Adult Neurogenesis - From Precursors To Network and Physiology (2005)

Physiol Rev 85: 523569, 2005; doi:10.1152/physrev.00055.2003.
Adult Neurogenesis: From Precursors to Network and Physiology

DJOHER NORA ABROUS, MURIEL KOEHL, AND MICHEL LE MOAL Laboratoire de Physiopathologie des Comportements, Institut National de la Sante et de la Recherche Me dicale, U588, Universite de Bordeaux 2, Bordeaux, France
I. Neurogenesis in the Adult Brain: a New Paradigm for Structure-Function Relationships II. From Newly Born Cells to Network A. Definitions B. In vivo evaluation of adult neurogenesis: methodological issues C. Integration of the newly born cells into neurogenic site networks D. Factors regulating adult neurogenesis III. The Anatomo-Functional Approach A. Environmental and physiological influences on neurogenesis B. Activation of the stress axis: acute and long-term effects on neurogenesis C. Aging and longitudinal observations D. Involvement of neurogenesis in pathologies IV. Conclusion
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Abrous, Djoher Nora, Muriel Koehl, and Michel Le Moal. Adult Neurogenesis: From Precursors to Network and Physiology. Physiol Rev 85: 523569, 2005; doi:10.1152/physrev.00055.2003.The discovery that the adult mammalian brain creates new neurons from pools of stemlike cells was a breakthrough in neuroscience. Interestingly, this particular new form of structural brain plasticity seems specic to discrete brain regions, and most investigations concern the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation (HF). Overall, two main lines of research have emerged over the last two decades: the rst aims to understand the fundamental biological properties of neural stemlike cells (and their progeny) and the integration of the newly born neurons into preexisting networks, while the second focuses on understanding its relevance in brain functioning, which has been more extensively approached in the DG. Here, we propose an overview of the current knowledge on adult neurogenesis and its functional relevance for the adult brain. We rst present an analysis of the methodological issues that have hampered progress in this eld and describe the main neurogenic sites with their specicities. We will see that despite considerable progress, the levels of anatomic and functional integration of the newly born neurons within the host circuitry have yet to be elucidated. Then the intracellular mechanisms controlling neuronal fate are presented briey, along with the extrinsic factors that regulate adult neurogenesis. We will see that a growing list of epigenetic factors that display a specicity of action depending on the neurogenic site under consideration has been identied. Finally, we review the progress accomplished in implicating neurogenesis in hippocampal functioning under physiological conditions and in the development of hippocampal-related pathologies such as epilepsy, mood disorders, and addiction. This constitutes a necessary step in promoting the development of therapeutic strategies.
I. NEUROGENESIS IN THE ADULT BRAIN: A NEW PARADIGM FOR STRUCTUREFUNCTION RELATIONSHIPS Developmental biology teaches us that brain functioning requires neurons of appropriate types to be generated in appropriate places and numbers, and then to migrate to their nal positions and rene their synaptic contacts to a high degree of precision and avoid aberrant
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connections. Finally, the brain must accommodate growth of the organism and new behavioral or cognitive capacities. For decades, neurobiologists have known that neuronal network organization as well as individual performances are altered by environmental events, experience, or internal signals such as hormones, aging, and various injuries (322). The adult brain faces two seemingly contradictory challenges. On the one hand it must maintain behavior
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and thus preserve the underlying circuitry, and on the other hand, it must allow circuits to adapt to environmental challenges. This dilemma between stability and plasticity is a subject of debate. It has been suggested that the structural changes underlying plasticity exist at the levels of dendritic spines, dendrites, and axons (28, 287, 297, 383, 408). However, direct observation of dendrites and spines in the adult brain supports two divergent view points, i.e., both long-term dendrite stability (192, 368) and experience-dependent synaptic plasticity (541). Data suggest that dendritic spines are heterogeneous in shape and structure and can be roughly divided in two groups: large spines that survive for months and even years and small spines that are motile, change form rapidly, and either disappear or transform into large spines (for review, see Refs. 132, 216, 255). During long-term potentiation (LTP) of synaptic transmission, which is known to involve modications 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 are generated during activity-dependent processes and acquisition of memories, providing an inexhaustible source of new synapses, and that the large spines are the structural basis of memories in the long-term (255). For many authors, all these local and cellular phenomena have been labeled as neuroplasticity, a concept used to account for the functional observations. In the search for structure-function relationships, great enthusiasm followed the discovery that embryonic neurons, for instance, dopaminergic neurons, could be transplanted into adult brains, survive and alleviate some postlesion behavioral alterations. Although it generated a considerable amount of data, this approach has not proven very successful so far in living up to functional and therapeutic hopes (157, 217). However, it has generated a considerable amount of data on the growth and the migration of these neurons, and on their ability to make synapse with the surrounding neurons of the host and to inuence the activity of their target neurons. However, the turning point has been the demonstration that the adult mammalian brain is also capable of mitosis and that the generated cells differentiate into neurons that migrate to integrate circuitries. Interestingly, this particular new form of structural brain plasticity seems specic to discrete brain regions and most investigations concern the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation (HF), although an interesting debate developed in the wake of the proposition that neurogenesis occurs in the neocortex of the adult primate. In brief, the discovery of neurogenesis in the adult brain confronted the persistent assumption that adult neurons did not undergo proliferation and that structure could not be changed in this way. In the 1960s, Altmans
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rst observations of adult neurogenesis (11), followed by the studies of Kaplan and Hinds (for a historical view, see Ref. 249), were followed by negative reactions and critical publications that did not conrm the existence of newborn neurons in adults (452). Ironically, at about the same period, data were published on neurogenesis in birds related to the appearance of seasonal song, a discovery that gave rise to new thoughts on brain plasticity and adaptation (for review, see Ref, 410). Overall, two main lines of research have emerged since the discovery that neurogenesis persists in discrete regions of the adult brain. The rst aims to isolate neural stem cells and understand their fundamental biological properties, the ultimate objective being to manipulate them and enhance repair and regeneration. The second focuses on understanding its functional relevance, especially in the DG. We will thus approach these two lines of research in the following chapters. As we will see, it has now been unambiguously demonstrated that persistent neurogenesis 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 studies performed in the SVZ paradigm that easily allow the dissection of the properties of the stem cells (and their progeny) and the integration of the newly born neurons into preexisting networks. Once the existence of the phenomenon had been established, the important step was to understand what triggers and inhibits it, and how it is regulated. Identifying the functional roles of these adultborn neurons in the context of structure-function relationships will be the main focus of the review. The considerable evidence supporting the participation of these new neurons in brain functioning has been collected in the DG, and their role in information storage and hippocampal-related pathology will be examined. On the assumption that the DG transforms entorhinal inputs to facilitate storage in CA3, adult neurogenesis may allow the DG to adapt to new ows of relevant information while at the same time preserving it for the processing of old memories. In more general terms, we will ask whether neurogenesis acts on memory consolidation in a specic and functional manner or whether it prepares the HF for general experiences and challenges. II. FROM NEWLY BORN CELLS TO NETWORK A. Denitions The recent interest in adult neurogenesis studies has led to a promiscuous use of the term stem cell and a broadening of its denition. However, based on their functional properties, one can distinguish stem cells from progenitor or precursor cells. Thus a stem cell is currently dened as an undifferentiated cell that exhibits
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the ability to proliferate, to self-renew, and to differentiate into multiple yet distinct lineages (356, 570). In the adult brain, most stemlike cells are in a quiescent stage, except in the two neurogenic zones considered here, the SVZ and the DG of the HF, where they have a very slow dividing turnover (a few weeks). In contrast, progenitor cells are mitotic cells with a faster dividing cell cycle that retain the ability to proliferate and to give rise to terminally differentiated cells but are not capable of indenite 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 is the case in vivo, both stem and progenitor cells are referred to as precursor cells. For an overview of the characteristics that can be used to differentiate neural stem from progenitor cells, and of the controversies that still persist around denitions, we refer the reader to reviews by Gage (160), Geuna et al. (167), and Seaberg and van der Kooy (494). B. In Vivo Evaluation of Adult Neurogenesis: Methodological Issues 1. Original studies: DNA synthesis staining and BrdU utilization The original studies on in vivo cell proliferation relied on the use of [3H]thymidine ([3H]dT), which is incorporated into the cell during DNA synthesis, i.e., the S phase of the cell cycle. Mitotically active cells are subsequently revealed by autoradiography. More recently, BrdU, an analog of thymidine, has been used in lieu of [3H]dT (412). These markers have comparable availability times and labeling efciencies (411). Although [3H]dT presents the advantage of good stoichiometry (allowing determination of the number of mitotic events after labeling), BrdU revealed by immunohistochemistry is more frequently used as the cost is lower, section processing is faster, and stereological analysis is possible. In addition, BrdU is easier to combine with other cellular markers, which makes it possible to phenotype the newly born cells by double or triple immunohistochemistry. The original protocols used for BrdU labeling, established by Gage and colleagues (268, 267), consisted of a dozen BrdU injections (50 mg kg1 day1 ip). Since this pioneering work, with the urry of data, protocols have diversied. As we will see in section III, the number and the doses of BrdU injections as well as the frequency of administration vary considerably from one experiment to another depending on the area of interest (fewer injections are required for studying the SVZ compared with the DG), the species, the phenomena being examined (a decrease or an increase in neurogenesis), and the subject type (young intact subjects, impaired or old individuals). To make the picture more complex, BrdU is sometimes
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administered in mice via drinking water (11.5 mg/ml for 2 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 is adjusted depending on the step of neurogenesis that is being investigated: cell proliferation, cell determination toward a given phenotype, cell migration and differentiation, or cell death. In this way, to study proliferation, animals are killed following the last BrdU injection within a short time lapse ranging from a few hours to a few days. As early as 2 h after a single injection, mitotic gures can be seen, and this time point has been proposed as a true measure of proliferation. However, in the case of senescent rats, multiple injections are required as cell proliferation and the frequency of labeled clusters are too low. Furthermore, when animals are killed within a short time after the last BrdU injection, newly born cells are small, irregular, and clustered (the clusters being more numerous with multiple BrdU injections), which renders quantitative analysis challenging. For this reason, a washout protocol of a few days allowing cells to migrate is applied in many experiments. Cell migration is followed by killing the animals at different days (110 days) after BrdU injection, in which case it is necessary to limit the number of BrdU injections (208). Survival of the newborn cells is usually studied by killing the animals after a long delay (several weeks) following BrdU administration, when the phenotype of the cells has been determined. Less frequently, retroviral tracing has also been used for developmental studies (81, 123, 439, 501). However, because retroviral infection is not controlled, labeling is quite variable and is thus unsuitable for quantitative analysis between different experimental groups (556). Finally, in most pharmacological and behavioral studies, the treatment under investigation is interrupted after BrdU pulses, and animals are killed after a chase period of several weeks. It is important to be aware that in this case, the inuence of the treatment on cell determination and cell survival is not addressed. To do so, the treatment should be prolonged over the chase period time (for example, see Refs. 267, 335). 2. Phenotyping cells One of the most important tasks is to phenotype cells, and markers specic to the dividing cells or the state of maturation of newly born cells are available for in vivo studies. A) PRECURSOR CELLS. So far, no marker that is exclusive to stemlike cells has been identied, which certainly reects the divergence in opinion on the identity of the stemlike cell population. However, markers of stem-cell candidates or simply dividing cells are now available and can be divided into two categories depending on the purpose
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of the studies. The rst category covers universal or general molecular markers that are used to dene the biological characteristics of stemlike cells (for an extensive review, see Ref. 440). Among these markers, the most widely used is nestin, which denes classes of intermediate lament proteins; it was rst described as the product of a gene whose expression distinguishes precursors from more differentiated cells in the neural tube (156) and was found to be specically expressed in neural progenitor cells (307). More recently, a family of molecular markers has been identied, which includes mouse-Musashi1 (m-Msi1), a neural RNA-binding protein expressed predominantly in proliferating neuronal and/or glial precursor cells but not in newly generated postmitotic neurons and oligodendrocytes (246, 479). The second category of markers is more specically used in research aimed at uncovering the functional role of adult neurogenesis and consists of antigens present in cycling cells that are used as proliferative markers. They are often used in combination with BrdU, since incorporation of BrdU alone identies cells undergoing DNA replication but does not formally provide evidence that these cells are actually capable of division. They include Ki-67, a nuclear protein expressed in dividing cells for the entire duration of their mitotic activity, the expression of which is neither linked to DNA repair nor to apoptotic processes (142, 259). Although less frequently used, proliferating cell nuclear antigen (PCNA) allows assessment of cell proliferation as well. It is an auxiliary protein of DNA polymerase which is increasingly expressed through G1, peaks at the G1/S interface, and decreases through G2 (146, 162, 294). This marker has been used successfully to study cell proliferation and cell cycle length in conjunction with BrdU cumulative labeling (39). Finally and much less used are P34cdc2, a key player in the initiation of mitosis (415), and phosphorylated Histone H3 (HH3) expression, which is conned to cells in the G2 and M phases of the cell cycle. In general, cells in the G2 phase exhibit punctuate HH3 nuclear staining that changes to a more condensed pattern once they enter the M phase (214). B) IMMATURE NEURONS. The mammalian RNA-binding protein Hu, the homolog of the Drosophila neuron-specic RNA-binding protein Elav, is exclusively expressed in postmitotic neurons (7, 479) and thus is frequently used as an early neuronal marker (31, 414). Other markers include neuron-specic class III -tubulin (TuJ1), a cytoskeletal protein expressed in all postmitotic neurons (360, 361), doublecortin (DCX), which encodes a microtubule-associated protein expressed in migrating neuroblasts (155, 168, 389), TOAD 64 (turned on after division, also called TUC-4, CRMP4, PUlip1), a cytoplasmic protein expressed transiently by postmitotic neurons (366), and the polysialylated-neuronal cell adhesion molecule PSANCAM (277, 498). Another candidate for immature neuroPhysiol Rev VOL
nal markers is the basic helix-loop-helix (bHLH) transcription factor NeuroD, which seems to be expressed from a very early stage to the stage where new neurons develop dendrites (496, 497). Some of these markers stain nonneuronal cells, and some of them (TOAD 64, PSANCAM, DCX) are present in the brain, for example, in the piriform cortex, independently of neurogenesis (113, 389, 392, 423, 498, 560), which makes the interpretation of results more difcult. C) MATURE NEURONS. The most frequently used specic markers for mature neurons are neuron specic enolase (NSE), neuronal specic nuclear protein (NeuN) (386), and microtubule-associated protein (MAP-2). However, the identication of the neuronal phenotype of newly generated cells using these markers is considered ambiguous as they also label other types of cells (189, 411, 453, 454). An alternative approach consists in demonstrating that adult-born cells do not express any marker for glial cells such as 2,3-cyclic nucleotide (CNP) for oligodendrocytes, and calcium binding proteins (S100, S100) or glial brillary acidic protein (GFAP) for astrocytes. 3. Current identied pitfalls In addition to the problem of neuronal identication, several methodological pitfalls have been identied. First, embryonic and postnatal injections of BrdU have been reported to induce physical, morphological, and behavioral abnormalities (282, 495). Although only a few studies have addressed the deleterious effects of BrdU injections in adulthood, a neurotoxic effect has been reported in aged rats, loss of body weight, and deterioration in the state of the coat being induced by repeated administrations of 150 mg kg1 day1 of BrdU for 5 days (130). Together with its early teratogenic effects, this suggests that incorporation of BrdU into mitotically active cells may inhibit cell formation and affect stemlike cell population. This raises the as yet unresolved problem that BrdU may alter the functioning of the labeled cells. Second, changes in neurogenesis detected by variations in BrdU staining may be related to a modication in BrdU availability through an alteration in blood ow or in blood-brain barrier permeability. To rule out such confounding parameters, using endogenous markers of the cell cycle (Ki67, PCNA, HH3, and P34cdc2) and evaluating changes in different brain regions may be helpful. For behavioral studies, adequate control groups should be used to measure the involvement of a potential modication of blood ow by exercise. Third, pharmacological treatments or behavioral and environment-induced changes in neurogenesis may exert their effects by modifying the length of the cell cycle, the number of proliferating cells, or both. However, in most functional studies, evaluating the cell cycle parameters is difcult if not impossible, and one might question the relevance of this
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exercise. Finally, BrdU or [3H]dT labeling might produce false negatives and positives. The most commonly used dose of BrdU (50 mg/kg) labels only a fraction of the proliferating cells (75), which may result in an apparent absence of effects of a given experimental setting on cell proliferation. However, multiple injections of this low dose may overcome this problem. Furthermore, because the precursor cell population most certainly does not divide synchronically, labeling all dividing cells with a single injection of BrdU, whatever the dose, appears utopist. On the other hand, higher doses of BrdU associated with an enhanced sensitivity of immunohistochemical methods might lead to labeling apoptotic cells or nonproliferating cells that synthesize DNA for repair (594), and thus to false positives. This problem is particularly relevant for studies on lesions, epilepsy, or ischemia, where a high rate of cell death is observed. There are several possible ways to rule out BrdU labeling of nonproliferative cells: 1) observing mitotic gures a few hours after BrdU or [3H]dT application; 2) using other endogenous cell cycle markers; 3) using electronic microscopy; 4) analyzing a time course of BrdU labeling (95); 5) combining BrdU with markers of cell death, although in this case false negative results due to the downregulation of markers by dying cells cannot be ruled out; 6) using retroviral labeling (81, 123, 439, 501, 556), which is not devoid of disadvantages (the type of cells incorporating the virus may not be fully controlled, and stereotaxic injection, known to cause injury, is required); and 7) visualizing neurogenic sites in nestin-promoter-GFP transgenic mice (577). 4. Summary This last decade has been marked by tremendous advances including the development of BrdU labeling methods, the discovery of selective markers that differentiate neurons from glial cells, and the use of new molecular and genetic tools to follow the development of the newly born cells. As we will see in the following sections, this technical progress has led to a lot of research and data that have conrmed observations made in the early 1960s and considered at that time by many specialists as nonconclusive. However, researchers are now aware of problems and agree that proper interpretations depend on accepted rules: 1) [3H]dT and BrdU labeling are not sufcient to unambiguously differentiate old neurons from newborn cells, 2) the neuron-specic markers presently used must be complemented by appropriate controls to detect false positives and by electrophysiological recordings to assert real neuronal phenotypes, and 3) the maturation and the integration of the adult-born neurons must be followed up.
