Finally, male tree shrewssubjected to a 7-day period of psychosocial stress exhibitreduced cell birth (evaluated 1 day after 1 100 mg/kgBrdU; Ref. 104). This stress-induced reduction in adultborncells leads to a decline in neurogenesis, the neuronalphenotype being inferred by the expression of NeuN (441)or NSE (177, 181) 1 mo after labeling.Because stressful events are known to activate theHPA axis, leading to a rise in plasma levels of corticosterone,and to activate the release of endogenous opioids,which are involved in defensive behaviors, the role ofthese two factors has been evaluated. To confirm theinvolvement of corticosterone, male rats were adrenalectomized,and low levels of hormone were restored. Inthese conditions, the prevention of the TMT-induced risein corticosterone blocks the downregulation of cell proliferation(537). In contrast, administration of naltrexone,an opioid antagonist (5 mg/kg, 30 min before TMT exposure),does not attenuate the effect of TMT on cell proliferation,whereas the expression of defensive behaviors(defensive burying, stretch approach) is partially attenuated(219), which indicates a dissociation between TMTinducedcell proliferation and defensive behaviors (149).The activity of the HPA axis is known to be regulated bycorticotrophin-releasing hormone and vasopressin, theroles of which have recently been evaluated. Thus thechronic blockade of CRF1 and V1B receptors (bySSR125543A and SSR149415, respectively, 30 mg · kg 1 ·day 1 for 28 days) starting 3 wk after the beginning ofchronic mild stress (CMS for 21 days) reverses the stressinducedreduction of cell proliferation (measured 24 hfollowing 1 75 mg/kg of BrdU injected at the end of thedrug treatment period) (10). These antagonists are alsoable to prevent the stress-induced reduction of neurogenesis(by means of NeuN labeling) estimated 30 days afterthe cessation of the drug treatment and BrdU pulse (3.75mg/kg every 2honthelast 3 days of the CMS). Thenormalization of neurogenesis is furthermore associatedwith a prevention of the stress-induced hippocampal atrophy.2. Interindividual differences in stress reactivityInterindividual differences in behavioral reactivity tostress or to novelty and coping abilities have been evidencedin our laboratory in an outbred population of rats.Animals are split into two groups according to the medianscore of behavioral response, the behaviorally high-reactive(HR) rats, and the low-reactive (LR) rats (443, 446).Compared with the LR phenotype, the HR phenotype ischaracterized by a series of adaptive defects of a cognitiveand motivational nature corresponding to a deficit in inhibitionand control processes (115, 304, 443, 447). Theseinterindividual differences have been related to differencesin corticosterone secretion, HR rats displaying ahyperactive HPA axis (305, 443, 444, 446).The behavioral trait of reactivity to stress has beenshown to predict the level of neurogenesis in the GCL ofthe DG (305). Two weeks after their behavioral characterization,rats were injected with BrdU (3 50 mg/kgspaced by 4-h intervals) and killed the next day or 14 dayslater. Cell proliferation was found to be negatively correlatedwith locomotor reactivity to novelty, and when thegroup was split according to the median behavioral scoreinto LRs and HRs, cell proliferation in LRs was twice thatobserved in HRs. Survival of nascent neurons was notinfluenced by this behavioral trait. A difference in theHPA axis reactivity most probably underlies the differencesin neurogenesis, primarily due to differences in cellgenesis. The functional significance of this difference inDG plasticity remains unclear but may reflect a disruptionof behavioral inhibition in the HRs (187).3. Perinatal manipulationsStudies on stress during the perinatal period havealso led to intriguing observations. It is well documentedfrom animal and human studies that during the perinatalDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 545period the development of an organism is subjected tocomplex environmental influences and that deleteriouslife events during development induce neurobiologicaland behavioral defects (207, 557, 569). Indeed, environmentalchanges and stimulations have the greatest impactwhen produced in the early stages of life and duringdevelopmental periods, leading to phenotypical orientationslasting throughout life. These environmental influences,which have been evidenced for decades, have beenexplored at structural and mechanistic levels only recently,revealing profound structural changes in the HF(see, for instance, Ref. 353). Stressful events during theprenatal period, such as prenatal stress which consists instressing pregnant dams, or during the postnatal period inthe rat, as for example maternal deprivation, i.e., longlastingseparations of the mum-pup dyad, alter brainchemistry, enhance emotional reactivity, produce cognitiveimpairments, and increase vulnerability to drugs ofabuse (185, 482, 569). We and others have shown thatstressful events during the prenatal (306) and the postnatal(300, 367, 431) periods downregulate hippocampalneurogenesis. In prenatally stressed rats, we found thatcell proliferation (4 50 mg/kg of BrdU over 3 days) isreduced from adolescence to senescence, indicating anacceleration in the age-related decline of cell proliferationin the GCL. Survival of the newly born cells and neuronaldifferentiation (measured with NeuN) are not modified,and thus the net reduction in the number of adult-bornneurons is associated with a decrease in the number ofgranule cells from adulthood to senescence. Given thatcorticosterone has been implicated in long-term behavioralchanges induced by prenatal stress (280), this downregulationof neurogenesis may result from heightenedcorticosterone secretion (see sect. IID2A). Similarly, maternallydeprived rats are characterized by reduced cellproliferation in the GCL both when infants (proliferationmeasured on postnatal day 21 following 7 days of maternalseparation and 7 50 mg/kg BrdU) (300, 431) andwhen adults [proliferation measured at 2–3 mo of agefollowing daily 3-h maternal separation bouts from postnatalday 1 to 14 and 1 200 mg/kg BrdU 2hor1wkbefore death (367)]. In this recent study, the authorsfound that maternal deprivation reduced the number ofimmature, but not mature, neurons that are added to theDG in adulthood (367). Because maternal separation isreported to alter the activity of the HPA axis (482), it hasbeen hypothesized that corticosterone mediates the effectof maternal separation on neurogenesis. In fact, it hasbeen shown that the maternal separation-induced decreasein cell proliferation is abrogated by adrenalectomyplus corticosterone treatment aimed at restoring basaldiurnal levels of the hormone. The authors proposed thathippocampal precursors might be hypersensitive to corticosterone,the diurnal basal and stress-induced levels ofwhich are not modified in their paradigm (367). However,because maternal separation is known to decrease corticosteroid-bindingglobulin (559), and thus enhance thefree, and active, fraction of corticosterone reaching thebrain, a higher level of “efficient” hormone could be responsiblefor the effects of maternal separation on hippocampalcell proliferation.Given the involvement of the HF in learning andmemory, we hypothesized that prenatal stress would leadto cognitive deficits via an inhibition of neurogenesis inthe DG. Thus we have shown that prenatal stress is associatedwith an alteration in learning and memory performances,and more importantly, that the learning-inducedincrease in cell proliferation observed in control animalsis blocked in prenatally stressed rats (306). This result isin accordance with our previous observation that cellproliferation is increased only when the animals reach anasymptotic level of