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C. Integration of the Newly Born Cells Into Neurogenic Site Networks 1. The SVZ
A) IDENTIFICATION OF THE STEMLIKE CELLS. The SVZ, located throughout the lateral wall of the lateral ventricle, harbors the largest population of proliferating cells in the adult brain of rodents (12, 448, 511), monkeys (178, 179, 182, 248, 286, 434), and humans (47, 144), and it has been estimated that 30,000 cells are generated bilaterally daily in the mouse SVZ (317). This region exhibits a rostrocaudal gradient of proliferative activity: proliferation is higher in the dorsolateral corner of the rostral ventricle and falls caudally, moving from the striatum towards the HF (511). This gradient has been correlated with the capability of the constitutively proliferative cells to divide and to form neurospheres (381, 493) and certainly reects the existence of two populations of dividing cells, one of quiescent stemlike cells and one of rapidly proliferating progenitor cells (381, 382). Four cell types have been described in the SVZ: 1) ependymal ciliated cells (type E) facing the lumen of the ventricle, whose function is to circulate the cerebrospinal uid; 2) proliferating type A neuroblasts, expressing PSA-NCAM, Tuj1, and Hu, and migrating in chains toward the olfactory bulb (OB); 3) slowly proliferating type B cells expressing nestin and GFAP, and unsheathing migrating type A neuroblasts; and 4) actively proliferating type C cells or transit amplifying progenitors expressing nestin, and forming clusters interspaced among chains throughout the SVZ (15, 55, 122, 124, 166, 220, 474). Although it has been proposed that the stemlike cells may be ependymal type E cells, which were shown to divide in vivo and to differentiate into neurons in the OB (242), this view has been challenged by van der Kooy and colleagues (85) who have found that ependymal cells generating spheres do not have the ability to self-renew or to produce neurons, and by Capela and Temple (79) who have shown that ependymal cells do not form neurospheres. It is more likely that the type B cells represent a stemlike cell type (123, 124). Indeed, after 1 wk of intracerebroventricular (icv) infusion of the antimitotic drug cytosine--D-arabinofuranoside (AraC), type C and type A cells are eliminated, whereas type B cells continue to divide. Between 1 and 2 days after treatment cessation, type C cells reappear, followed 2 days later by type A cells, 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 into GFAP-positive cells, which include type B cells, labeled cells migrate towards the OB where they give rise to new neurons (123). Thus the lineage progression B 3 C 3 A has been proposed (123, 124). However, Doetsch et al. (126) have also shown that after exposure to high concentrations of EGF, the type C cells retain stemlike cell
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properties (126). In fact, there are opposing views on whether neurospheres are derived from GFAP-positive cells (type B cells) or from fast proliferating type C cells (225, 380) (see Fig. 1).
B) MIGRATION OF THE NEWLY BORN CELLS THROUGH THE ROSTRAL MIGRATORY STREAM.
The newly generated cells originating from different levels of the SVZ migrate in chains rostrally, up to 5 mm in rodents and to 20 mm in monkeys, to reach the OB (122, 286, 317). This migration, which follows the rostral migration stream (RMS) and requires 2 6 days in rodents (220, 317, 325), involves PSA-NCAM (100, 220, 418, 474, 540) and a chemorepulsion mechanism through Slit-Robo signaling (574). Although a role of the OB as a chemoattractant structure has been suggested, its involvement in proliferation and guidance of the newly born cells still remains unclear. Indeed, whereas OB removal (275), transection of the olfactory peduncle (231), or unilateral nostril occlusion (96) does not prevent SVZ precursors from proliferating and migrating towards the OB, a transection through the RMS (9) or a removal of the rostral OB (314) impedes neuroblast migration. It has thus been proposed that a diffusible attractant is secreted in specic layers in the OB, including the glomerular layer (314). After reaching the middle of the OB, the newborn cells detach from chains, migrate radially, and progress into one of the overlying cell layers whereupon they undergo terminal differentiation. Neuroblast detachment from chains is initiated by Reelin and tenascin, whereas radial migration depends on tenascin-R (198, 478). C) LIFE AND DEATH OF THE NEWLY BORN CELLS. Massive cell death has been observed during the rst 2 mo after a BrdU
pulse (572). This elimination mechanism is prominent in the OB compared with the RMS and the SVZ (39, 50, 439) and may maintain constant OB cell number by a continuous cell turnover, as was suggested during earlier development (419). The number of newly born cells that survive 1 mo after a BrdU pulse (50 mg kg1 day1 of BrdU for 4 consecutive days in 2-mo-old female wistar rats) has been estimated to be 60,000 per granule cell layer in one study (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 periglomerular layer) that survived the initial period of cell death survived for at least 19 mo (572), conrming earlier work (253). With the use of retroviral labeling of precursors in the SVZ, it was conrmed that one-half of the labeled cells died shortly after their arrival in the OB (between 15 and 45 days after neuronal birth) and that most dying cells were mature, harboring dendritic arborization, and receiving connections (439). It was further shown in this study that survival of the newly generated granule cells depends on sensory input.
D) DIFFERENTIATION OF THE NEWLY BORN CELLS IN THE OLFACTORY BULB.
The newly born cells differentiate mainly into neurons that grow dendritic trees and differentiate into two types of intrabulbar interneurons. Most of the cells (75 99%) differentiate into GABA granule cells (GCs), whereas a smaller number (125%) differentiate into periglomerular cells expressing GABA and/or tyrosine hydroxylase (38, 81, 256, 326, 439, 475, 572). Several months after their birth, 10,000 GABAergic granule neurons, 100 periglomerular GABAergic neurons, and 60 new dopa-
FIG. 1. Neurogenesis in the subventricular zone (SVZ)/olfactory bulb (OB) system. Top panel: a sagittal view of a rodent brain showing the sites of neurogenesis in the SVZ/OB system is given. Cells proliferate mainly in the SVZ, migrate along the rostral migratory stream (RMS) to reach the OB, where they migrate radially and undergo terminal differentiation. Bottom panel: a sequence of cell types involved in neuronal lineage and specic markers allowing cell identication are presented. Markers appearing in bold are specic to each stage (see text for further details).
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minergic periglomerular neurons have survived and are added per bulb daily (572). The different maturation stages of adult-born granule cells have been observed using retroviral labeling of precursors in the SVZ (439). Five different classes of adultborn cells were distinguished according to their morphology and location: 1) migrating neuroblasts in the rostral extension of the RMS (days 27), 2) neuroblasts migrating radially (days 57), 3) GCs with dendritic processes that do not extend beyond the mitral cell layer (days 9 13), 4) GCs with a nonspiny dendritic arborization in the external plexiform layer (days 1122), and 5) mature GCs with extensive dendritic arborization (days 1530). The newly born GCs and periglomerular neurons appear to be synaptically integrated into the existing circuitry as they are labeled following an injection (within the piriform cortex) of a green uorescent protein (GFP) expressing pseudorabies virus (PVR GS518) known to be transported along the neurons and to cross synapses (80). E) FUNCTIONAL PROPERTIES OF THE NEWLY BORN CELLS. The temporal sequence of electrophysiological changes in the adult born neurons has been observed by coupling live imaging (the newly born cells being labeled with a replication-defective retrovirus expressing eGFP) and patchclamp recordings (81). Migrating neuroblasts [class 1 and 2 according to the description of Petreanu and AlvarezBuylla (439)] were found to be silent, action potentials appearing later. Class 1 cells expressed functional GABAA receptors and AMPA receptors, and when they started migrating radially (class 2), they expressed functional N-methyl-D-aspartate (NMDA) receptors. Synaptic (GABAergic then glutamatergic) inputs were present in nonspiking neurons (class 3 and 4) while they were growing their dendrites. Spiking activity was the last property acquired by class 5 neurons, their electrophysiological characteristics being indistinguishable from those of older GCs. The functionality of adult-born neurons was further examined using the induction of the immediate early gene product c-Fos, a marker for mapping activated neurons (222). With this approach, it has been shown that 1) in mice, 3- to 7-wk-old adult-born periglomerular neurons respond to physiological (odors) stimuli (80); and 2) in hamsters, sociosexual cues are able to activate the adultborn neurons localized in both the accessory and the main OB (221). 2. The DG
A) IDENTIFICATION OF THE STEMLIKE CELLS. Cell proliferation was rst demonstrated in the DG of rodents 40 years ago by autoradiography in a germinal zone which is not, in contrast to the SVZ, located close to the walls of the ventricle. This subgranular zone (SGZ) is located at the interface between the granule cell layer (GCL) and the hilus of the DG, deep within the parenchyma (12, 13). This
cell proliferation is also a feature of monkeys (178, 182, 284) and humans (144). The nature of the proliferating cells is still a matter of debate. According to work carried out in Alvarez-Buyllas laboratory (501), the stemlike cells may correspond to a subpopulation of GFAP-positive cells, equivalent to the type B cells described in the SVZ, since 2 h after their birth a large majority of newly born cells express GFAP (501). While the number of these cells decreases in the following days, the proportion of dividing GFAP-negative cells increases. These small dark cells, originally described by Kaplan and Bell (251), are called D cells. Chronic treatment with the antimitotic AraC eliminates most dividing cells, D cells, and astrocytes, but soon after treatment cessation, some surviving B cells begin to divide, whereas D cells reappear only at 4 days. Type B cells, specically labeled with an avian retrovirus, give rise to granule neurons with mossy bers reaching the CA3 subeld. These results indicate that B cells act as stemlike cells, regenerate D cells, which function as transient precursors, and give rise to new granule neurons. This hypothesis is reinforced by the observation that astrocytes retain expression of m-Msi1 (480). On the basis of the analysis of nestin-promoter GFP transgenic mice, two classes of cells have been identied: type 1 cells (GFAP, S100, DCX, PSA-NCAM), which correspond to type B cells, and are the putative stem cell, and type 2 cells (GFAP, S100, DCX, PSA-NCAM) supposed to be the type D cells (154, 159, 289, 521). Because there is no overlap between glial and neural markers in type 2 cells, an observation inconsistent with Seri et al. lineage (501), it has been proposed that either type 1 cells divide asymmetrically and thus generate a neuronal lineage-restricted progenitor cell (type 2) and a glial lineagerestricted progenitor cell, or alternatively that a transient stage (lacking glial and neuronal markers) exists between the type 1 and type 2 cells (521). On the other hand, Palmer et al. (424) reported that very few proliferating cells in the adult DG are GFAP-positive (424), a discrepancy as yet unexplained. Finally, the assumption that the DG harbors stemlike cells has been challenged by showing that this region contains progenitor cells with restricted properties rather than stemlike cells with selfrenewing properties (475, 493) (see Fig. 2). B) LIFE AND DEATH OF THE NEWLY BORN CELLS. Following a single pulse with [3H]dT or BrdU, the number of labeled cells doubles within 24 h and then roughly doubles again over the next 2 days in rats (204, 416) and tree shrews (177), indicating that cells continue to divide during this time lapse (416). These data are in agreement with the measured length of the cell cycle estimated to be 24 h in 3-mo-old rats (75). It has been proposed that the progeny continue to divide further during the rst week after their birth as the number of labeled cells continues to rise (204). Recently, it has been conrmed that the cells are still in the cell cycle 3 days after their initial division (521).
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FIG. 2. Neurogenesis in the hippocampal system. Top panel: a frontal view of a rodent brain showing the sites of neurogenesis in the dentate gyrus (DG) of the hippocampal formation (HF) is given. The HF forms a trisynaptic network: multimodal inputs are transferred from neocortical regions to the DG via the entorhinal cortex; information is then transferred from the DG to CA3 through the mossy bers, onward through the Schaffer collaterals to CA1 (and the subiculum) and then via the entorhinal cortex back out to the cortical associative areas (16). Cells proliferate in the subgranular layer (SGL) located at the interface between the hilus and the granular layer (GL), where they migrate and differentiate into mature neurons. Bottom panel: a sequence of cell types involved in neuronal development, along with specic markers allowing cell identication, is proposed [see text and recent review from Kempermann et al. (265) for further details].
The clusters of dividing cells have been shown to include several cell types: neural precursors, committed neuroblasts, glial precursors, and endothelial precursors (angioblasts representing 37% of proliferative cells) that are proximal to vessels (256, 363, 424). This suggests that neurogenesis most probably occurs within the context of vascular recruitment. Within this niche, endothelial cells may constitute a critical regulator for self-renewal of stemlike cells (505) through the release of trophic factors (see sect. IID2C and Table 1). In the rodent DG, the vast majority of newly born cells are postmitotic and at least partially differentiated between 3 and 7 days (111, 416), since during this period BrdU-labeled cells express NeuroD (417). The cells that do not terminally differentiate die within 1 wk of their generation, a process affecting 60% of the newborn cells (111, 204). In the macaque, a similar time course has been demonstrated with an initial rise in BrdU-labeled cells followed by a fall after 5 wk (182). Interestingly, the GCL harbors a much lower number of proliferating cells compared with the SVZ. Thus, in a study performed in 9- to 10-wk-old rats, 9,000 newborn cells were found to be generated per day (75). In a more recent study, only 4,000 new cells, out of which 3,000 were found to be new neurons, were shown to be added daily in the DG of 4-mo-old rats (456); this discrepancy in the number of newborn cells is certainly linked to the difference in the age of the animals used in the studies, as the production of new neurons in the DG diminishes with age (see sect. IIIC1A). In the macaque, the number of newborn cells per day (200) represents 0.004% of one GCL (284). C) FATE OF THE NEWLY BORN CELLS. The newborn cells differentiate mainly into neurons in the GCL. In his original
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study using electron microscopy, Kaplan and co-workers (249 252) reported that the newborn cells exhibit the ultrastructural characteristics of neurons. Then, they were shown to express neuronal markers. During the rst 2 days after their birth, most BrdU-labeled cells express nestin (95), then TuJ1 (75) or TOAD-64 (75, 536) in the following 3 days, and DCX between 1 and 14 days after their generation (65). DCX-BrdU-colabeled cells show features of progenitor cells as some of them coexpress Ki-67 and are thus still able to divide (58, 154, 521). This rapid postmitotic status of new cells has been conrmed with calretinin, a calcium binding protein that is transiently expressed by postmitotic cells, the expression of which is observed as early as 1 day after labeling dividing cells, a peak being reached after 1 wk (58). Although newly born cells express NeuN as early as 72 h after their generation (58, 193), only half of the BrdU-IR cells expressed NeuN over 3 wk (65). Using NSE, half of the newly born cells were 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 differentiates into astrocytes (GFAP/S100), and rare are those that adopt a microglial or oligodendrocyte phenotype (521). It should be emphasized that even 4 mo after their labeling a nonnegligible proportion of BrdU-IR cells have an unknown phenotype. In monkeys, most newly generated cells are claimed to be neurons as well since they express TuJ1, TOAD-64, NeuN, NSE, and calbindin, and rarely markers of astrocytes (GFAP) or oligodendrocytes (CNP) (178, 182, 284). It was rst thought that the newly born cells did not survive, thereby constituting a continuously refreshed pool of neurons (189). However, it was
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TABLE
1. Extrinsic factors regulating in vivo cell proliferation and neurogenesis in the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampal formation under physiological conditions
Subventricular Zone/Olfactory Bulb Dentate Gyrus
Factors
Cell Neuronal Long-term Cell Neuronal Long-term proliferation Neurogenesis differentiation survival proliferation Neurogenesis differentiation survival Hormones and peptides
Reference Nos.
Corticosterone Suppression (adx) Cort. treatment Estradiol Estrus cycle OVX OVX acute 17-E OVX chronic 17-E 17-E Prolactin PACAP
m n mproE n m then n 0 m (4h) 0 m Neurosteroids m m n Neurotransmitters
m n 0
0 0
71, 74, 176, 465 17, 71, 76, 212 536 29, 536 29, 422, 536 435 421 506 362
0 0 m m m m
n 0 0
DHEA PregS Allopreg
m m
254 349 349
Glutamate Ent. Cx. lesion NMDA activation NMDA blockade AMPA potentiation mGluR II blockade Serotonin 5-HT depletion Lesion graft Reuptake inhibition 5-HT1A blockade 5-HT1A activation 5-HT1B blockade 5-HT1B activation 5-HT2A/2c blockade 5-HT2A/2c activation 5-HT2c blockade 5-HT2c activation Norepinephrine Depletion Reuptake inhibition No donor
m n m m m n 0 m m m 0 m 0 m 0 m m m m m m m m m n m m m n 0 m 0 n m m n m 0 0 n 0 0 0 n m m Growth or trophic factors 0 0 m m 0 m m Morphogenic factors m n m n m n m Vitamins and retinoids
73 73, 76 46, 73, 76, 177, 390 27 581 29, 61 63 10, 335, 483 451 30, 483 30
m m
0 0
0 n m 0 n m m (ovx) m 0 n 0 or m (hpx) m 0 0 0 292 335 587
bFGF EGF HB-EGF TGF- IGF-I BDNF CNTF VEGF
238, 240, 291 291 236, 238, 240 98 1, 310, 435, 542 593 141 241
Shh BMP Noggin
295 311 311
Vitamin E Deciency Supplementation (tocopherol) Retinoic acid (chronic treatment)
m n n
m n
n m n
86, 87 83, 102 99
Adx, 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.
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more recently found that they do not have an ephemeral existence and survive for at least 11 mo (263). Recently, it has been shown that beside glutamatergic granule neurons, a small percentage of newly born cells (14%) differentiate into GABAergic basket cells (316). Furthermore, under specic circumstances (ischemia or neonatal kainate administration), pyramidal cells in Ammons horn are also generated (see also sect. IIID1B; Refs. 128, 399, 489). However, the progenitors responsible for the regenerating pyramidal neurons originate from the periventricular region rather than from the SGZ (399). D) INTEGRATION OF THE NEWLY BORN CELLS. The newborn cells integrate the GCL 4 10 days after their generation. As they form dendrites, they receive synaptic contacts and extend axons into the CA3 region, suggesting that they make synapses long before being fully mature (75, 204, 252, 344, 517). Indeed, using virus-based transynaptic activity neuronal tracing (PVR GS518), the neurons generated in the DG have been shown to be synaptically integrated into the preexisting circuitry 4 8 wk after their birth (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 still located at the interface of the hilus, the newly born cells exhibit electrophysiological properties characteristic of immature neurons: they are completely unaffected by GABAA receptor inhibition, and they exhibit paired-pulse facilitation, have a lower threshold for induction of longterm potentiation (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 input resistance values, whereas the type II cells (type D cells, expressing PSA-NCAM) exhibited higher input resistance and voltage-dependent sodium currents (159). Recently, PSA-NCAM expressing cells have been shown to differ from mature neurons in their passive (input resistance) and active membrane properties (such as calcium spikes that boost fast sodium action potentials) and in their enhanced ability to develop LTP (490). One month after their birth, the newborn neurons, labeled by a retroviral vector expressing GFP, exhibit some electrophysiological properties (input resistance, threshold potential for spiking and ring) similar to those of mature granule neurons (556). The stimulation of the perforant pathway, the main excitatory afference to the DG, elicits responses in newborn GFP-labeled cells, indicating that they receive functional synaptic inputs and are therefore functionally integrated into the preexisting network. However, a depression of synaptic currents is evoked in these cells following the paired-pulse stimulation of the perforant pathway, whereas a facilitation response is observed in mature cells, a discrepancy attributed to differences in presynaptic release properties (556). The functionality of the adultborn granule cells has been further demonstrated by
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showing, using c-fos, that 40% of 1-mo-old newborn granule neurons were able to respond to various chemoconvulsants (232, 234). In contrast, following a more physiological form of hippocampal stimulation consisting in a hippocampal-dependent learning task, only 3% of cells are activated (232). Finally, besides these functional excitatory adult-born granule cells, it has been shown that GABAergic newborn basket cells form functional inhibitory synapses with the granule cells (316). This discovery raises the question of the mechanisms and factors involved in the production of excitatory granule neurons versus inhibitory interneurons. 3. The cortex Although very controversial, the existence of adult neurogenesis in the cortex deserves attention. Indeed, Altman and co-workers in the 1960s (11, 12, 14) and Kaplan in the early 1980s (247249) reported evidence for neurogenesis 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, and posterior parietal cortex of macaques (179, 182). Within 2 wk after BrdU injection(s), the number of BrdU-labeled cells increased and then fell after 5 wk, indicating that a large number of newly born cells died. The surviving cells were assumed to be neurons since they extended axons locally and expressed markers of immature (TOAD 64, TuJ1) and mature (38 52% of BrdU-NeuN cells) neurons but did not express GFAP or CNP. Although the site of origin of the newly born neurons remains unclear, it has been proposed that they may be generated into the SVZ and migrate to neocortical areas through the white matter or may be recruited from local quiescent stemlike cells (179, 182, 284). In contrast to these data, other groups have reported a complete absence of neurogenesis in the mouse (134, 332) and monkey cortex (281, 453). Neurogenesis was observed in the neocortex of mice only following a targeted apoptotic degeneration of corticothalamic neurons (332), and in this case, endogenous neural precursors migrated and differentiated into neocortical neurons in a layer- and region-specic manner and reformed appropriate long-distance corticothalamic connections; thus they appeared to reconstruct the lesioned circuits. In the primate neocortex, although cell proliferation occurs, the newly born cells do not seem to differentiate into neurons (285). These discrepancies may be due to differences in housing conditions, the animals histories, and genetic background, and other technical considerations (survival times, BrdU dosage and administration mode, immunohistochemistry. . .), but generally, the existence of this cortical neurogenesis is still a matter of debate (411).
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4. Summary Following a century of doubt and controversies, there is now a consensus that neurogenesis occurs in the adult brain in at least two regions, the SVZ and the DG. In both structures, stemlike cells proliferate, migrate, and differentiate mainly into granule neurons that will synthesize GABA in the OB and glutamate in the DG. Although less studied, a small proportion of adult-born cells differentiate into other types of interneurons (the periglomerular in the OB and the basket cells in the DG). Altogether this adult neurogenesis leads to the birth of 30,000 new neurons per day in the SVZ and between 3,000 and 9,000 in the DG of young adult rats, depending on their age. The reasons for which, 1) the SVZ and the DG harbor adult neurogenesis, 2) neurogenesis is curtailed in the DG compared with the OB, and 3) genesis rates are much lower in primates, are currently unknown. Furthermore, because these structures do not grow in size, a homeostatic compensatory equilibrium must be attained through an increase in cell death that must be equivalent to the initial addition of neurons. This poorly understood phenomenon, in particular in the DG, deserves more attention for it is an important partner of neurogenesis. Finally, recent evidence indicates that the adult-born neurons of the OB and the DG are functional and thus play a physiological role. Although these ndings suggest a relevant contribution of these newly generated neurons to the bulbar or hippocampal function, further studies are needed to conrm these reports and fully unravel their fundamental consequences on the animals behavior (see sect. III). D. Factors Regulating Adult Neurogenesis Although various factors that affect the division, migration, and differentiation of neural precursor cells have been isolated, the precise mechanisms that control neuronal fate in the adult nervous system remain largely unknown. Both cell intrinsic programs and extracellular/ environmental factors, which we will review below, are at play. 1. Intrinsic programs controlling neurogenesis Two fundamental decisions are involved in order for a precursor cell to generate a neural cell. The rst one is to decide whether to self-renew or to undergo mitotic arrest, and the second is to interpret mitotic arrest, using cell autonomous cues that direct toward a particular fate. Much of our current understanding of these cell intrinsic programs comes from work performed when neurogenesis is at its best, i.e., during development. However, it is important to emphasize that the rules that govern neuronal specication during development may not be the same in the adult brain. Furthermore, since a description of the
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detailed molecular mechanisms involved in cell proliferation and determination is beyond the scope of this review, we here propose only a brief overview of the intrinsic factors involved, with a special mention whenever their involvement has been extended to the adult neurogenic zones. A) CONTROL OF CELL PROLIFERATION. Among the cell cycle factors regulating cellular proliferation, Rb (retinoblastoma) and its related proteins (p107, p130), necdin, and the E2F protein families are key players (for a review, see Ref. 580). Thus, during the G1 phase, Rb predominates in a hypophosphorylated form that can bind to E2F, a positive regulator of the cell cycle (403), thereby repressing its transcriptional activity and preventing the cells from entering the S phase. In cycling cells, phosphorylated Rb accumulated during the late G1 phase releases E2F, thus allowing S phase entry. This phosphorylation depends on the activation of cyclin-dependent kinases (CDK) acting sequentially. Early to mid-G1, cyclins of the D class (D1, D2, and D3) activate CDK4/CDK6, and in late G1, cyclin E activates CDK2, leading to hyperphosphorylation of the Rb protein. Two families of CDK inhibitors (CDKIs) that can suppress cell proliferation by inhibiting Rb phosphorylation have been identied (566): members of the inhibitors of CDK4 family (INK4 family), including p15Ink4b, p16Ink4a, p18Ink4c, and p19Ink4d, and members of the kinase inhibitory protein family (Cip/Kip family) such as p21Waf1/Cip1, p27Kip1 or p57Kip2 (see Fig. 3). It is now clear that the Rb and E2F protein families are differentially expressed in proliferative and postmitotic cells of the adult brain. Thus, in the two neurogenic sites, the DG and the SVZ, Rb immunoreactivity is high in proliferating neuronal precursors and reduced during terminal differentiation (415), which implies that the transient increase in the level of Rb is an important step in the initiation of terminal mitosis in neuronal progenitors. Moreover, the Rb protein family was found to be essential for the development of a neural lineage and the exit from the cell cycle, whereas it does not seem to be involved in the maintenance of postmitotic neurons (69, 89, 228, 299). The role of E2F1 as a key factor in regulating adult neurogenesis has been further emphasized in a recent study performed in mice lacking E2F1. These mice, when adult, exhibit a lower level of cell proliferation and a reduction in the number of neurons generated in adult neurogenic areas (94). The role of cell cycle regulators in the control of neuron production has been studied as well. Transgenic mice that lack p27Kip1 expression display a higher rate of cell proliferation versus differentiation in the SVZ, leading to an increased number of type C cells, a reduced number of type A neuroblasts, and no change in the number of type B cells (127). Finally, distinct functions for CDK inhibitors, either in the control of cell cycle exit and differentiation during neurogenesis (respectively, p27Kip1
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FIG. 3. Schematic representation of the mammalian cell cycle. The cyclin D/cdk4 6 complex phosphorylates the Rb protein leading to sequential phosphorylation by cyclinE/cdk2 and the release of free E2F. Phosphorylation of Rb relieves transcriptional repression of genes involved in the induction of S-phase entry. The ability of the cyclin/cdk enzymes to phosphorylate Rb is inhibited by cyclin-dependent kinase inhibitors (cdkis), the activation of which thus suppresses cell proliferation. The basic helix-loop-helix (bHLH) proneural genes NeuroD, Mash1, and Ngn1 control the switch from cell proliferation to neural differentiation by activation of the Kip/Cip Cdki family, thus preventing progression through the G1-S phases. The HLH proteins Id1 and Id3 (inhibitor of differentiation) repress neuronal determination by direct binding with proneural bHLH proteins, but also favor progression through the cell cycle via inhibition of the INK4 and Kip/Cip Cdki families. Activating and inhibiting inuences are represented by blue arrows and red lines, respectively.