performance, i.e., when the task hasbeen mastered (see sect. IIIA2A and Fig. 4). Furthermore,the behavioral deficits induced by prenatal stress, similarto those observed in animals exposed to X-irradiations(37), confirm an enabling role for hippocampal neurogenesisin cognition.C. Aging and Longitudinal Observations1. Neurobiology of the age-related declinein neurogenesisA) INFLUENCE OF AGING ON NEUROGENESIS. Aging is a life-longprocess beginning with conception and ending withdeath. Within this developmental continuum, sexualmaturity (2–3 mo in rodents) is used to define the startof adulthood. Although the definition of “how old isold” varies depending on species, genetic background,and experimental conditions, studies addressing theeffects of age on biobehavioral parameters in rodentshave identified at least three ages: adult (up to 10 mo),middle-aged, and “old” or “aged” or senescent (from 20mo) (91, 92).The persistence of neurogenesis in the DG of senescentrats was first reported by Kaplan and Bell (248,250, 251). An age-related decline in DG neurogenesishas been confirmed in mice and rats using several BrdUlabeling protocols (54, 208, 290, 306, 310, 499), whereasconflicting results have been reported for the SVZ (238,253, 290, 543).The decline in DG neurogenesis, which mainly occursbetween 2 and 12 mo of age, does not seem to berelated to 1) an alteration in adult-born cell survival asthe percentage of surviving BrdU-labeled cells 1 moafter their birth is independent of the age of the animals(54, 208, 269, 310) or 2) a general change in metabolicconditions, as neuronal precursors respond to BDNF’sinfluence to the same extent throughout life (169).Rather, it may be a decline in proliferative activity thatDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

546 ABROUS, KOEHL, AND LE MOALunderlies the age-related decline in neurogenesis, sincethe number of newly born cells a few hours after labeling(54, 290) and the number of nestin-positive cells(391) are lower in aged rats. However, it remains to bedetermined whether the reduction in proliferative activityis a consequence of a developmental lengtheningof the cell cycle time and/or of a shrinking of theproliferative cell population. Finally, neuronal differentiationseems to be delayed with advancing age assuggested by the high percentage of cells that do notexpress a neuronal or an astrocytic phenotype 1 moafter their birth (54, 208, 264, 310, 391).B) FACTORS REGULATING NEUROGENESIS IN THE SENESCENT BRAIN.The progressive decline in cell proliferation could derivefrom inadequate local environmental cues; theaged DG may be under the influence of inhibitory factorsand/or may lack stimulatory factors that sustaindivision, differentiation, and/or survival of the newlyborn cells.I) Inhibitory factors. Corticosterone has receivedparticular attention since basal levels of this hormone,known to inhibit cell proliferation in young rats (see sect.IID2A), increase during aging (324, 484). Thus, 1 wk afteradrenalectomy in old rats, cell proliferation is upregulatedin the GCL (373) and in the DG (GCL and hilus, Ref. 74).On the other hand, survival of the newly born cells isunrelated to corticosterone levels (373), and most of themdifferentiate into neurons expressing TOAD-64 or NeuN(74, 373).Glutamate is also known to inhibit DG neurogenesisin young rats (see sect. IID2B). Similarly, in middleagedand aged rats, a single injection of a NMDA receptorantagonist (CGP-43487, 5 mg/kg 2 h after an injectionof BrdU, 200 mg/kg) increases hippocampal cellproliferation 5 days later. By 3 wk, despite a decline inthe number of newly born cells, more cells survived inthe treated aged rats compared with saline aged counterparts(391).II) Activating factors. The involvement of the neurosteroidPreg-S in the hippocampal neurogenesis of oldrats has been examined. Indeed, 1) hippocampal levels ofPreg-S in the HF of senescent rats correlate with spatialmemory abilities, 2) intrahippocampal infusion of Preg-Sin cognitively impaired aged rats reverses memory disturbances(551), and 3) Preg-S stimulates neurogenesis inthe adult DG (see sect. IID2A). We have shown that icvPreg-S infusion increases cell proliferation in the senescentDG (348). This suggests that the age-related decreasein Preg-S levels could lead to a loss of stimulation ofhippocampal neurogenesis and to subsequent cognitivedeficits. Finally, because Preg-S acts as a negative allostericmodulator of GABA A receptors, our results supportthe inhibitory hypothesis of neurodegenerative disorderssuch as Alzheimer’s disease and age-related brain impairments,which postulates the involvement of abnormallystrong inhibitory GABAergic transmission (341).Because adult neurogenesis can be enhanced by theadministration of growth factors (see sect. IID2C), theresponsiveness of the aged brain has been the subject ofinvestigation. In particular, a stimulatory effect of IGF-Ihas been examined since 1) IGF-I brain levels decreasewith age (90), 2) IGF-I receptor mRNA is upregulated as afunction of aging and cognitive decline (522), and 3) IGF-Iinfusion improves cognitive function in aged rats (345).The chronic icv administration of IGF-I (1.2 g/day for 14days) in senescent rats elicits an approximately threefoldincrease in BrdU-labeled cells (BrdU, 2 50 mg · kg 1 ·day 1 on days 7–11) in the SGZ and the hilus (310). In a4-wk survival study, IGF-I and saline-treated animals displayeda similar number of newly born cells (BrdU-labeledon days 7–11) compared with animals killed after ashort survival delay, indicating that IGF-I acts on cellproliferation rather than on cell survival. Finally, in contrastto what was observed in adult rats (1), IGF-I did notmodify cell fate in old animals, with 20% of newly borncells differentiating into neurons (inferred from NeuNexpression). Thus the threefold increase in BrdU-positivecells elicited by IGF-I translated into a threefold increasein adult-born neurons.The influences of FGF-2 and HB-EGF were also examinedin 20-mo-old mice (icv infusion of 10 g/ml for 3days concurrent with 50 mg · kg 1 · day 1 BrdU). Oneweek after the cessation of the treatments, the number ofnewly born cells was higher in both the SGZ and the SVZ;these cells expressed DCX and occasionally GFAP (238).More speculatively, it may be hypothesized thatproinflammatory cytokines such as interleukin 6 (IL-6)also play an important role in age-related decline in neurogenesis.Indeed, 1) it is involved in the appearance ofage-related cognitive disorders in humans (59, 120, 328,355, 466, 565), 2) chronic stress increases its productionin aged patients (272), 3) IL-6 expression is increased inthe HF of senescence-accelerated mice (539), and 4) hippocampalneurogenesis is reduced in adult transgenicmice with chronic IL-6 production (552) or after administrationof bacterial lipopolysaccharide, a potent activatorof IL-6 (138, 372).In summary, precursors that are able to enter the cellcycle are still present in the aged brain, and low levels ofneurogenesis are linked to the accumulation of inhibitorysubstances and/or the decrement of stimulatory factors.The mechanisms of action of these modulators are stillunknown and, in particular, it remains to be determinedwhether they act on the length of the cell cycle or on thenumber of dividing cells. Whatever the underlying mechanism,these results point to possible pharmacologicalactions for preventing or treating age-related cognitiveimpairments.Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 5472. Functional implications of age-related modulationof neurogenesis in memoryThe hypothesis that the decline in neurogenesis maybe responsible for age-related alteration in cognitive functionhas been tested by examining the influence of anenriched environment, and by taking advantage of theexistence of interindividual differences in age-related cognitivefunctions. The influence of enriched environmentson spatial memory and on neurogenesis (cell proliferation,cell survival, and neuronal differentiation) has beenstudied in 18-mo-old mice (269). Although the effects arenot as strong as those observed in young animals, after 68days of enrichment, neuronal differentiation is enhancedwhereas cell proliferation and cell survival remain unchangedcompared with nonenriched aged animals; performancesin spatial memory are slightly improved. Asimilar conclusion was reached when middle-aged femalemice were raised for 10 mo in an enriched environment(264), which indicates that as was found in younger subjects(see sect. IIIA1A), long-term exposure to an enrichedenvironment in old subjects does not afford any furtherbeneficial effect compared with short-term exposure asneither cell proliferation nor cell survival are increased. Inthis study, the improvement in learning parameters observedafter enrichment was suggested to be aspecific,resulting from better adaptive skills in exploration,greater locomotor aptitude, and endurance following enrichment,leading the authors to suggest that the contributionof adult hippocampal neurogenesis to hippocampalplasticity might require a physically active pursuit asopposed to a passive sensory stimulation (264).Large individual differences exist in cognitive abilities,and all aged rats do not exhibit cognitive disorders;some rats perform as well as young controls, whereasothers present spatial memory impairments (457). Theexistence of such individual differences has been used asa naturalistic strategy to study the neurobiological correlatesof cognitive aging, and it has been shown that theextent of memory dysfunction is related to the magnitudeof changes occurring in the HF. Following a characterizationof the cognitive abilities of aged rats in the watermaze, we have shown (Fig. 6) that neurogenesis (i.e., cellproliferation, cell determination, and cell survival) ishigher in cognitively unimpaired rats than in impairedones (130).Because age-impaired and -unimpaired rats did notdiffer in granule cell number, as previously described(458), it seems that the rejuvenation of granule cellsrather than a change in their absolute number is the mainfactor sustaining memory formation. In other words, successfulaging, i.e., preserved cognitive functions, is associatedwith the maintenance of a relatively high neurogenesislevel, whereas pathological aging, i.e., memorydeficits, is linked to exhaustion of neurogenesis. Thesedifferences in hippocampal neurogenesis may be due todifferences in stimulatory and/or inhibitory substances,which may respectively prevent or accelerate pathologicalaging. We propose that the age-related increase incorticosterone levels, resulting from repeated stressfulevents, may lead, through life-span inhibition of neurogenesis,to defects in hippocampal networks that wouldbe responsible for cognitive dysfunctions. The observationthat lowering corticosterone levels in middle-agedanimals significantly increases hippocampal neurogenesisand postpones the onset of spatial memory deficits supportsthis hypothesis (M. F. Montaron, E. Drapeau, C.Aurousseau, M. Le Moal, P. V. Piazza, and D. N. Abrous,unpublished data).During pathological aging, alterations in hippocampalneurogenesis most probably mirror a more generalfailure in the mechanisms underlying neuronal plasticity(364). Similarly, it has been shown that lipofuscin deposits,an index of cell suffering, are higher in aged rats withimpaired cognitive function (64) and are decreased inaged mice housed in an enriched environment (264). Accordingto the hypothesis of the “Red Queen Theory” (5),during aging there is competition for the available plasticityto compensate for neuronal degeneration or to storenew information. Thus, in pathological aging, hippocampalplasticity is exhausted, and the capacity of the oldDownloaded from physrev.physiology.org on November 25, 2005FIG. 6. Hippocampal neurogenesis depends onthe cognitive status of the aged rats. To demonstratea quantitative correlation between neurogenesis andperformance in a hippocampal-dependent test, wetook advantage of the well-established presence ofindividual differences in spatial memory abilitieswithin a population of old rats. Indeed, in the watermaze, some old individuals show clear impairment inspatial reference memory while others are not impairedand exhibit cognitive capacities similar tothose of younger individuals. We found that cell proliferation(A), the survival of adult-born cells (B), andthe number of adult-born neurons (C) are higher inthe dentate gyrus of aged unimpaired (AU) than agedimpaired rats (AI). *P 0.05, **P 0.01 comparedwith AU. [Modified from Drapeau et al. (130).]Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

548 ABROUS, KOEHL, AND LE MOALbrain to acquire new information and to compensate forongoing degenerating processes is impeded.D. Involvement of Neurogenesis in Pathologies1. Pathological conditions associated with anupregulation of neurogenesisA) EPILEPSY. Human temporal lobe epilepsy (TLE) isassociated with atrophy of the HF, an effect known sincethe beginning of the 19th century, and a loss of hippocampaland DG neurons (57, 384). In this pathology, thedentate granule cells give rise to abnormal axonal projectioninto the supragranular inner molecular layer of theDG and to an aberrant reorganization of the mossy fibers(MF) in the CA3 subfield of Ammon’s horn (529). It hasbeen suggested that the sprouting of MF is relevant in thehyperexcitability of the TLE (426). This has led to investigationinto whether newly born cells are important inthe genesis of dentate MF sprouting (MFS) and participatein the reorganization of the network.Kindling, an animal model of TLE, is characterized bya permanent epileptic state produced by a series of seizuresinduced by electrical stimulations made in variousbrain areas such as the hippocampus (42), the perforantpath (396), and the amygdala (425, 492). Single and repeatedkindling stimulations in the ventral CA1 regioninduce a facilitation of mitotic activity 2 wk later (42).Stimulation in the perforant pathway leads to a markedincrease in the number of BrdU-labeled cells as early as 3days after the last stimulation, whereas repeated kindlingdoes not evoke further stimulation of cell proliferation(396). Cell division is in fact suppressed, suggesting adiminished efficiency of repeated or prolonged stimulationto elicit a neurogenic response. In the amygdalakindling model, it has been reported that during the earlyphases of kindling, when focal seizures are present, DGcell proliferation remains unchanged, whereas it is upregulatedduring the later phase of kindling, when motorseizures are present (425, 492).In various chemoconvulsant (pilocarpine or kainate)models of human TLE, the induction of seizures is accompaniedby a dramatic increase in neurogenesis in the SGZof the DG (430). This increase is observed after a latentperiod of a few days following the status epilepticus (SE)and persists during the first week, before levels of neurogenesisreturn to baseline over the following weeks (396,430). The recruitment of proliferative cells after kainatetreatment occurs preferentially in GFAP cells, suggestingan increase in proliferative glial-like astrocytes (type B)(223). The expression patterns of multiple bHLH transcriptionfactors have been studied following epileptogenesis;some were found to be increased (Mash1, Id2), somedecreased (Hes5), and others unchanged (NeuroD, NeuroD2,Id3, and Math2), suggesting that molecules controllingcell-fate decisions in the developing dentate gyrus arealso operative during seizure-induced neurogenesis (140).The newly born cells induced by seizures, which survivefor