and p19Ink4d) or in the maintenance of a quiescent state in neural progenitors (p18Ink4c) or neurons (p21Cip1) in adults have been underlined (303). B) CONTROL OF CELL FATE. Data from developmental biology have clearly indicated that a core genetic program involving multiple bHLH transcription factors is required for both neuronal differentiation and determination. These factors, deriving from proneural and neurogenic genes, antagonistically control the switch from cell proliferation to neural differentiation: cascades of neuronal bHLH genes promote differentiation, whereas antineuronal bHLH genes repress them under the control of Notch and keep cells at a precursor stage (for recent general reviews, see Refs. 358, 473). Two classes of proneural genes can be distinguished: the determination factors, such as Mash1 (mammalian achaete-scute homolog), Math1 (mammalian atonal homolog), and Ngns (Neurogenins) including Ngn2, expressed early in mitotic neural precursor cells, and the differentiation factors, including NeuroD, NeuroD2, and Math2, expressed later in postmitotic cells (for reviews, see Refs. 49, 379). It was recently determined that these proneural genes are downstream effectors of Pax6 (for a review, see Ref. 174), a transcription factor that promotes neurogenesis (210). These proneural genes are components of a cell-cell signaling mechanism whereby a cell that becomes committed to a neural fate inhibits its neighbor from doing likewise. This process of lateral inhibition, which restricts the domains of the proneural gene activity and involves neurogenic genes, is mediated by the Notch pathway (for reviews, see Refs. 23, 32, 161, 244, 491, 567). Among the effectors of Notch, three families of negative regulators of
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the bHLH transcription factors are known: the HES, Id, and HES-related (HESR or HERP) families (226, 413, 481, 545). These effectors repress neuronal determination and differentiation in those cells not destined to become neuroblasts. Paralleling this regulation of neuronal proliferation by inhibiting neuronal fate, Notch was also found to be involved in determining glial fate (186, 398, 467). Recent studies have highlighted that some of these factors, which are at play during development, may be involved in neuronal cell fate during adulthood. Thus Notch1 and Hes5 were found to be expressed at high levels and with a similar pattern in both the adult SVZ and DG, whereas numb and numblike, which negatively regulate the Notch signal transduction, were not, suggesting an active Notch signal in the adult neurogenic zones (523). Similarly, the mRNA expression of several bHLH factors was found to be present at various degrees in the adult HF, ranging from the restricted expression of Mash1 within the proliferative SGZ, which is consistent with its role in maintaining a precursor cell phenotype, to the widespread prole of Hes5 throughout the HF (140). In conclusion, despite the considerable advances achieved recently with the development of molecular tools, the complex intrinsic machinery that controls and coordinates proliferation and differentiation is still poorly understood. As is the case for hematopoiesis, for which much progress has been achieved, understanding the gene expression patterns of progenitor cells and their progeny will be a critical step in elucidating the mechanisms underlying cell fate.
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2. Extrinsic factors regulating neurogenesis A) HORMONES AND NEUROSTEROIDS. I) Adrenal corticosteroids. Historically, corticosteroids were the rst factors to be studied for their inuence on adult neurogenesis (354). Corticosteroids are released into the blood circulation following the activation of the hypothalamo-pituitary-adrenal (HPA) axis, primarily by stress (351). Corticosterone, the main corticosteroid in rodents, regulates its own secretion through negative feedback, by interacting with two receptors (the mineralocorticoid MR, the glucocorticoid GR), present in the DG. Suppression of corticosterone 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-specic inhibitory inuence of corticosteroids. It was further shown that proliferation increases within 24 h after adx and remains constant over the 6 subsequent days; the newly generated cells survive for at least 4 wk in the absence of corticosterone, indicating that their survival is corticosterone independent (465). Cell death is also enhanced, but the populations of cells undergoing mitosis or apoptosis are distinct: immature cells divide at the interface of the hilus, whereas more mature neurons, located at the interface of the molecular layer, die (72). These alterations are prevented by corticosterone replacement (176, 465). The respective roles of MR and GR on adrenalectomy-induced structural modications have recently been examined (374). Treatment with a low dose of the MR agonist, aldosterone, prevents adrenalectomy-induced increase in cell death, whereas a higher dose is necessary to normalize cell proliferation. Furthermore, treatment with a GR agonist, RU 28362, at doses that should fully occupy this receptor prevents both adrenalectomy-induced cell death and birth. Thus the stimulation of both MR and GR mediates the effects of corticosterone on cell proliferation and protects mature cells from cell death. This inhibitory action of corticosterone on neurogenesis has also been found in other models: 1) acute corticosterone administration {2 40 mg/kg administered 1 h before a single [H3]dT injection (71, 76); implantation of a 200-mg corticosterone pellet followed by 1 200 mg/kg BrdU (17)}, 2) chronic corticosterone treatment [1 40 mg/kg for 21 days; BrdU 10 50 mg/kg every 12 h on days 1721 (212)], 3) stress (see sect. IIIB1), and 4) interindividual differences in the activity of the HPA axis (305; see sect. IIIB2). The mechanisms by which corticosterone hampers cell proliferation remain unknown. In vitro, glucocorticoids block the G1 phase of the cell cycle, notably through repression of cyclin D1, cyclin D2, Cdk4 and Cdk6, and induction of the CDKIs p21Cip1 and p27Kip1 (438, 585, 592). However, it remains to be determined which of these mechanisms is involved in vivo. Because only a small minority of precursor cells express corticosteroid recepPhysiol Rev VOL
tors (77), corticosterone may not act directly on proliferating precursors, although it cannot be excluded that immature forms of receptors that are not recognized by current antibodies are involved. Corticosterone could act on neighboring glial or neuronal cells expressing corticosteroid receptors, which could control the cell cycle by releasing growth factors (515). Alternatively, corticosterone could regulate proliferation indirectly by increasing glutamate release in the DG (520) (see sect. IID2B) as the effects of adx or high levels of corticosterone can be blocked by NMDA receptor activation or inactivation, respectively (76). Corticosterone may also inhibit cell proliferation by dowregulating the production of insulinlike growth factor I (IGF-I) (585, 592). II) Gonadal hormones. The inuence of female gonadal hormones has been investigated in the DG since estrogen replacement therapy seems to reduce the risk of age-related cognitive impairments (213). Although cell proliferation in the GCL (and not the hilus) is higher in female than in male rats, the newly born cells do not survive, which explains the lack of sex differences in the number of BrdU-IR cells 2 wk after labeling (536). Sexdependent proliferative activity involves the stimulatory inuence of estrogens, since the number of BrdU-labeled cells is highest during the proestrus phase of the estrus cycle, when circulating levels of estrogens are highest (536), and acute administration of 17-estradiol reverses the ovariectomy-induced decrease in cell birth (29, 536). In contrast, using TOAD-64 and calbindin as early and late neuronal markers, it has been shown that estradiol does not alter neuronal differentiation (536). However, discrepant results have been reported following chronic administration of estradiol to ovariectomized adult female rats (435), spontaneous hypertensive rats (436), or adult wild meadow voles (163). Cell proliferation in the GCL (measured 24 h after a single intraperitoneal injection of [3H]dT) is lower in female meadow voles captured during the breeding season, when estradiol levels are high, compared with reproductively inactive females. A similar relationship has been conrmed in laboratory-reared female meadow voles (421). These apparently contradictory results might be explained by a complex regulatory mechanism. In fact, a single administration of estradiol initially enhances (within 4 h) and subsequently suppresses (within 48 h) cell proliferation in the DG of ovariectomized female rats or meadow voles (420, 421). The increase in cell proliferation is mediated by serotonin (29), whereas the decrease is prevented by adx (422), suggesting an involvement of corticosterone. However, although corticosterone-induced regulation of cell birth certainly involves NMDA receptors, estradiol inuences on cell proliferation are not mediated by these receptors (420). Finally, estrogen may act directly on estrogen receptors subtype (ER )
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present on hippocampal precursors (435) or through IGF-I receptors (see sect. IID2C). III) Neurosteroids. Neurosteroids represent a subclass of steroids synthesized de novo in many regions of the brain, independently of peripheral sources (36). They are synthesized in the HF, by glial cells mainly, and inuence hippocampal-mediated functions (349). Two principal families can be distinguished according to their pharmacological properties (333). In particular, dehydroxyepiandrosterone (DHEA) and pregnenolone sulfate (Preg-S) act as allosteric antagonists of the GABAA receptors while allopregnanolone (AlloP) is a positive modulator of these receptors. Chronic treatment of young adult male rats with subcutaneous pellets of DHEA (200 mg/pellet for 12 days) has been shown to stimulate hippocampal cell proliferation measured 24 h after BrdU injections (50 mg kg1 day1) given on the last 4 days of the steroid treatment (254). After an additional 16 days of treatment, the newly born cells survive and express the neuronal marker NeuN. Interestingly, DHEA treatment is also able to reverse the suppressive effect of corticosterone on neurogenesis, suggesting that 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 DG of young adult rats within 24 h, whereas treatment with AlloP (2 6.3 nmol/7 l) decreases it (348). The newly generated cells survive for at least 1 mo and differentiate mainly into neurons (expressing NeuN). These actions of Preg-S are mediated by GABAA receptors present on hippocampal precursors, since icv administration of muscimol, a GABAA agonist, blocks Preg-S-induced cell proliferation. Furthermore, a direct action of Preg-S was suggested as this compound stimulates in vitro the proliferation of spheres derived from the adult SVZ (348). Altogether, the reported effects of DHEA and Preg-S are congruent with the observations that in vitro activation of GABAA receptors inhibits cortical cell proliferation, whereas GABAA receptors antagonists stimulate it (21, 318, 327). B) NEUROTRANSMITTERS AND NEUROREGULATORS. I) Glutamate. Destruction of the perforant pathway, the main glutamatergic afference to the DG arising from the entorhinal cortex, increases cell proliferation, thus indicating that under these experimental conditions glutamate exerts an inhibitory inuence (73). As expected, blockade of NMDA subtypes of glutamate receptors by injection of a noncompetitive antagonist (MK801) increases cell genesis within a few hours in rats (1 mg/kg; Refs. 73, 76), tree shrews (1 mg/kg; Ref. 177), gerbils (3 3 mg/kg; Ref. 46), and ovariectomized adult female meadow voles (30 mg/kg; Ref. 420), and treatment with the competitive NMDA receptor antagonist CGP 37849 (5 mg/kg) increases both cell proliferation and granule neurons density (73). Conversely, administration of NMDA (30 mg/kg) decreases
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cell proliferation in several species within hours (73, 76, 420), which is congruent with the antiproliferative properties of glutamate on in vitro cortical cell proliferation (318). However, it should be mentioned that an inhibitory inuence of glutamate receptor blockade on neurogenesis has been reported in stroke-damaged brains (see sect. IIID1B). The newly born cells induced by the inactivation of NMDA receptors differentiate into neurons, expressing DCX, TOAD-64, NSE, or NeuN markers (73, 177, 390, 417). Furthermore, the MK-801-induced neurons are functional as they respond to NMDA stimulation, measured by the phosphorylation of extracellular signal-regulated kinase (ERK), 29 days after their birth date (417). This indicates that newly born neurons acquire components for the intracellular signal transduction cascade linking NMDA receptors to phosphorylation of ERK (114). The mechanisms by which precursor proliferation is inhibited by glutamate in vivo through NMDA receptors remain unknown, but they most probably do not involve collateral deleterious effects as treatment with CGP 43487 upregulates cell birth without inducing cell death or astrogliosis (390). Because glutamate also acts onto AMPA receptors, detected in neural progenitors (165), the inuence of potentiators of AMPA receptors such as LY451646 has been evaluated on hippocampal mitotic activity. Acute administration of LY451646 (0.025, 0.05, 0.125 mg/kg) does not inuence the number of newly born cells observed 24 h after BrdU pulse (4 75 mg/kg every 2 h). However, the median dose increases the number of cells per 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 proliferating cells, of cells per cluster, and of clusters in a dose-dependent manner (27). Altogether, these results suggest that glutamate exerts a complex inuence 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 are cotransmitted at the mossy bers synapses adds further complexity to the respective role of each neurotransmitter in neurogenesis regulation (196). II) Serotonin. In the 1970s, it was proposed that early forming serotonin (5-HT) neurons act as humoral signals governing neuronal development and neurogenesis in particular (26, 298). Since then, several approaches have shown that serotonin upregulates cell proliferation in the adult DG and SVZ (see also sect. IIID2A). Inhibition of 5-HT synthesis (by subchronic injections of PCPA for 6 days) and selective lesions of 5-HT neurons of the raphe decrease the number of BrdU- and PSA-NCAM-IR cells in the DG and the SVZ (BrdU 50 mg/kg ip injected on the last 3 days of PCPA treatment at 12h intervals and animals killed 6 h after the last injection; Ref. 61). This upregulawww.prv.org
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tion of hippocampal cell proliferation depends on serotonin as it is reversed by intrahippocampal grafts of embryonic 5-HT neurons (63). Partial lesions of 5-HT raphe neurons lead, after an initial deprivation of hippocampal 5-HT bers, to a spontaneous reinnervation of this structure by 5-HT bers. At this time, the fall of mitotic activity (and PSA-NCAM expression) is reversed (62). These actions of serotonin are mediated by 5-HT1A receptors in both the DG and the SVZ (30, 451) while 5-HT2A and 5-HT2C receptors are selectively involved in the regulation of cell proliferation in the DG and SVZ, respectively (30). Finally, 4 wk after chronic treatment with 5-HT1A or 5-HT2A agonists (daily injection of 8-OH-DPAT or RO 600175 for 15 days, 75 mg/kg of BrdU injected twice on the last 8 days of the treatment), the newly born cells in the DG and/or the OB express NeuN (30). III) Nitric oxide. Nitric oxide (NO), a free radical molecule synthesized from L-arginine by NO synthase, serves as a neurotransmitter in the brain (8). In the SVZ of adult mice, neuronal precursors have been found to be within the sphere of inuence of a NO source and to express NO synthase at the sites of terminal differentiation (377). Administration of DETA/NONOate, a NO donor, to young adult rats signicantly increases both cell proliferation and migration in the SVZ and the DG (587). C) TROPHIC FACTORS. Many trophic factors have been shown to have mitogenic actions in the adult brain neurogenic regions. Thus the proliferative effects of basic broblast growth factor (bFGF or FGF-2) have been clearly demonstrated for the SVZ. Chronic administration of bFGF intracerebroventrically (360 ng/day for 14 days, 50 mg kg1 day1 of BrdU being injected during the last 12 days of the treatment; Ref. 291) or intranasally (5 0.2 g/day at 5-min intervals for 1 wk concurrent with 2 50 mg kg1 day1 of BrdU at 8-h intervals; Ref. 240) increases the number of mitotic nuclei in the SVZ within 24 h. This leads to an increased number of newly born neurons (expressing DCX in the SVZ; Ref. 240) that reach the OB where they express NeuN (4 wk after their birth; Ref. 291). In contrast, in the DG, a lack of effect (291) or a small but nonsignicant increase in cell birth (25%, following 3 days icv infusion of 10 g/ml) was reported (238). Consistently, in mice lacking bFGF, basal hippocampal neurogenesis is normal, suggesting that other factors may maintain low levels of precursor proliferation under resting conditions (582). However, overexpression of bFGF by gene transfer in wild-type and bFGF-decient mice upregulates DG cell proliferation, which indicates that a robust and constant bFGF expression is a necessary condition for increasing cell birth in this structure (582). Epidermal growth factor (EGF; 350 ng/day for 14 days, 50 mg kg1 day1 of BrdU being injected during the last 12 days of the treatment; Ref. 291) and heparinbinding EGF (HB-EGF; 3 days icv infusion of 10 g/ml
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concurrent with 2 50 mg kg1 day1 of BrdU at 8-h intervals; Refs. 236, 238) stimulate cell birth in the SVZ (1 and 7 days after growth factor infusion, respectively) certainly via EGF receptors (381, 416, 502). However, these two factors probably have distinct actions, since HB-EGF increases the number of BrdU-IR cells expressing DCX or NeuroD in the SVZ as well as the number of newly generated cells reaching the OB (236, 240), whereas EGF reduces the number of newly born neurons reaching the OB (291). In the DG, HB-EGF (236, 238) but not EGF (291) increases cell proliferation by interacting most probably with EGF receptors expressed by the dividing cells (416). The adult-born cells express the neuronal marker NeuroD (236). Transforming growth factor (TGF)- is required for SVZ precursor proliferation. Indeed, icv administration of TGF- (400 ng/day for 6 days) induces a dramatic increase in precursor proliferation (98), whereas TGF- null mice show a decrease in proliferating cells in the SVZ, and in the total number of newly born cells within their target, the OB (543). No data on the inuence of TGF- on hippocampal precursors are yet available. IGF-I is a growth-promoting peptide hormone that is produced in the CNS by neurons and glial cells (20) and exhibits neurotrophic properties in adulthood (405). Its inuence on neurogenesis has been examined in hypophysiectomized rats presenting low levels of circulating IGF-I (1). Thus peripheral administration of IGF-I (1.25 mg kg1 day1) induces an increase of cell proliferation in the dentate GCL and the hilus after 6 days. Long-term treatment (0.39 mg kg1 day1 for 20 days) increases both BrdU-labeled cell number and their differentiation into neurons as measured by the percentage of BrdU-IR cells expressing calbindin. In contrast, an IGF-Iinduced increase in cell proliferation in nonhypophysiectomized rats is not associated with an enhancement of their differentiation potential toward a neuronal fate (542). In vitro experiments (2) strongly suggest that IGF-I regulates cell proliferation in vivo by acting directly on IGF-I receptors expressed by newly born cells (542), but a recent study has also shown that estrogen receptors are necessary for the induction of in vivo hippocampal cell proliferation by IGF-I (435). Brain-derived neurotrophic factor (BDNF) is a member of a family of related neurotrophic proteins, the function of which is to prevent neurons from dying during development. Chronic icv infusion of BDNF (0.012 l/day for 12 days) increased BrdU-labeled cells in the SVZ and in the GCL of the OB (593). The newly born cells expressed TuJ1 or MAP2. Survival (169, 276) and/or differentiation (6, 22) of the neuronal precursors and their progeny rather than proliferation seem to be inuenced by BDNF. Concerning the DG, it has been shown that heterozygous BDNF knockout mice exhibit reduced proliferation and survival of BrdU-labeled cells (301), sugwww.prv.org
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gesting a role for BDNF as a positive regulator of both proliferation and survival. However, repeated, but not single, administration of a compound that stimulates endogenous BDNF, riluzole, increases cell birth (3-fold) but not cell survival. Most of the newly generated cells (90%) differentiate into granule neurons (expressing NeuN) (257). This effect is blocked by icv administration of BDNF-specic antibodies, suggesting that an increase in BDNF is necessary for the promoting effect of riluzole on precursor proliferation. Altogether these data show that BDNF plays an important role in the maintenance of basal neurogenesis, a conclusion similar to that obtained following a developmental loss of function of this gene (312). Vascular endothelial growth factor (VEGF) is a hypoxia-induced angiogenic protein that exhibits neurotrophic and neuroprotective properties (359). Given that neurogenesis occurs in close proximity to blood vessels and that clusters of dividing cells contain endothelial precursors (see sect. IIC2B), VEGF may constitute the link between neurogenesis and angiogenesis. This is supported by the observation that icv administration of VEGF (0.24 g/day for 3 days concurrent with 2 50 mg kg1 day1 BrdU) stimulates cell proliferation in the rodent SVZ and SGZ by 7 days after treatment onset (241). At that time, the newly born cells express DCX and NeuN markers. The neuroproliferative effect of VEGF is associated with an upregulation of cyclin D1, Cyclin E and cdc25, and an increase in the nuclear expression of E2F1, E2F2, and E2F3 (591), which is consistent with a regulation of the G1/S phase transition of the cell cycle. D) MORPHOGENIC FACTORS. Sonic hedgehog (Shh), an important morphogen in development, is a signaling glycoprotein that acts through Patched 1-Smoothened (Ptc1Smo) receptor complex to trigger various events during CNS development, including determination of ventral neural phenotypes, induction of oligodendrocyte precursors, proliferation of specic neuron progenitor populations, and modulation of growth cone movements (for a review, see Ref. 346). In a comprehensive study, Lai and co-workers (295) investigated the role of Shh in the adult brain and showed that it increased proliferation of cultured adult rat hippocampal progenitors in a dose- and time-dependent fashion. In vivo, the exogenous administration of Shh and the inhibition of its signaling increased and reduced cell proliferation, respectively. Finally, the presence of the Shh receptor Patched in the DG and Ammons horn in the HF, and the high levels of expression of Shh in structures that project towards the DG support the assumption that Shh could be an endogenous positive regulator of cell proliferation in the adult DG (295). Another group of early neural morphogens, the bone morphogenic proteins (BMPs), belongs to the TGF- superfamily, which includes TGF-, activins, and the relaPhysiol Rev VOL
tives named growth/differentiating factors (GDF). These glycoproteins play a crucial role in bone remodeling and in the regulation of dorsoventral patterning of the neural tube and cell fate during embryonic development. Furthermore, several BMPs, including BMP4, are involved in repression of the oligodendroglial lineage and generation of 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 the type E cells antagonizes the type B cells expressing BMP (311). Furthermore, BMP2, BMP4, and BMP7 have been found to activate a promoter of the gene for the HLH factor Id1, which is known to inhibit the function of neurogenic transcription factors such as Mash1 and neurogenin. Thus the switch from neuronal to astrocyte fate realized by BMPs certainly involves HLH proteins (578). These ndings were extended to the HF. Indeed, a novel secretory factor, neurogenesin-1 (Ng1), released by hippocampal astrocytes and dentate granule cells adjacent to progenitor cells, was found to promote neuronal fate in the adult HF through antagonism of BMPs, which alter the fate of neural stemlike cells from neurogenesis to astrogliogenesis by upregulating the expression of the negative HLH factors Id1, Id3, and Hes5 (548). E) REGULATION BY GLIAL CELLS. Regulation of adult neurogenesis by glial cells has been emphasized (500). Astrocytes, which play an important role as sensors of changes in their extracellular microenvironment, could regulate neurogenesis by secreting local signals (514). These signals, unknown so far, may be ionic uxes, neurosteroids, cytokines, growth factors, and glutamate metabolites (48, 243, 245, 296, 486, 516, 579, 595). The observation that some proliferating cells in the DG express a receptor for S100, a small acidic calcium binding neurotrophic protein released by astrocytes, reinforces the putative contribution of glial cells in the regulation of adult neurogenesis (339). F) REGULATION BY CELL DEATH. An equilibrium between neurogenesis and cell death probably ensures a homeostatic balance in the adult brain. This hypothesis, based on the observation that the neurogenic structures do not grow in size, implies that cell death provides a stimulus for increased neurogenesis, a hypothesis reinforced by several lines of argument: 1) during development, there is a balance between the birth and death of granule cells (183); 2) mechanical lesions, aspiration, and transection stimulate neuronal precursor proliferation in the GCL and/or the SVZ (180, 242, 531, 546, 568); 3) proliferation in the SVZ is upregulated under inammatory conditions (70); 4) adrenalectomy, limbic seizures, and ischemia enhance both cell death and cell birth; and 5) the apoptotic degeneration of corticothalamic neurons (by means of targeted photolysis) induces endogenous neural precursors to difwww.prv.org
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ferentiate into mature neurons in regions of the cortex undergoing targeted neuronal death (332). The induction of neurogenesis in these regions of the adult neocortex that do not normally undergo any neurogenesis (332) may result from the removal of a normal inhibitory inuence or the loss of a secreted stimulatory factor produced by the dying cells. G) SUMMARY. Adult neurogenesis within each neurogenic site is regulated differently by a growing list of epigenetic factors [to which should be added prolactin (506), norepinephrine (35, 292), the pituitary adenylate cyclase-activating polypeptide (PACAP) (362), ciliary neurotrophic factor (141), retinoic acid (99), and vitamin E (83, 86, 87); see Table 1 for a complete summary]. Although most of these factors modulate cell proliferation through unknown mechanisms, a regulation of Cyclin D1 and p27Kip1 expressions may constitute a common pathway (438). The specicities of each neurogenic site may be related to differences in the intrinsic properties of the dividing cells (for example, their intrinsic ability to sense neural activity; Ref. 114) and/or in their microenvironment, which corresponds to the summation of local neurogenic signals expressed or synthesized locally by healthy neighboring cells or by dying cells. These signals may also be synthesized peripherally and released in neurogenic sites by neuronal afferences or by blood vessels. In this context, the role of the cerebral vasculature has gained importance as adult neurogenesis occurs within an angiogenic niche, and an alteration in the vascular microenvironment, or its ability to respond to changes in metabolic demands, may be responsible for a disruption in neurogenesis (371, 372, 460). III. THE ANATOMO-FUNCTIONAL APPROACH Complementary to the neuroanatomic studies that revealed some key biological properties of adult neural stemlike cells, the integration of the adult newborn neurons into preexisting networks has prompted the fundamental question of their functional relevance. So far, most studies have focused on the role of adult neurogenesis in hippocampal functioning. Parsimoniously, this region, included in the limbic-cognitive system, is part of an integrated network involved in learning and memory, attentional processes, motivational states, and emotion (68, 135, 136, 227, 352, 484). As pointed out by Hampton et al. (201), current theories of hippocampal function wrestle with two major conceptual issues: whether the structure encodes spatial, nonspatial, or both types of information (139) and whether the information encoded is episodic or semantic. Recent evidence infers that hippocampal neuronal networks could support the cognitive mechanisms of declarative memory by encoding features of experiPhysiol Rev VOL
ences. Indeed, declarative memory involves a record of everyday experiences, which includes information about the content of that experience and the spatial and temporal context in which it occurred (episodic memory), woven together into the framework of the individuals knowledge (semantic memory) (135). According to the memory space model of declarative memory, the HF plays a critical role in 1) representing experiences as a series of events and places and 2) linking memories together by identifying common features into a network that supports inferential expression. This said, the role of the HF in long-term memory is in dispute as the standard theory assumes that the HF becomes dispensable after the conversion of short-term memory into long-lasting memory, whereas the multiple trace theory makes the assertion that the HF is involved in the storage and retrieval of episodic memory regardless of the age of memory (394). Although current advances do not yet allow the attribution of a specic role for newborn neurons in this conceptual framework, in the following sections we will review the progress achieved in implicating neurogenesis in both hippocampal functioning under physiological conditions and the apparition of hippocampal-related pathologies, which are mainly studied in preclinical animal models. Operationally, two approaches have been considered: the rst consists of relating changes in hippocampal neurogenesis to changes in the ability to perform hippocampal-related tasks, and the second consists of studying the inuence of hippocampal-related tasks on neurogenesis. A. Environmental and Physiological Inuences on Neurogenesis 1. Experience in enriched environments, neurogenesis, and learning
A) OLD PROBLEM, NEW DATA. Rosenzweig and co-workers (470 472) were the rst to introduce the concept of an enriched situation, i.e., a complex environment enriched in sensorial stimulations, social experiences, and physical and cognitive exercises (555). This concept has given rise to a wealth of studies showing that exposure to such environments, which are considered as enriched for standard laboratory conditions, modies brain functioning, learning, problem-solving ability, brain chemistry, and several structural aspects of brain organization. The consequence of environment enrichment on hippocampal neurogenesis was originally studied in juvenile female C57Bl/6J mice. Exposure to an enriched environment between 3 and 13 wk of age was found to increase survival of newly born cells (measured 4 wk after daily injections of 50 mg BrdU for 12 consecutive days from days 28 to 40 of enrichment), whereas cell proliferation (measured 1 day after the BrdU pulses) remained unchanged in the GCL and in the hilus (267). Similar results have been
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obtained with adult female rats (after injecting BrdU 50 mg kg1 day1 on days 26 30 of enrichment) (407). These rst reports led Kempermann and Gage (262) to further investigate the impact of environmental enrichment on mice, and it was later shown that cell proliferation in the GCL was increased only when mice were killed 3 mo after their removal from the enriched environment (262). In addition, a comparison of different strains of mice showed that enriched experience affects hippocampal neurogenesis differently according to genetic background: as reported above, it increases cell survival but not cell proliferation in C57BL/6 mice (267) which have a high baseline level of neurogenesis (268), whereas it increases cell proliferation in 129/SvJ mice (261) which have low levels of neurogenesis (268). This interesting nding indicates that environment has a differential impact depending on inheritable traits, an effect still unexplained. Finally, in most experiments, enrichment led to an improvement in spatial memory in the water maze, a learning task that requires the subjects to learn multiple extra-maze visual cues, allowing them to build a dynamic spatial representation of their surroundings to navigate to a platform hidden underneath the water surface (378). However, whether these genetic variations of neurogenesis have a functional signicance in spatial memory remains unknown (266).