up to 4 wk and differentiate into neurons (430), migrateto abnormal locations such as the CA3 cell layer, thedentate hilus and inner molecular layer (108, 430, 487).These ectopic granulelike neurons retain many, but notall, of their granule cell intrinsic properties (487). Incidentally,ectopic locations of SVZ-derived neuroblasts havealso been observed in the striatum and the cortex followingpilocarpine treatment (428).Seizure-induced neurogenesis appears to precedeMFS, suggesting that newly born cells could be importantin the genesis of the ectopic innervation of Ammon’s hornby dentate fibers. This hypothesis has been tested bycoadministrating kainate or pilocarpine with cycloheximide(CHX), a protein synthesis inhibitor known to abolishMFS (40). Contrary to what was expected, CHX didnot influence chemoconvulsant-induced neurogenesis, indicatingthat its effect on MFS is independent of cellproliferation (97). Similarly, a single session of X-raytreatment, which attenuates pilocarpine-induced neurogenesis,fails to prevent MFS (427), indicating that neurogenesisupregulation is not sufficient to generate MFS.Thus the participation of the newly born cells in networkreorganization and in the recurrence of epileptic seizure isstill open to debate.The mechanisms by which seizure activity stimulatesneurogenesis are unknown. They may involve electricalactivation since 1) physiological activity such as LTPelicitedmossy fiber stimulation is sufficient to increaseneurogenesis in the DG (118), and 2) pure electrical activation,consisting in a continuous stimulation of the perforantpath, elicits focal hippocampal seizure dischargesand increases BrdU cell number 6 days later (430). Seizure-inducedupregulation of neurogenesis may also involve1) an alteration in excitatory amino acid transmissiondue to degeneration of the entorhinal afferences tothe granule neurons of the DG (430); 2) activation by thedying cells (42, 50); 3) a change in bFGF, as kainateinducedupregulation of neurogenesis is blocked in micelacking bFGF, an effect reversed by gene transfer (582);4) changes in other neurotrophic factors (145, 164, 172,583); and 5) activation of the 5-HT 1A receptor as infusionsof a 5-HT 1A receptor antagonist (WAY-100,635) impedethe increase in pilocarpine-induced neurogenesis whereascell death, MF sprouting, and the onset of spontaneouslyrecurring seizure are not prevented (451).In summary, neurogenesis is altered by epileptiformstatus, and surprisingly maintenance of the newly borncells (in homotypic and ectopic locations) is systematicallyobserved in the different models of epilepsy. Theabnormal circuits may contribute to the unstable hippocampalcircuitry and the development of chronic TLE.As proposed by Gray and Sundstrom (188), the DG couldDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 549“regulate as a gate with respect to controlling the propagationof seizure with granule cells controlling thethroughput of epileptiform activity transition through theHF by virtue of a feed forward inhibitory pathway.” Thesealterations in neurogenesis may participate in the memorydysfunction associated with epilepsy (530). Althoughunverified, this latter finding suggests that the presence ofmore new neurons is not necessarily associated with agood memory and that neurogenesis and memory functionmay follow an inverted U-shaped curve.B) ISCHEMIA. Until recently it was thought that the functionalrecovery that occurs in some cases following braindamage (such as stroke and trauma, see sect. IIID1D) wasrelated to the remodeling of neuronal pathways in nondamagedareas. The discovery of adult neurogenesisprompted researchers to investigate the role played bynew neurons in recovery of lost functions.Transient global ischemia, induced in gerbils and ratsby bilateral common carotid artery occlusions, increasescell proliferation in the DG in a dose-dependent manner(260, 315, 575, 576). A peak in cell proliferation occurs 1–2wk after ischemia, and a quarter of the newly generatedcells die during the first month (315). During the first 2 wkafter their birth, the newly born cells transiently expressNeuroD and DCX (258). Those cells that survive differentiateinto granule neurons expressing NeuN or MAP2 at 1mo of age (258, 315). They acquire functional features ofmature neurons as NMDA stimulation induces the phosphorylationof ERK in 34 and 61% of BrdU-NeuN labeledcells of 1 and 2 mo of age, respectively (258).After focal cerebral ischemia, induced by unilateralmiddle cerebral artery occlusion (MCAO) (24, 237, 589,590), cell genesis is increased to various degrees in theipsilateral DG (as well as in the SVZ, OB, and cortex) overa period of several weeks. Increased BrdU incorporationin the DG (as in the others structures) contralateral to theinfarct, occurring following a lapse of a few days, suggestsa role for diffusible or humoral factors (237, 534). Thenewly born cells differentiate into granule neurons withoutany apparent degeneration (590). The enhancement ofBrdU-labeled cells in the OB and the cortex has beenattributed to the migration of neuronal precursors fromthe SVZ towards their normal target or towards the infarct,respectively (588). The presence of cell clusters incortical areas, in the vicinity of blood vessels, also suggeststhe recruitment of resident quiescent stemlike cellsor the infiltration of blood-borne cells (589). New cellsarising from the SVZ also colonize the striatum afterischemia, 20% of which survive (representing 0.2% of thecell loss) and assume the phenotype of cells lost due tothe lesion (24, 239, 429).Neurogenesis upregulation in the DG has been attributedto cell death in the entorhinal cortex or the CA1region (46), a hypothesis not always verified (25, 315). Ithas been proposed that the neuronal damage that followsischemia involves the release of glutamate and overstimulationof glutamate receptors, which in turn upregulatesneurogenesis. Indeed, the blockade of NMDA or AMPA/kainate glutamate receptors by specific antagonists(MK801; NBQX) inhibits the stroke-induced increase inneurogenesis (25, 46); however, these effects are surprisingin light of the stimulatory influence of glutamate receptorblockade on neurogenesis in control brains (seesect. IID2B).Mitotic factors such as bFGF are certainly involvedas ischemia-induced upregulation of neurogenesis isblocked in mice genetically deficient in bFGF (582) and isincreased following adenovirally mediated transfer ofbFGF (347). Chronic icv infusions of bFGF and EGFgreatly enhance the potential of endogenous progenitorsto proliferate in response to ischemia and the cells thenregenerate CA1 pyramidal neurons. The regenerated neuronsare integrated into the neural circuitry as they receiveafferences, project onto their normal target, thesubiculum, and reverse the ischemia-induced deficits incognitive functions (399). This constitutes the most impressiveexample of network reconstruction leading tobehavioral recovery that takes advantage of adult endogenousneurogenesis. Infusion of VEGF (0.54 g/day ondays 1–3 of reperfusion concurrent with 2 50 mg ·kg 1 · day 1 BrdU) increases the number of adult-borncells 1 mo (and not 3 days) after labeling, beyond theincrease caused by ischemia (526). Ischemia-induced cellproliferation, measured within 3 wk post-BrdU pulse (2 50mg · kg 1 · day 1 BrdU injected for 6 days starting 1 dayafter MCAO), is also increased by icv infusion of IGF-I andglial-derived neurotrophic factor (117).Modulation of cell birth by ischemia also involves theproduction of several classes of inflammatory moleculemetabolites. Administration of inhibitors of cyclooxygenase(Cox; i.e., acetylsalicylic acid, indomethacin, NS398),the rate-limiting enzyme for prostaglandin synthesis, curtailsischemia-induced proliferation after transient globalischemia in adult gerbils or rats (293, 485, 547). Mutationof one of the Cox isoenzymes, Cox-2, suppresses theischemia-induced increase in hippocampal cell proliferation(485). Cox-2 may affect neurogenesis through theproduction of prostaglandin E 2 (547), which may act directlyvia prostaglandin EP3 receptors expressed in theGCL (397) or indirectly through bFGF (477). Alternatively,the production of NO, a key factor in inflammation,may be at play as administration of a NO donor (DETA/NONOate) to rats subjected to MCAO significantly increasescell proliferation in the SVZ and the DG, andsignificantly improves neurological recovery (587). Thisenhanced neurogenesis is certainly associated with theactivation of inducible NOS since its inhibition (by aminoguanidine)prevents ischemia-induced neurogenesis.Furthermore, stroke-induced neurogenesis is abolished inmice lacking the iNOS gene (590). The participation ofDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

550 ABROUS, KOEHL, AND LE MOALleukotrienes, another key class of inflammatory molecules,has been postulated in cell proliferation induced bystroke (340). Finally, factors produced as part of theischemia-hypoxic response such as the cytokine erythropoietin(507) and the recently discovered “stem cell factor”(SCF) acting through the c-kit receptor tyrosine kinase(235), may also modulate neurogenesis afterischemia.In summary, enhancement of neurogenesis in the DGand other brain regions may compensate for disconnectedcircuits that occur after ischemia and contribute tothe improvement of functional outcome. Exploiting thisplasticity potential of the ischemic brain may provide apossible strategy for enhancing recovery in patients sufferingfrom this injury.C) HUNTINGTON’S DISEASE. Huntington’s disease (HD) is aneurodegenerative disease that leads to neuronal loss inthe caudate-putamen. The discovery of progenitor cells inthe human brain (144) has raised the possibility thatprogenitors from the SVZ may provide a source of replacement.Postmortem analysis of control and HD humanbrains has revealed that cell proliferation, evaluatedwith PCNA, is increased in the subependymal layer in HDbrains as a function of the severity of the illness (103).The newly generated cells expressed neuronal and glialmarkers (Tuj1 and GFAP, respectively).These pioneer data indicate that the diseased adultbrain is still capable of neuronal regeneration, whichopens new avenues in the treatment of neurodegenerativediseases.D) OTHER TYPES OF CEREBRAL INJURY. Traumatic brain injury(TBI), the most common cause of death in developedcountries, increases cell proliferation in the SGZ (as wellas in the SVZ and the cortex; Refs. 107, 319, 459). Thenumber of newly born cells increases as early as 24 hpost-TBI; the cells accumulate over time and expressTOAD-64 and NeuN (65%) 9 and 21 days, respectively,after the last BrdU injection (200 mg/kg for 9 days; Ref.107). Similarly to what can be observed after ischemia,DETA/NONOate administration (for 7 days starting 1 dayafter TBI) to rats subjected to TBI significantly increasesproliferation, survival, migration, and differentiation ofneural progenitors in the DG (as well as other brainstructures) and significantly improves neurological functionaloutcome (319).2. Pathologies associated with a downregulationof neurogenesisA) AFFECTIVE DISORDERS. In unipolar major depression,bipolar mood disorders, and other chronic diseases associatedwith affective disorders [posttraumatic stress disorder(PTSD), Cushing’s disease], brain imaging studieshave consistently described hippocampal atrophy (60,195, 329, 504, 518, 519, 550). Although a role for neurogenesisin mood disorders is speculative, it has beensuggested that a fall in neurogenesis in the DG contributes,together with atrophy and death of hippocampalneurons, to hippocampal attrition.I) Antidepressants. It has been suggested that biogenicamine deficiency underlies mood disorders, andindeed, treatments increasing extracellular levels of serotoninor norepinephrine are effective in the remediationof depressive symptoms. Because serotonin and norepinephrinestimulate cell genesis (see sect. IID2B and Table1), and given that it takes weeks for antidepressants totake effect, it has been proposed that they may exert theiraction via a remodeling of neuronal networks by promotingeither neurogenesis or the survival of hippocampalneurons believed to be endangered (131). Chronic (andnot acute) treatments with different classes of antidepressantssuch as a selective serotonin reuptake inhibitor(fluoxetine, 5 or 10 mg · kg 1 · day 1 for 11–28 days), aselective norepinephrine reuptake inhibitor (reboxetine,mg·kg 1 · day 1 for 21 days), a monoamine oxidaseinhibitor (tranylcypromine, 7.5 mg · kg 1 · day 1 the firstweek and 10 mg · kg 1 · day 1 the second week), andtricyclic antidepressants (TCAs, imipramine and desipramine:20 mg · kg 1 · day 1 for 28 days) increase hippocampalcell proliferation evaluated 2 or 24 h after thelast BrdU pulse (1 75 mg/kg or 4 75 mg/kg every 2 h)performed on the final day or 4 days after the treatment(335, 483). Three weeks after labeling, most of the newlyborn cells express NeuN (70%), independently of theclasses of antidepressants (335, 483). It was furthershown that a fluoxetine- but not an imipramine-inducedincrease in cell proliferation is mediated by 5HT 1A receptors,since it is abolished in mice lacking 5HT 1A receptors(483).To determine effects of fluoxetine on cell survival,BrdU (4 75 mg/kg spaced by 2 h) was administeredbefore intitiation of the chronic treatment (5 mg/kg for 14days). Neither survival nor maturation of the cells, evaluated28 days after the last BrdU injection, was influencedby fluoxetine treatment (335). The preclinical contributionof hippocampal neurogenesis has been examined inthe learned helplessness paradigm, a classical animalmodel for depression, and it was reported that inescapablestress induced a decrease in cell proliferation thatwas reversed, together with behavioral despair, by a 7-daycourse of fluoxetine (10 mg/kg) (334). A strongest linkbetween “depression” and neurogenesis was evidencedfollowing X-irradiation that blocked the effects of fluoxetineand imipramine on both novelty-suppressed feeding(another test used to assess chronic antidepressant effects)and neurogenesis (483).Although the etiologies of mood disorders are numerous,ranging from various environmental factors to geneticvulnerability, several lines of evidence suggest thatstress-induced cellular changes in the adult HF, mediatedDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 551by an upregulation of the HPA axis, contribute to thepathophysiology of these disorders, at least in animalmodels. The impact of antidepressants on neurogenesiswas therefore tested in various stress models. In adultmale tree shrews exposed to chronic psychosocial stress(see sect. IIIB1), chronic treatment with tianeptine (50mg·kg 1 · day 1 for 28 days), a modified TCA, reversedthe stress-induced decline in hippocampal volume, hippocampalactivity, and hippocampal neurogenesis (104).In rat pups, fluoxetine treatment (5 mg/kg for 7 daysconcurrent with 50 mg/kg BrdU) counteracted the downregulationof cell proliferation observed in the DG of2-wk-old maternally separated pups (300). In a chronicmild stress model (CMS; see sect. IIIB1), chronic treatmentwith the antidepressant fluoxetine (10 mg/kg for 28days starting 3 wk after the beginning of the CMS) reversedthe stress-induced reduction of cell proliferationand prevented the stress-induced reduction of neurogenesisand hippocampal atrophy (10).II) Electroconvulsive therapy. Electroconvulsivetherapy (ECT) is one of the most effective treatments formajor depression, especially in subjects who do not respondto antidepressants, but its mechanisms of actionremain largely