B) MECHANISMS INVOLVED IN ENRICHMENT-INDUCED NEUROGENESIS.
The social environment may also contribute to enrichment-induced neurogenesis. This hypothesis has been tested in rats reared for 4 wk in isolation and injected with BrdU (2 50 mg kg1 day1) on the last 3 days of the rearing treatment. Compared with grouped-reared rats, isolation decreases hippocampal cell proliferation within 24 h, the number of newly born cells surviving over an additional period of 4 wk of isolation, and the percentage of newly born cells expressing TOAD-64. Interestingly, the isolation-induced decrease in cell proliferation is reversed by a subsequent 4 wk of group housing (BrdU being injected on the last 3 days of the rearing period; Ref. 320). Together, these results indicate that social environment is a highly relevant factor underlying the anatomical effects of an enriched environment. 2. Reciprocal relation between learning and neurogenesis
A) LEARNING INFLUENCES SEVERAL ASPECTS OF NEUROGENESIS. The effect of learning on survival of newly born cells has been examined in the water maze and in eyeblink conditioning using a trace protocol (175). In this latter test, which requires an intact HF (385, 512), animals have to associate an auditory tone (conditioned stimulus) with a corneal airpuff or electrical stimulation (unconditioned stimulus) that is temporally separated by a trace interval (350). In both learning tasks, rats are tested 1 wk after a single BrdU injection (200 mg/kg). The number of BrdU-labeled cells is enhanced by learning immediately or 1 wk after the end of training, an effect accompanied by a decrease in cell death. In associative learning, the performance of individual rats positively predicts the life span of 1-wk-old BrdU-labeled cells, i.e., rats exhibiting the best behavioral scores possessed more newborn cells; this also suggests that learning (and not training) is a sufcient condition to increase the survival of adult-born cells (309). This learning-induced increase in cell survival was maintained 2 mo after acquisition of associative learning (309). The observed enhancement of cell survival is specic to learning because neurogenesis remains unchanged in rats exposed to unpaired conditions in eyeblink conditioning or in rats producing the same amount of motor responses in the water maze. Furthermore, learning-induced upregulation of neurogenesis may be specically attributed to hippocampal functioning as delay-eyeblink conditioning, classically attributed to the cerebellum, and training on a cued test in the water maze, a hippocampal-independent type of learning, do not modify neurogenesis (508). Although these experiments indicate an enhancing effect of learning in the water maze on cell survival, contradictions exist concerning cell proliferation. When animals are injected daily for the entire testing period (50 mg kg1 day1 for 12 days; Ref. 554) or the very last day of testing (200 mg/kg; Ref. 175), the number of BrdU-
Exposure to an enriched environment is known to inuence brain chemistry, in particular neurotransmitters and trophic factors, which may underlie its action on neurogenesis (151, 370, 442, 471, 555, 584). In addition to these factors, several components of this environment may be involved in the regulation of neurogenesis. Thus the effects of an enriched environment on neurogenesis and spatial memory may be related to an enhancement of motor exercise rather than learning. To examine this hypothesis, female mice were housed with a running wheel, injected with BrdU (50 mg kg1 day1 for the rst 12 days) and killed 1 or 30 days after the last BrdU injection. In these conditions, cell proliferation and cell survival in the GCL, and performances in spatial learning tasks were enhanced, suggesting that physical activity is an important mediator of enrichment-induced neurogenesis (553, 554). Further studies proposed that the 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 a major factor in the effects of enrichment on brain and behavior (471), which suggests that it could be a relevant factor involved in enrichment-induced neurogenesis as well. The observation that exposure to enriched conditions for an extended period of 6 mo does not add further benet certainly lends weight to this hypothesis (262).
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labeled cells remains unchanged. However, when animals are injected at the end of the learning phase (50 mg kg1 day1 for 3 days), when an asymptotic level of performance is reached, then the number of newly born neurons in the GCL of the DG increases (306). To reconcile these data, we hypothesized that different phases of the learning process have distinct actions on cell proliferation. To test this hypothesis rats were injected with BrdU (50 mg kg1 day1) either during the initial phase (4 days, Fig. 4, A and E), characterized by a fast and large improvement in performance, or during the late phase (4 days, Fig. 4C), when an asymptotic level of performance
FIG. 4. Learning can increase or decrease the production of newborn cells. The aim of these experiments was to distinguish the effects of the early phase () of learning (characterized by a rapid and large improvement in performance) and of the late phase of learning (when asymptotic levels of performance are reached) on neurogenesis. To this end, 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 had been mastered (C and E, at the end of the late ). The early of learning did not modify the number of cells generated during this period (B). The late of learning increased the number of newly born cells generated during this period (D), whereas it decreased the number of newly born cells produced during the early (F). C, control group; L, learning group. **P 0.001 compared with control group. [Modied from Do bro ssy et al. (121).]
was reached. We found that the early phase of learning does not modify proliferation (Fig. 4A), whereas the late one does (121). Indeed, the number of newly born cells increased contingently with the late phase of learning (Fig. 4B), and these new cells differentiated into neurons that persisted in the DG for at least 5 wk after the animals had acquired the task. In contrast, the late phase of learning induced a decrease in the number of newly born cells produced during the early phase (Fig. 4C). Most importantly, the extent of BrdU cell loss was inversely related to learning performances: rats with the highest and lowest cell loss have the best and worst performances, respectively. This decline in adult-born cells most probably mirrors cell death, since learning induces an increase in numbers of pyknotic cells (129) and tunnel-positive cells (18). The observations that learning in the water maze increases the expression of proteins involved in apoptosis (82) and that intrahippocampal administration of anticaspases, which blocks cell death, impairs long-term but not short-term spatial memory (106), strengthen the hypothesis that cell death is an important component of hippocampal learning. The mechanisms by which cell survival and proliferation are regulated during learning are so far unknown. A nonspecic effect of training or exercise on blood ow to the brain that may increase BrdU availability is unlikely, since neurogenesis is unchanged in control swimmers (121, 175). Trophic factors known to support the viability and function of many types of neurons are likely mediators of learning-dependent changes in the HF. Indeed, hippocampal bFGF and BDNF are increased during task learning and decreased once an asymptotic performance is reached (171, 271). B) A BLOCKADE OF NEUROGENESIS DISTURBS LEARNING. The participation of neurogenesis in memory formation has been more directly tested by using the DNA methylating agent methylazoxymethanol (MAM; 5 mg/kg for 14 days concurrent with 75 mg kg1 day1 of BrdU on days 10 12-14). This treatment decreases the number of adult-born cells by 80% and alters trace conditioning, whereas delay conditioning, neuronal responsiveness (presynaptic neurotransmitter release and excitability), and synaptic plasticity are not disrupted (509). Three weeks after treatment cessation, the replenishment of immature neurons is associated with a recovery to acquire the trace conditioned response. Altogether, these results suggest that newly born cells are necessary for the formation of trace memories. Because MAM treatment for 6 days only is unable to affect trace conditioning, adult-born cells may not be functional until 12 wk after birth. Although it has been shown that newborn cells extend their axons in the CA3 subeld within 4 10 days after birth (204), a basic temporal study following their functional maturation (by means of electrophysiological properties or c-fos expression) is still lacking.
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Recently, it has been reported that the formation of spatial memories may not be associated with neurogenesis. Indeed, the blockade of cell proliferation by the same 14-day MAM treatment as described above does not alter spatial learning in the water maze or contextual conditioning in fear conditioning (510). In our opinion, this lack of effect is due to the residual newly born cells that continue to be generated under MAM (700/day for 3 BrdU injections), indicating that learning can occur with a very small percentage of new neurons. This assumption is based on the observation that some aged rats are able to acquire spatial navigation learning despite a very low number of newly born cells [200/day for 5 BrdU injections; see sect. IIIC2, Fig. 6 (130)]. An emerging strategy to clarify the role of neurogenesis in learning consists of using ionizing-irradiation known 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 dosedependent manner (following a 60 mg/kg injection of BrdU 1 h before death) and the number of cells expressing p34cdc2 or Ki-67 in the adult DG (369, 433, 532). Two months after irradiation, the production of adult-born neurons (expressing NeuN) is signicantly reduced cer-
tainly as a consequence of an altered neurogenic microenvironment (369, 372). The reduction in hippocampal mitotic activity is accompanied 1 wk postirradiation by behavioral decits in a hippocampal-dependent task of spatial short-term memory (place-recognition). In contrast, performances in the water maze remain unaffected 2 wk postirradiation, a time by which proliferative activity has resumed, albeit at a low level (75 nascent cells daily in the dorsal DG; Ref. 330). 3. Discussion Data accumulated in the past decade suggest that the birth of new cells is a necessary condition for the acquisition of memory traces (see also data on prenatal stress and aging). However, a higher reduction in cell genesis seems to be required for the appearance of decits in learning spatial cues than in trace conditioning, a difference which may be related to task difculty (508). Furthermore, hippocampal-dependent behaviors inuence cell proliferation, cell survival, and cell death. The question of how adult neurogenesis participates in memory processing (i.e., encoding, consolidation, retrieval) is as
FIG. 5. Inuence of the different phases of learning on neurogenesis. The early phase () of learning increases the survival of cells that predate exposure to the task (175). These cells could be involved in the encoding of memory traces, allowing task acquisition (see sect. IIIA3A). Since the learning-induced increase in cell survival is longlasting (309), the surviving adult-born neurons could participate in the long-term storage of information and to recall remote memories. Two distinct processes take place after completion of the late phase of learning (121; see Fig. 4 and sect. IIIA3, B and C): 1) death of the cells born during the early phase of learning, which may be involved in memory trace consolidation. This cell death phenomenon could constitute a trimming mechanism that suppresses old unnecessary neurons and/or the immature neurons that are too old or have not established learning-related synaptic connections. 2) There is an increase in the number of cells generated contingently with the late phase training. Given that the learning-induced increase in cell proliferation is long-lasting, these newly born cells could be involved in a resetting process rendering the DG available for the acquisition of new memories (forgetting and exibility).
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yet unresolved. Although speculative, the following framework is proposed (Fig. 5).
A) DO ADULT-BORN NEURONS PRODUCED BEFORE LEARNING HAVE A ROLE IN MEMORY PROCESSING?
Since survival of the newly born cells whose birth predates the beginning of learning is increased during the learning task (175), the encoding of memory traces may be processed in these adult-born neurons. According to the use it or lose it principle, the cells that survived and integrated into the granule cells/ mossy ber system could function as postsynaptic detectors of correlated afferent activity and thereby update the bearing map, which is constructed in the DG from directional cues (229). After processing, which relies on pattern separation properties (270), episodic memories are stored temporally by virtue of the CA3 auto-associative system (468). The adult-born neurons could also be involved in temporal pattern completion: if a degraded version of a stimulus is presented after learning, the represented feature can be recalled from this incomplete input information. The role of adult-born neurons in long-term storage and retrieval of remote memories is still elusive as the role of the HF and the DG is still a matter of debate. One view stipulates that the HF has a limited storage capacity as 1-mo-old memories do not require the HF, memory traces being transferred within cortical areas where they are consolidated and permanently stored (19, 56, 273, 274, 342, 573). In relation to this apparent time-limited role of the HF, it was originally thought that after encoding and conversion of short-term memory into long-lasting memory, the adult-born neurons were eliminated (189). However, adult-born neurons that have been recruited by learning survive for several weeks (121, 309) and thus outlive the time required for cortical transfer. This timewindow is, in our opinion, hardly reconcilable with the consolidation transfer hypothesis. Furthermore, if one considers that adult-born neurons are integrated into the DG, which is no longer necessary for maintaining the memory traces, they may have adopted another, as yet undetermined, role (508). However, the view that the HF becomes dispensable after the conversion of short-term memory into longlasting memory is disputed, as it is supposed to be involved, together with neocortical areas, in the storage and the retrieval of remote memories (387, 388, 393395). In particular, 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-term survival of adult-born neurons (121, 309), which could act as binding detector cells capable of memorizing bindings between items (503) or could store a memory index, i.e., an index of neocortical areas that are activated by experiential events and contain no intrinsic meaning in terms of representation of external events (538). In these cases, adult-born neurons most probably do not store the memPhysiol Rev VOL
ory traces themselves but may play a critical role in linking representations of distinct experience, and longterm storage of spatial representations could be achieved by synaptogenesis occurring within this CA3 (455). Alternatively, adult-born neurons could store the contextual information regarding the episode (the so-called contextual trace; Ref. 394). B) A ROLE OF CELL DEATH IN STABILIZATION? A surprising phenomenon is that the death of old and/or newly born neurons also plays an important role in enabling hippocampal learning. This may constitute a trimming mechanism replacing the unnecessary old neurons and/or the immature neurons that have not established learning-related synaptic connections with freshly minted ones. This may serve the function of increasing the signal-to-noise ratio, thus consolidating the memory trace. This phenomenon, which on one hand is consistent with the use it or lose it principle and on the other hand goes against the classic assumption in learning-induced structural plasticity that more is better, recalls the regressive events observed during development (450).
C) IS LEARNING-INDUCED CELL PROLIFERATION INVOLVED IN MEMORY CLEARANCE OR FLEXIBILITY?