unknown. Electroconvulsive seizure (ECS)differs from kindling and chemoconvulsant treatments inthat it does not lead to an epileptiform state and does notcause cell death. ECS (one daily for 10 days) enhances (2or 24 h after a BrdU pulse) cell proliferation in the DG,and the newly born cells survive for at least 3 mo, a timepoint when most of them express NeuN (75%) and fewGFAP (13%) (331, 335). This proliferative effect is dosedependentas a series of seizures further increases neurogenesis(331). The neurogenic efficacy of ECS has beeninvestigated in conditions mimicking stress-induced depression,i.e., in animals with high corticosterone levels.The downregulation of neurogenesis (75%) in the GCL ofrats chronically treated with corticosterone was eliminatedby ECS performed at the end of the treatment (212).Because ECS upregulates several factors described asstimulating neurogenesis, such as bFGF, neuropeptide Y,VEGF, BDNF, and Cox-2 (404, 406), these factors arelikely mediators of the proliferative effect of ECS. Amongthem, BDNF deserves special mention as ECS-inducedMFS is diminished in BDNF knockout mice (549).III) Mood stabilizers. Chronic treatment with lithiumcan reverse the hippocampal attrition in sufferers of manicdepressiveillness (MDI) and enhance the levels of N-acetylaspartate, a putative marker of neuronal viability(375, 376, 544). Chronic treatment of mice with lithium(2.4 g/kg during 3–4 wk) increases the number of BrdUlabeledcells by 25% 1 day after BrdU treatment (1 50mg/kg over 12 days), two-thirds of which coexpressNeuN. Interestingly, the expression of bcl-2, an antiapoptoticregulator, is also increased suggesting that survivalof the newly born neurons might be enhanced (84).IV) Summary. These results suggest that antidepressants,ECT, and mood stabilizers may exert some of theirtherapeutic effects on mood disorders by stimulating neurogenesis.They also suggest that alternative strategies forstimulating neurogenesis may provide new avenues forthe treatment of mood disorders. Since a fall in neurogenesishas been associated with an alteration in cognitivefunctions, further studies are needed to clarify the involvementof neurogenesis, and hippocampal function, inthe development of cognitive deficits observed in depressionin young and elderly patients.B) SCHIZOPHRENIA AND NEUROLEPTICS. Developmental dysfunctionof the HF is thought to play a major role in thepathogenesis of schizophrenia (206, 488), and defectssuch as a reduction in hippocampal volume (53, 400, 558),hippocampal shape deformations (101), abnormalities inthe GCL (357), the MF pathway (170), the hippocampalcell density (41, 150, 233) and orientation (93, 288), and inseveral cellular markers (203, 313) have been reported.These changes are believed to underlie the progressivedeficit in cognition that is a hallmark of schizophrenia.Interestingly, models of aberrant neurogenesis (prenatalstress, X-rays, or MAM manipulations) are thought toreproduce some of the behavioral characteristics associatedwith schizophrenia (313).The influence on neurogenesis of chronic treatmentwith the typical neuroleptic haloperidol, a mainstay in thetreatment of schizophrenia, has been evaluated, leadingto controversial results. Indeed, haloperidol has beenshown to increase (110) or to have no effect (199, 335,483, 562) on neurogenesis in the rodent DG. Differences indosage, time course of drug treatment, species and age ofthe animals, and BrdU labeling protocol could account forthe observed discrepancy. On the other hand, chronictreatment with atypical neuroleptics such as risperidone(0.5 mg · kg 1 · day 1 for 21 days) or olanzapine (2 mg ·kg 1 · day 1 for 21 days) increases cell proliferation (24 hafter 1 100 mg/kg BrdU on the 20th day of neuroleptictreatment) in the SVZ but not in the DG (562). A low doseof clozapine (0.5 mg · kg 1 · day 1 for 4 wk before a singleinjection of BrdU at 200 mg/kg) enhances the number ofBrdU-IR cells in the DG; however, this effect is transientas the newly born cells do not survive 3 wk after labeling.Although these data clearly show that further work isrequired to sort out discrepancies in results, they alsosuggest that schizophrenia may be associated with reducedneurogenesis in the DG, where normal levels couldbe reestablished by neuroleptic treatment, a hypothesisthat awaits confirmation.C) ADDICTION TO DRUGS OF ABUSE. Long-term neuroadaptivechanges in the mesolimbic dopaminergic system haveclassically been observed in drug abuse (283, 402). Apotential role of the HF in addiction has been suggestedbased on the observation that both a reduction in hippocampalvolume and structural abnormalities are ob-Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

552 ABROUS, KOEHL, AND LE MOALserved in patients with chronic alcoholism (4, 112, 357,524) and in psychostimulant addicts (33). In animals,chronic treatment with different drugs of abuse leads tostructural changes in the HF (308, 432, 461, 463), to cellloss (563), and to LTP alterations (109, 158, 191, 200, 202,449). The possible involvement of the HF in addiction issupported by the observation that 1) inhibiting the activityof the calcium/calmodulin-dependent protein kinase IIimpairs drug conditioning (321, 535) and attenuates thedependence on morphine and relapse (321), 2) dorsalhippocampal lesions disrupt acquisition of cocaine conditioning(365), 3) electrical stimulation of the glutamatergicefferent pathway of the HF to the nucleus accumbensreinstates cocaine-seeking behavior (561) and D-amphetamine self-administration behavior (533), and 4)inactivation of the ventral subiculum decreases reinstatementof cocaine-seeking behavior (525). These resultssuggest that memory traces of the association between aspecific context and the availability of the drug could bestored in the HF, and the hypothesis that drug addiction isan aberrant form of learning mediated by maladaptiverecruitments of hippocampal-dependent memory systemhas recently gained interest (45, 147, 401, 462, 571). In thiscontext, the involvement of neurogenesis in addiction hasbeen studied by examining the influence of several drugsof abuse on adult hippocampal neurogenesis and by comparingneurogenesis in animals that differ in their vulnerabilityto developing drug abuse.I) Opiates. Among the multiple actions of opiates inthe brain, their influence on cognition and reward is withouta doubt the most relevant parameter with regard toopiate addiction. Eisch et al. (137) were the first to demonstratethat the exogenous chronic (daily implantationof subcutaneous pellets containing 75 mg morphine during5 days) and not acute (10 mg/kg) administration ofmorphine decreases cell proliferation in the GCL by 28%(measured 2 h after an injection of BrdU, 100 mg/kg, onday 6). When cells are allowed to mature for 4 wk,survival of BrdU-labeled cells is halved and 90% of thenewly born cells differentiate into neurons. More relevantto addiction, the influence of heroin self-administrationhas been investigated. After 26 days of heroin intake (60g ·kg 1 · injection 1 ), a downregulation of cell proliferation(30%) is observed in both the GCL and the hiluswhile cell death is unaffected. The downregulation of cellproliferation is independent of corticosterone secretion(137), a hormone known to have a major influence inaddiction (343). Finally, it was recently reported that invitro reduced signaling through - and -opioid receptorspresent on adult hippocampal progenitors, although decreasingcell proliferation, leads to a net increase in thenumber of newly generated neurons (437).II) Nicotine. The neuroactive compound nicotine isconsidered to be responsible for the development and themaintenance of tobacco addiction. To analyze the effectsof nicotine abuse on hippocampal neurogenesis, rats weretrained to self-administer nicotine (0.02, 0.04, and 0.08mg·kg 1 · infusion 1 ) for 42 days. A profound decreasein hippocampal cell proliferation was observed for thetwo highest doses of nicotine 1 day after BrdU pulse (4 50 mg/kg on days 39–41). This effect is not simply due toa difference in blood flow leading to a decrease in BrdUavailability, since nicotine intake does not affect cell proliferationin the SVZ. Half of the newly born cells in theDG were found to express NeuN. In parallel with thedecrease in cell proliferation, cell death, measured by thenumber of pyknotic cells, was increased by the two highestnicotine doses (3). Similar results were obtained followingimposed administration of nicotine (1 mg · kg 1 ·day 1 for 3 days concurrent with 50 mg/kg BrdU) toadolescent rats (230). Although the mechanisms involvedin the effects of nicotine have not yet been investigated,nicotine could act directly on nicotinic acetylcholine receptorsthat are present on immortalized hippocampalprogenitor cells (44), or indirectly through an upregulationof the HPA axis (67) and/or a downregulation of theserotoninergic system (43).III) Alcohol. The possibility that alcohol brings aboutdamage in the adult brain by disrupting neurogenesis hasbeen examined. Thus both acute (gavage with 5 g/kgethanol) and chronic (ethanol infusion 3 times/day over 4days for a mean dose of 9.3g·kg 1 · day 1 ) binge alcoholtreatments halve cell proliferation in the SGZ of the DGwithin 5 h (409). Furthermore, after 28 days, chronicbinge treatment decreases the survival rate of the newlyborn cells (409). In contrast, in animals fed for 6 wk witha moderate dose of ethanol (6.4% vol/vol), the number ofnewly born cells (labeled by 7 BrdU injections at 2-hintervals) is not reduced when animals are killed 1 h afterthe last BrdU injection (218). In fact, the number ofnascent cells decreases only after 2 wk suggesting that, inthis experimental model, cell survival, rather than cellproliferation, is affected by ethanol exposure, a hypothesisthat was confirmed by showing that cell death wasdramatically increased in the DG. Finally, these effectsare specific to the DG as bulbar neurogenesis is notinfluenced by chronic alcoholism. Similar results wereobtained with imposed injections of alcohol to adolescentrats (1 mg · kg 1 · day 1 for 3 days concurrent with 50mg·kg 1 · day 1 BrdU), which led to a downregulation ofhippocampal cell proliferation and increased cell death(230). Furthermore, coadministration of alcohol with nicotinereduces cell proliferation and cell death more potentlythan treatment with either one of the agents (230).Although these effects of ethanol could be mediated byNMDA or GABA A receptors (224), oxidative stress mightalso play a role since the antioxidant ebselen, used in thetreatment of cognitive disorders of alcoholic patients,prevents ethanol effects on hippocampal neurogenesis(218).Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 553IV) Cannabinoid. Derivatives of cannabis sativasuch as marijuana are acknowledged to be the most commonlyused illicit drugs (336). The structure of their activecomponents, the cannabinoids, the identification in thebrain of the cannabinoid-1 (CB1) receptors, and the isolationof an endogenous substance acting on these receptors,the endocannabinoid anandamide, have been reportedonly recently. It has been suggested that the CB1receptors that are expressed in the HF by the GABAergicinterneurons are important in learning and memory (109).Chronic treatment with anandamide (5 mg · kg 1 · day 1for 4 days) inhibits neurogenesis in the DG by decreasingthe number of newly born cells that differentiate intogranule neurons 12 days after the cessation of the treatment(100 mg/kg BrdU on day 2). Conversely, blockingthe endogenous cannabinoid tone with SR14716 (1 mg ·kg 1 · day 1 together with anandamide), an antagonist ofthe CB1 receptors, increases hippocampal neurogenesisby favoring neuronal differentiation (476). These effectsare in accordance with a potentiality to modulate neuralcell fate (197) in particular through the ERK signalingpathway (476). In addition to showing that endocannabinoidsconstitute a physiological system regulating neurogenesis,these data raise the possibility that cannabinoidaddiction could be associated with an alteration in hippocampalneurogenesis.V) Neurogenesis as a substrate for vulnerability toaddiction. The high responder rats (see sect. IIIB2) andthe prenatally stressed rats (see sect. IIIB3) characterizedby curtailed neurogenesis share some similarities that arerelevant to drug addiction. Indeed, the HRs spontaneouslydevelop amphetamine (443, 445) or nicotine (528) selfadministrationbehavior, and prenatally stressed rats exhibitgreater sensitivity to the psychomotor-stimulant effectsof nicotine (279) and amphetamine (215) and aremore vulnerable to drug addictive effects as they developintravenous amphetamine self-administration (116). Thussubjects starting off with the lowest neurogenesis may bemost vulnerable to the development of addictive behavior.It is noteworthy that there is high comorbidity betweendrug abuse and many psychiatric illness, amongwhich depression and schizophrenia (34, 152). Becausehippocampal neurogenesis is reduced in preclinical modelsof these pathologies, it may be hypothesized thatimpaired hippocampal neurogenesis may constitute a potentialsubstrate for vulnerability to drug abuse, depression,and schizophrenia (see also Fig. 8).VI) Conclusions. The downregulation of hippocampalneurogenesis, together with other maladaptive plasticityprocesses, i.e., dendritic remodeling and synapticplasticity modifications, are associated with permanentfunctional alterations in behavioral inhibition and learning,hallmarks of addiction. An alteration in hippocampalplasticity could be responsible for the cognitive deficitsthat appear in the course of the “illness” (88, 109, 133, 194)or during drug withdrawal (211). Because drug-seekingand -taking behaviors are sensitive to the presence ofdrug-associated stimuli (contextual cues), initially lowhippocampal plasticity and a drug-induced decrease inhippocampal plasticity may be involved in the vulnerabilityand the maintenance of drug abuse. Changes in hippocampalactivity could lead to a dysregulation of thedopaminergic mesoaccumbens reward system (283, 402)through the hippocampal glutamatergic output that gatesinformation in the nucleus accumbens (173) and/orthrough the hippocampal glutamatergic output to themesencephalic dopaminergic cell bodies. Indeed, stimulationof the ventral subiculum increases the firing ofdopaminergic neurons (51) and enhances dopamine releasewithin the nucleus accumbens (302). Finally, drugtakingin subjects vulnerable to drug addiction most probablyfurther increases corticosterone secretion, stimulatesthe dopaminergic reward system, and decreaseshippocampal neurogenesis, thereby constituting a pathophysiologicalloop.IV. CONCLUSIONThe discovery of neoneurogenesis in discrete areasof the adult brain has opened up an extremely interestingfield of research in itself. Indeed, although it was initiallyconfronted with the universal belief that after a certainperiod of development neither neural cell genesis nordivisions were any longer possible, it now constitutes aprototypic model of developmental neuroscience. Thestudy of the mechanisms that preside over cell proliferation,migration, differentiation, and survival is essentiallyperformed in the SVZ-OB paradigm as these phenomenaoccur in distinct compartments (cell proliferation in theSVZ, migration in the RMS, differentiation in the OB) thusrendering their analysis easier. However, the evaluationof their behavioral consequences is most frequently examinedin relation to the HF (with the exception of Ref.464).To conclude, the main issues raised by neurogenesisare as follows.1) From a cellular point of view, a true characterization,and thus definition of stemlike and progenitor cellsin the adult brain is still lacking. Although immenseprogress has been achieved in the description of differentcell types (and their properties) in the SVZ, no consensushas been reached. Furthermore, although it has beensuggested that adult neural stemlike cells could behavesimilarly to embryonic stem cells as far as the generationof neurons and differentiation into any neuronal type areconcerned, little is known regarding their intrinsic propertiesand the nature of the signals that lead to the generationof neurons in the adult brain. It is expected thatfunctional genomic technologies may help in defining theDownloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