Learning-induced cell proliferation is not correlated with learning performances, suggesting that these newly born cells do not directly sustain ongoing learning and may rather be involved in future behaviors. This phenomenon may represent a resetting process ensuring that the hippocampal system is available to process new memories. This hypothesis is strengthened by the observation that presenilin-1 knockout mice that present normal basal neurogenesis exhibit a reduction in enrichment-induced cell proliferation and better retrieval of contextual fear memory traces compared with control mice (153). Thus a deciency in the upregulation of cell proliferation induced by the late phase of learning may prevent memory clearance, thereby impairing forgetting processes and disabling hippocampal functions. It is also possible that this alteration in cell proliferation alters the inferential use of past memories in a novel situation (exibility) and thus leads to rigidity and perseverance. B. Activation of the Stress Axis: Acute and Long-Term Effects on Neurogenesis Exposure to stressful events prepares animals to engage in ght or ight responses, and a role of the HF in these defensive behaviors has been proposed (52, 205). Moreover, as stressful events have deleterious effects on hippocampal integrity (351, 352, 484), the inuence of different types of stress on hippocampal neurogenesis has been studied. 1. Effects of stress on neurogenesis In most studies, a decrease in cell proliferation has been observed after stressful events, but this effect apwww.prv.org
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pears highly dependent on the nature and the timing of stress. In male but not female rats, exposure to the odor of a predator [trimethyl thiazoline (TMT), the major component of fox feces] downregulates the number of proliferating cells estimated 2 h, 24 h, and 1 wk after a single BrdU injection (100 200 mg/kg) (149, 537). However, this effect is transient as TMT-induced downregulation of BrdU cell numbers disappears 3 wk after labeling when dividing cells express NeuN or NSE (149). Likewise, in male tree shrews (Tupaia belangeri), a single exposure to an unknown congener, which results in the establishment of a dominant/subordinate relationship, brings down the number of dividing cells (labeled by one injection of BrdU, 75 mg/kg) in the DG of the subordinate within 2 h (177). In the marmoset (Callithrix jacchus) however, a single exposure to a resident-intruder model of stress reduces the number of newly born cells (2 h after 1 75 mg/kg BrdU) in the DG of the intruder (181). Repeated (3 or 6 wk) but not acute (2 or 6 h) restrain stress decreases cell proliferation duration-dependently in the SGZ of rats (2 h after 1 200 mg BrdU/kg; Ref. 441). In contrast, the acute stress of cold immobilization and a forced swim reduce cell proliferation (1 day after a 1 200 mg/kg BrdU injection before the stress) in the DG and not the SGZ, an effect that is normalized within 1 day (209). Chronic, unpredictable stress exerted over 3 wk reduces mitotic activity in the SGZ (and not the DG) as estimated by KI-67 staining. At this time point, another batch of animals was injected with BrdU (1 200 mg/kg), and 3 wk later, the effect of chronic stress on the survival of BrdU-labeled cells was examined. Because the BrdU cell number was unchanged, it was concluded that cell survival is not inuenced by stress. Finally, male tree shrews subjected to a 7-day period of psychosocial stress exhibit reduced cell birth (evaluated 1 day after 1 100 mg/kg BrdU; Ref. 104). This stress-induced reduction in adultborn cells leads to a decline in neurogenesis, the neuronal phenotype being inferred by the expression of NeuN (441) or NSE (177, 181) 1 mo after labeling. Because stressful events are known to activate the HPA 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 of these two factors has been evaluated. To conrm the involvement of corticosterone, male rats were adrenalectomized, and low levels of hormone were restored. In these conditions, the prevention of the TMT-induced rise in 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 TMTPhysiol Rev VOL
induced cell proliferation and defensive behaviors (149). The activity of the HPA axis is known to be regulated by corticotrophin-releasing hormone and vasopressin, the roles of which have recently been evaluated. Thus the chronic blockade of CRF1 and V1B receptors (by SSR125543A and SSR149415, respectively, 30 mg kg1 day1 for 28 days) starting 3 wk after the beginning of chronic mild stress (CMS for 21 days) reverses the stressinduced reduction of cell proliferation (measured 24 h following 1 75 mg/kg of BrdU injected at the end of the drug treatment period) (10). These antagonists are also able to prevent the stress-induced reduction of neurogenesis (by means of NeuN labeling) estimated 30 days after the cessation of the drug treatment and BrdU pulse (3.75 mg/kg every 2 h on the last 3 days of the CMS). The normalization of neurogenesis is furthermore associated with a prevention of the stress-induced hippocampal atrophy. 2. Interindividual differences in stress reactivity Interindividual differences in behavioral reactivity to stress or to novelty and coping abilities have been evidenced in our laboratory in an outbred population of rats. Animals are split into two groups according to the median score 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 is characterized by a series of adaptive defects of a cognitive and motivational nature corresponding to a decit in inhibition and control processes (115, 304, 443, 447). These interindividual differences have been related to differences in corticosterone secretion, HR rats displaying a hyperactive HPA axis (305, 443, 444, 446). The behavioral trait of reactivity to stress has been shown to predict the level of neurogenesis in the GCL of the DG (305). Two weeks after their behavioral characterization, rats were injected with BrdU (3 50 mg/kg spaced by 4-h intervals) and killed the next day or 14 days later. Cell proliferation was found to be negatively correlated with locomotor reactivity to novelty, and when the group was split according to the median behavioral score into LRs and HRs, cell proliferation in LRs was twice that observed in HRs. Survival of nascent neurons was not inuenced by this behavioral trait. A difference in the HPA axis reactivity most probably underlies the differences in neurogenesis, primarily due to differences in cell genesis. The functional signicance of this difference in DG plasticity remains unclear but may reect a disruption of behavioral inhibition in the HRs (187). 3. Perinatal manipulations Studies on stress during the perinatal period have also led to intriguing observations. It is well documented from animal and human studies that during the perinatal
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period the development of an organism is subjected to complex environmental inuences and that deleterious life events during development induce neurobiological and behavioral defects (207, 557, 569). Indeed, environmental changes and stimulations have the greatest impact when produced in the early stages of life and during developmental periods, leading to phenotypical orientations lasting throughout life. These environmental inuences, which have been evidenced for decades, have been explored at structural and mechanistic levels only recently, revealing profound structural changes in the HF (see, for instance, Ref. 353). Stressful events during the prenatal period, such as prenatal stress which consists in stressing pregnant dams, or during the postnatal period in the rat, as for example maternal deprivation, i.e., longlasting separations of the mum-pup dyad, alter brain chemistry, enhance emotional reactivity, produce cognitive impairments, and increase vulnerability to drugs of abuse (185, 482, 569). We and others have shown that stressful events during the prenatal (306) and the postnatal (300, 367, 431) periods downregulate hippocampal neurogenesis. In prenatally stressed rats, we found that cell proliferation (4 50 mg/kg of BrdU over 3 days) is reduced from adolescence to senescence, indicating an acceleration in the age-related decline of cell proliferation in the GCL. Survival of the newly born cells and neuronal differentiation (measured with NeuN) are not modied, and thus the net reduction in the number of adult-born neurons is associated with a decrease in the number of granule cells from adulthood to senescence. Given that corticosterone has been implicated in long-term behavioral changes induced by prenatal stress (280), this downregulation of neurogenesis may result from heightened corticosterone secretion (see sect. IID2A). Similarly, maternally deprived rats are characterized by reduced cell proliferation in the GCL both when infants (proliferation measured on postnatal day 21 following 7 days of maternal separation and 7 50 mg/kg BrdU) (300, 431) and when adults [proliferation measured at 23 mo of age following daily 3-h maternal separation bouts from postnatal day 1 to 14 and 1 200 mg/kg BrdU 2 h or 1 wk before death (367)]. In this recent study, the authors found that maternal deprivation reduced the number of immature, but not mature, neurons that are added to the DG in adulthood (367). Because maternal separation is reported to alter the activity of the HPA axis (482), it has been hypothesized that corticosterone mediates the effect of maternal separation on neurogenesis. In fact, it has been shown that the maternal separation-induced decrease in cell proliferation is abrogated by adrenalectomy plus corticosterone treatment aimed at restoring basal diurnal levels of the hormone. The authors proposed that hippocampal precursors might be hypersensitive to corticosterone, the diurnal basal and stress-induced levels of which are not modied in their paradigm (367). However,
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because maternal separation is known to decrease corticosteroid-binding globulin (559), and thus enhance the free, and active, fraction of corticosterone reaching the brain, a higher level of efcient hormone could be responsible for the effects of maternal separation on hippocampal cell proliferation. Given the involvement of the HF in learning and memory, we hypothesized that prenatal stress would lead to cognitive decits via an inhibition of neurogenesis in the DG. Thus we have shown that prenatal stress is associated with an alteration in learning and memory performances, and more importantly, that the learning-induced increase in cell proliferation observed in control animals is blocked in prenatally stressed rats (306). This result is in accordance with our previous observation that cell proliferation is increased only when the animals reach an asymptotic level of performance, i.e., when the task has been mastered (see sect. IIIA2A and Fig. 4). Furthermore, the behavioral decits induced by prenatal stress, similar to those observed in animals exposed to X-irradiations (37), conrm an enabling role for hippocampal neurogenesis in cognition. C. Aging and Longitudinal Observations 1. Neurobiology of the age-related decline in neurogenesis
A) INFLUENCE OF AGING ON NEUROGENESIS. Aging is a life-long process beginning with conception and ending with death. Within this developmental continuum, sexual maturity (23 mo in rodents) is used to dene the start of adulthood. Although the denition of how old is old varies depending on species, genetic background, and experimental conditions, studies addressing the effects of age on biobehavioral parameters in rodents have identied at least three ages: adult (up to 10 mo), middle-aged, and old or aged or senescent (from 20 mo) (91, 92). The persistence of neurogenesis in the DG of senescent rats was rst reported by Kaplan and Bell (248, 250, 251). An age-related decline in DG neurogenesis has been conrmed in mice and rats using several BrdU labeling protocols (54, 208, 290, 306, 310, 499), whereas conicting results have been reported for the SVZ (238, 253, 290, 543). The decline in DG neurogenesis, which mainly occurs between 2 and 12 mo of age, does not seem to be related to 1) an alteration in adult-born cell survival as the percentage of surviving BrdU-labeled cells 1 mo after their birth is independent of the age of the animals (54, 208, 269, 310) or 2) a general change in metabolic conditions, as neuronal precursors respond to BDNFs inuence to the same extent throughout life (169). Rather, it may be a decline in proliferative activity that
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underlies the age-related decline in neurogenesis, since the 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 be determined whether the reduction in proliferative activity is a consequence of a developmental lengthening of the cell cycle time and/or of a shrinking of the proliferative cell population. Finally, neuronal differentiation seems to be delayed with advancing age as suggested by the high percentage of cells that do not express a neuronal or an astrocytic phenotype 1 mo after their birth (54, 208, 264, 310, 391).
B) FACTORS REGULATING NEUROGENESIS IN THE SENESCENT BRAIN.
The progressive decline in cell proliferation could derive from inadequate local environmental cues; the aged DG may be under the inuence of inhibitory factors and/or may lack stimulatory factors that sustain division, differentiation, and/or survival of the newly born cells. I) Inhibitory factors. Corticosterone has received particular 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 after adrenalectomy in old rats, cell proliferation is upregulated in the GCL (373) and in the DG (GCL and hilus, Ref. 74). On the other hand, survival of the newly born cells is unrelated to corticosterone levels (373), and most of them differentiate into neurons expressing TOAD-64 or NeuN (74, 373). Glutamate is also known to inhibit DG neurogenesis in young rats (see sect. IID2B). Similarly, in middleaged and aged rats, a single injection of a NMDA receptor antagonist (CGP-43487, 5 mg/kg 2 h after an injection of BrdU, 200 mg/kg) increases hippocampal cell proliferation 5 days later. By 3 wk, despite a decline in the number of newly born cells, more cells survived in the treated aged rats compared with saline aged counterparts (391). II) Activating factors. The involvement of the neurosteroid Preg-S in the hippocampal neurogenesis of old rats has been examined. Indeed, 1) hippocampal levels of Preg-S in the HF of senescent rats correlate with spatial memory abilities, 2) intrahippocampal infusion of Preg-S in cognitively impaired aged rats reverses memory disturbances (551), and 3) Preg-S stimulates neurogenesis in the adult DG (see sect. IID2A). We have shown that icv Preg-S infusion increases cell proliferation in the senescent DG (348). This suggests that the age-related decrease in Preg-S levels could lead to a loss of stimulation of hippocampal neurogenesis and to subsequent cognitive decits. Finally, because Preg-S acts as a negative allosteric modulator of GABAA receptors, our results support the inhibitory hypothesis of neurodegenerative disorders
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such as Alzheimers disease and age-related brain impairments, which postulates the involvement of abnormally strong inhibitory GABAergic transmission (341). Because adult neurogenesis can be enhanced by the administration of growth factors (see sect. IID2C), the responsiveness of the aged brain has been the subject of investigation. In particular, a stimulatory effect of IGF-I has been examined since 1) IGF-I brain levels decrease with age (90), 2) IGF-I receptor mRNA is upregulated as a function of aging and cognitive decline (522), and 3) IGF-I infusion improves cognitive function in aged rats (345). The chronic icv administration of IGF-I (1.2 g/day for 14 days) in senescent rats elicits an approximately threefold increase in BrdU-labeled cells (BrdU, 2 50 mg kg1 day1 on days 711) in the SGZ and the hilus (310). In a 4-wk survival study, IGF-I and saline-treated animals displayed a similar number of newly born cells (BrdU-labeled on days 711) compared with animals killed after a short survival delay, indicating that IGF-I acts on cell proliferation rather than on cell survival. Finally, in contrast to what was observed in adult rats (1), IGF-I did not modify cell fate in old animals, with 20% of newly born cells differentiating into neurons (inferred from NeuN expression). Thus the threefold increase in BrdU-positive cells elicited by IGF-I translated into a threefold increase in adult-born neurons. The inuences of FGF-2 and HB-EGF were also examined in 20-mo-old mice (icv infusion of 10 g/ml for 3 days concurrent with 50 mg kg1 day1 BrdU). One week after the cessation of the treatments, the number of newly 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 that proinammatory 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 of age-related cognitive disorders in humans (59, 120, 328, 355, 466, 565), 2) chronic stress increases its production in aged patients (272), 3) IL-6 expression is increased in the HF of senescence-accelerated mice (539), and 4) hippocampal neurogenesis is reduced in adult transgenic mice with chronic IL-6 production (552) or after administration of bacterial lipopolysaccharide, a potent activator of IL-6 (138, 372). In summary, precursors that are able to enter the cell cycle are still present in the aged brain, and low levels of neurogenesis are linked to the accumulation of inhibitory substances and/or the decrement of stimulatory factors. The mechanisms of action of these modulators are still unknown and, in particular, it remains to be determined whether they act on the length of the cell cycle or on the number of dividing cells. Whatever the underlying mechanism, these results point to possible pharmacological actions for preventing or treating age-related cognitive impairments.