554 ABROUS, KOEHL, AND LE MOALtranscriptional program of neural progenitors and thechanges in gene expression in progenitors over time (105,323).2) Future studies will have to better characterize theearly development of adult-born neurons to dissect thesteps that are influenced by experience and vulnerable totraumatic conditions (stress, drug, epilepsy. . .). Thisraises the problem of tracking the fate of adult-born cellsusing BrdU, [ 3 H]dT, or a retrovirus, which may alter thefunctioning of the adult-born neurons under investigation.3) Undoubtedly one of the most interesting sets ofdata accumulated concerns the factors that powerfullyregulate neurogenesis. However, the mechanisms bywhich these regulations are exerted in the normal andpathological brain remain obscure.4) Although most work is focused on the generationof glutamatergic excitatory granule neurons in the adultDG, the recent discovery that GABAergic inhibitory neuronsare also produced raises the important possibilitythat external factors (from molecules to modifications inanimals’ environments) might diversely affect the genesisof either type of neurons and thus have distinct functionalconsequences.5) Functional studies are too often restricted to theevaluation of a single parameter; they should be extendedto the different components of neurogenesis (basal neurogenesisand experimentally induced cell proliferation,cell death, and cell survival) and to other parametersrelated to the anatomical (e.g., the presence of synapticcontacts) and functional (electrophysiological properties,ERK phosphorylation, immediate early gene activation. . .) integration of new neurons into the preexistingnetworks. Finally, the contribution of newly born neuronsto the functioning of the HF and its output should beevaluated as well as their influence on the activity of otherrelated structures (e.g., the frontal cortex).6) Functional evaluation of hippocampal neurogenesishas, in fact, been the object of relatively few studiesthat have been restricted to a limited number of behavioraltasks (mainly the Morris water maze). A more completediversified behavioral analysis is therefore necessaryto understand the contribution of neurogenesis tohippocampal functioning.7) Except for the elegant work of Shors et al. (509),which relies on the use of MAM which is unfortunately ahighly toxic compound, most studies correlate changes inrates of neuron addition with behavioral changes, in particularcognitive functions. Thus it is not clear whetherthese changes are coincidental or coregulated. A moredirect approach to address the existence of a causal relationshipbetween behavioral changes and neurogenesiswill probably depend on the development of inducibleDownloaded from physrev.physiology.org on November 25, 2005FIG. 7. Variation of hippocampal functioning as afunction of hippocampal neurogenesis and associatedpathological states.Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

NEUROGENESIS IN THE ADULT BRAIN 555transgenic models allowing a structure-specific blockadeof neurogenesis at a given time during behavioral testing.However, this approach is a real challenge since it isbased on the invalidation of the crucial genes controllingneurogenesis site specifically, which have not yet beenidentified.8) From a phylogenetic point of view, the apparentreduction in neuropoiesis, when moving from rodents toprimates, raises the question of the associated evolutionaryadvantage.9) From studies that have correlated changes in ratesof neuron addition with hippocampal functioning, an invertedU curve shape can be proposed (see Fig. 7). Thusadult neurogenesis may be beneficial for adult brain functioningonly within a physiological adaptive range. Beyonda critical level of neurogenesis, which is over passedby stressful life events, aging, and drug abuse, dysfunctionappears. On the other hand, the addition of adult-bornneurons above a critical set point (i.e., following epileptiformstatus) may lead to pathological states and behavioralimpairments most probably by introducing noise inthe networks, as a consequence of ectopic connectivity.10) Within this framework, it is not known whetheran alteration in neurogenesis is the cause or the result ofpsychiatric illness (Fig. 8). Indeed, in preclinical studies ithas been shown that phenotypes vulnerable to the developmentof affective or cognitive disorders are characterizedby lower hippocampal neurogenesis. It may be hypothesizedthat these subjects who start off with impairedneurogenesis may be predisposed to the development ofaffective disorders, addictive behavior, and age-relatedcognitive disorders. Alternatively, the onset of pathologycould produce changes in brain plasticity by actingthrough several mechanisms (for example, stress andHPA activity are important mediators in the genesis ofcognitive impairment, depression, addiction). Repeated“traumatic” episodes, together with a genetic predisposition,may lead to reduced neurogenesis and participate inthe worsening of the symptoms. Although these propositionsare highly speculative, they highlight the fact thattreatments that increase neurogenesis may help to cure orprevent the development of affective and/or cognitivedisorders.Address for reprint requests and other correspondence: D. N.Abrous, INSERM U588, Univ. of Bordeaux 2, Institut FrançoisMagendie, 146 rue Léo Saignat, 33077 Bordeaux Cedex,France (E-mail: abrous@bordeaux.inserm.fr).REFERENCESFIG. 8. Is impaired neurogenesis acause or a consequence of affective andcognitive disorders? Based on the reciprocalinfluences of neurogenesis on affectiveand cognitive states, two modelscan be proposed. In the first model, impairmentin neurogenesis processes resultingfrom both genetic and environmentalinfluences would predispose theindividual (vulnerable phenotype) to developingaffective and cognitive disordersin response to environmental challenges.In the second model, genetic andenvironmental influences may orientbrain functions toward deleterious developmentsresulting in affective and cognitivedisorders that would, in turn, impairthe normal course of neurogenesis.1. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, and ErikssonPS. Peripheral infusion of IGF-I selectively induces neurogenesisin the adult rat hippocampus. J Neurosci 20: 2896–2903,2000.2. Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P, Rosengren LE, Olsson T, Gage FH, andEriksson PS. IGF-I has a direct proliferative effect in adult hippocampalprogenitor cells. Mol Cell Neurosci 24: 23–40, 2003.3. Abrous DN, Adriani W, Montaron MF, Aurousseau C, RougonG, Le Moal M, and Piazza PV. Nicotine self-administration impairshippocampal plasticity. J Neurosci 22: 3656–3662, 2002.4. Agartz I, Momenan R, Rawlings RR, Kerich MJ, and HommerDW. Hippocampal volume in patients with alcohol dependence.Arch Gen Psychiatry 56: 356–363, 1999.Downloaded from physrev.physiology.org on November 25, 2005Physiol Rev • VOL 85 • APRIL 2005 • www.prv.org

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