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2. Functional implications of age-related modulation of neurogenesis in memory The hypothesis that the decline in neurogenesis may be responsible for age-related alteration in cognitive function has been tested by examining the inuence of an enriched environment, and by taking advantage of the existence of interindividual differences in age-related cognitive functions. The inuence of enriched environments on spatial memory and on neurogenesis (cell proliferation, cell survival, and neuronal differentiation) has been studied in 18-mo-old mice (269). Although the effects are not as strong as those observed in young animals, after 68 days of enrichment, neuronal differentiation is enhanced whereas cell proliferation and cell survival remain unchanged compared with nonenriched aged animals; performances in spatial memory are slightly improved. A similar conclusion was reached when middle-aged female mice 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 enriched environment in old subjects does not afford any further benecial effect compared with short-term exposure as neither cell proliferation nor cell survival are increased. In this study, the improvement in learning parameters observed after enrichment was suggested to be aspecic, resulting from better adaptive skills in exploration, greater locomotor aptitude, and endurance following enrichment, leading the authors to suggest that the contribution of adult hippocampal neurogenesis to hippocampal plasticity might require a physically active pursuit as opposed 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, whereas others present spatial memory impairments (457). The existence of such individual differences has been used as a naturalistic strategy to study the neurobiological correlates of cognitive aging, and it has been shown that the extent of memory dysfunction is related to the magnitude of changes occurring in the HF. Following a characteriza-
tion of the cognitive abilities of aged rats in the water maze, we have shown (Fig. 6) that neurogenesis (i.e., cell proliferation, cell determination, and cell survival) is higher in cognitively unimpaired rats than in impaired ones (130). Because age-impaired and -unimpaired rats did not differ in granule cell number, as previously described (458), it seems that the rejuvenation of granule cells rather than a change in their absolute number is the main factor sustaining memory formation. In other words, successful aging, i.e., preserved cognitive functions, is associated with the maintenance of a relatively high neurogenesis level, whereas pathological aging, i.e., memory decits, is linked to exhaustion of neurogenesis. These differences in hippocampal neurogenesis may be due to differences in stimulatory and/or inhibitory substances, which may respectively prevent or accelerate pathological aging. We propose that the age-related increase in corticosterone levels, resulting from repeated stressful events, may lead, through life-span inhibition of neurogenesis, to defects in hippocampal networks that would be responsible for cognitive dysfunctions. The observation that lowering corticosterone levels in middle-aged animals signicantly increases hippocampal neurogenesis and postpones the onset of spatial memory decits supports this 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 hippocampal neurogenesis most probably mirror a more general failure 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 with impaired cognitive function (64) and are decreased in aged mice housed in an enriched environment (264). According to the hypothesis of the Red Queen Theory (5), during aging there is competition for the available plasticity to compensate for neuronal degeneration or to store new information. Thus, in pathological aging, hippocampal plasticity is exhausted, and the capacity of the old
FIG. 6. Hippocampal neurogenesis depends on the cognitive status of the aged rats. To demonstrate a quantitative correlation between neurogenesis and performance in a hippocampal-dependent test, we took advantage of the well-established presence of individual differences in spatial memory abilities within a population of old rats. Indeed, in the water maze, some old individuals show clear impairment in spatial reference memory while others are not impaired and exhibit cognitive capacities similar to those of younger individuals. We found that cell proliferation (A), the survival of adult-born cells (B), and the number of adult-born neurons (C) are higher in the dentate gyrus of aged unimpaired (AU) than aged impaired rats (AI). *P 0.05, **P 0.01 compared with AU. [Modied from Drapeau et al. (130).]
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brain to acquire new information and to compensate for ongoing degenerating processes is impeded. D. Involvement of Neurogenesis in Pathologies 1. Pathological conditions associated with an upregulation of neurogenesis
A) EPILEPSY. Human temporal lobe epilepsy (TLE) is associated with atrophy of the HF, an effect known since the beginning of the 19th century, and a loss of hippocampal and DG neurons (57, 384). In this pathology, the dentate granule cells give rise to abnormal axonal projection into the supragranular inner molecular layer of the DG and to an aberrant reorganization of the mossy bers (MF) in the CA3 subeld of Ammons horn (529). It has been suggested that the sprouting of MF is relevant in the hyperexcitability of the TLE (426). This has led to investigation into whether newly born cells are important in the genesis of dentate MF sprouting (MFS) and participate in the reorganization of the network. Kindling, an animal model of TLE, is characterized by a permanent epileptic state produced by a series of seizures induced by electrical stimulations made in various brain areas such as the hippocampus (42), the perforant path (396), and the amygdala (425, 492). Single and repeated kindling stimulations in the ventral CA1 region induce a facilitation of mitotic activity 2 wk later (42). Stimulation in the perforant pathway leads to a marked increase in the number of BrdU-labeled cells as early as 3 days after the last stimulation, whereas repeated kindling does not evoke further stimulation of cell proliferation (396). Cell division is in fact suppressed, suggesting a diminished efciency of repeated or prolonged stimulation to elicit a neurogenic response. In the amygdala kindling model, it has been reported that during the early phases of kindling, when focal seizures are present, DG cell proliferation remains unchanged, whereas it is upregulated during the later phase of kindling, when motor seizures are present (425, 492). In various chemoconvulsant (pilocarpine or kainate) models of human TLE, the induction of seizures is accompanied by a dramatic increase in neurogenesis in the SGZ of the DG (430). This increase is observed after a latent period of a few days following the status epilepticus (SE) and persists during the rst week, before levels of neurogenesis return to baseline over the following weeks (396, 430). The recruitment of proliferative cells after kainate treatment occurs preferentially in GFAP cells, suggesting an increase in proliferative glial-like astrocytes (type B) (223). The expression patterns of multiple bHLH transcription factors have been studied following epileptogenesis; some were found to be increased (Mash1, Id2), some decreased (Hes5), and others unchanged (NeuroD, NeuroD2, Id3, and Math2), suggesting that molecules control-
ling cell-fate decisions in the developing dentate gyrus are also operative during seizure-induced neurogenesis (140). The newly born cells induced by seizures, which survive for up to 4 wk and differentiate into neurons (430), migrate to abnormal locations such as the CA3 cell layer, the dentate hilus and inner molecular layer (108, 430, 487). These ectopic granulelike neurons retain many, but not all, of their granule cell intrinsic properties (487). Incidentally, ectopic locations of SVZ-derived neuroblasts have also been observed in the striatum and the cortex following pilocarpine treatment (428). Seizure-induced neurogenesis appears to precede MFS, suggesting that newly born cells could be important in the genesis of the ectopic innervation of Ammons horn by dentate bers. This hypothesis has been tested by coadministrating kainate or pilocarpine with cycloheximide (CHX), a protein synthesis inhibitor known to abolish MFS (40). Contrary to what was expected, CHX did not inuence chemoconvulsant-induced neurogenesis, indicating that its effect on MFS is independent of cell proliferation (97). Similarly, a single session of X-ray treatment, which attenuates pilocarpine-induced neurogenesis, fails to prevent MFS (427), indicating that neurogenesis upregulation is not sufcient to generate MFS. Thus the participation of the newly born cells in network reorganization and in the recurrence of epileptic seizure is still open to debate. The mechanisms by which seizure activity stimulates neurogenesis are unknown. They may involve electrical activation since 1) physiological activity such as LTPelicited mossy ber stimulation is sufcient to increase neurogenesis in the DG (118), and 2) pure electrical activation, consisting in a continuous stimulation of the perforant path, elicits focal hippocampal seizure discharges and increases BrdU cell number 6 days later (430). Seizure-induced upregulation of neurogenesis may also involve 1) an alteration in excitatory amino acid transmission due to degeneration of the entorhinal afferences to the granule neurons of the DG (430); 2) activation by the dying cells (42, 50); 3) a change in bFGF, as kainateinduced upregulation of neurogenesis is blocked in mice lacking bFGF, an effect reversed by gene transfer (582); 4) changes in other neurotrophic factors (145, 164, 172, 583); and 5) activation of the 5-HT1A receptor as infusions of a 5-HT1A receptor antagonist (WAY-100,635) impede the increase in pilocarpine-induced neurogenesis whereas cell death, MF sprouting, and the onset of spontaneously recurring seizure are not prevented (451). In summary, neurogenesis is altered by epileptiform status, and surprisingly maintenance of the newly born cells (in homotypic and ectopic locations) is systematically observed in the different models of epilepsy. The abnormal circuits may contribute to the unstable hippocampal circuitry and the development of chronic TLE. As proposed by Gray and Sundstrom (188), the DG could
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regulate as a gate with respect to controlling the propagation of seizure with granule cells controlling the throughput of epileptiform activity transition through the HF by virtue of a feed forward inhibitory pathway. These alterations in neurogenesis may participate in the memory dysfunction associated with epilepsy (530). Although unveried, this latter nding suggests that the presence of more new neurons is not necessarily associated with a good memory and that neurogenesis and memory function may follow an inverted U-shaped curve. B) ISCHEMIA. Until recently it was thought that the functional recovery that occurs in some cases following brain damage (such as stroke and trauma, see sect. IIID1D) was related to the remodeling of neuronal pathways in nondamaged areas. The discovery of adult neurogenesis prompted researchers to investigate the role played by new neurons in recovery of lost functions. Transient global ischemia, induced in gerbils and rats by bilateral common carotid artery occlusions, increases cell proliferation in the DG in a dose-dependent manner (260, 315, 575, 576). A peak in cell proliferation occurs 12 wk after ischemia, and a quarter of the newly generated cells die during the rst month (315). During the rst 2 wk after their birth, the newly born cells transiently express NeuroD and DCX (258). Those cells that survive differentiate into granule neurons expressing NeuN or MAP2 at 1 mo of age (258, 315). They acquire functional features of mature neurons as NMDA stimulation induces the phosphorylation of ERK in 34 and 61% of BrdU-NeuN labeled cells of 1 and 2 mo of age, respectively (258). After focal cerebral ischemia, induced by unilateral middle cerebral artery occlusion (MCAO) (24, 237, 589, 590), cell genesis is increased to various degrees in the ipsilateral DG (as well as in the SVZ, OB, and cortex) over a period of several weeks. Increased BrdU incorporation in the DG (as in the others structures) contralateral to the infarct, occurring following a lapse of a few days, suggests a role for diffusible or humoral factors (237, 534). The newly born cells differentiate into granule neurons without any apparent degeneration (590). The enhancement of BrdU-labeled cells in the OB and the cortex has been attributed to the migration of neuronal precursors from the SVZ towards their normal target or towards the infarct, respectively (588). The presence of cell clusters in cortical areas, in the vicinity of blood vessels, also suggests the recruitment of resident quiescent stemlike cells or the inltration of blood-borne cells (589). New cells arising from the SVZ also colonize the striatum after ischemia, 20% of which survive (representing 0.2% of the cell loss) and assume the phenotype of cells lost due to the lesion (24, 239, 429). Neurogenesis upregulation in the DG has been attributed to cell death in the entorhinal cortex or the CA1 region (46), a hypothesis not always veried (25, 315). It has been proposed that the neuronal damage that follows
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ischemia involves the release of glutamate and overstimulation of glutamate receptors, which in turn upregulates neurogenesis. Indeed, the blockade of NMDA or AMPA/ kainate glutamate receptors by specic antagonists (MK801; NBQX) inhibits the stroke-induced increase in neurogenesis (25, 46); however, these effects are surprising in light of the stimulatory inuence of glutamate receptor blockade on neurogenesis in control brains (see sect. IID2B). Mitotic factors such as bFGF are certainly involved as ischemia-induced upregulation of neurogenesis is blocked in mice genetically decient in bFGF (582) and is increased following adenovirally mediated transfer of bFGF (347). Chronic icv infusions of bFGF and EGF greatly enhance the potential of endogenous progenitors to proliferate in response to ischemia and the cells then regenerate CA1 pyramidal neurons. The regenerated neurons are integrated into the neural circuitry as they receive afferences, project onto their normal target, the subiculum, and reverse the ischemia-induced decits in cognitive functions (399). This constitutes the most impressive example of network reconstruction leading to behavioral recovery that takes advantage of adult endogenous neurogenesis. Infusion of VEGF (0.54 g/day on days 13 of reperfusion concurrent with 2 50 mg kg1 day1 BrdU) increases the number of adult-born cells 1 mo (and not 3 days) after labeling, beyond the increase caused by ischemia (526). Ischemia-induced cell proliferation, measured within 3 wk post-BrdU pulse (2 50 mg kg1 day1 BrdU injected for 6 days starting 1 day after MCAO), is also increased by icv infusion of IGF-I and glial-derived neurotrophic factor (117). Modulation of cell birth by ischemia also involves the production of several classes of inammatory molecule metabolites. Administration of inhibitors of cyclooxygenase (Cox; i.e., acetylsalicylic acid, indomethacin, NS398), the rate-limiting enzyme for prostaglandin synthesis, curtails ischemia-induced proliferation after transient global ischemia in adult gerbils or rats (293, 485, 547). Mutation of one of the Cox isoenzymes, Cox-2, suppresses the ischemia-induced increase in hippocampal cell proliferation (485). Cox-2 may affect neurogenesis through the production of prostaglandin E2 (547), which may act directly via prostaglandin EP3 receptors expressed in the GCL (397) or indirectly through bFGF (477). Alternatively, the production of NO, a key factor in inammation, may be at play as administration of a NO donor (DETA/ NONOate) to rats subjected to MCAO signicantly increases cell proliferation in the SVZ and the DG, and signicantly improves neurological recovery (587). This enhanced neurogenesis is certainly associated with the activation of inducible NOS since its inhibition (by aminoguanidine) prevents ischemia-induced neurogenesis. Furthermore, stroke-induced neurogenesis is abolished in mice lacking the iNOS gene (590). The participation of
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leukotrienes, another key class of inammatory molecules, has been postulated in cell proliferation induced by stroke (340). Finally, factors produced as part of the ischemia-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 after ischemia. In summary, enhancement of neurogenesis in the DG and other brain regions may compensate for disconnected circuits that occur after ischemia and contribute to the improvement of functional outcome. Exploiting this plasticity potential of the ischemic brain may provide a possible strategy for enhancing recovery in patients suffering from this injury. C) HUNTINGTONS DISEASE. Huntingtons disease (HD) is a neurodegenerative disease that leads to neuronal loss in the caudate-putamen. The discovery of progenitor cells in the human brain (144) has raised the possibility that progenitors from the SVZ may provide a source of replacement. Postmortem analysis of control and HD human brains has revealed that cell proliferation, evaluated with PCNA, is increased in the subependymal layer in HD brains as a function of the severity of the illness (103). The newly generated cells expressed neuronal and glial markers (Tuj1 and GFAP, respectively). These pioneer data indicate that the diseased adult brain is still capable of neuronal regeneration, which opens new avenues in the treatment of neurodegenerative diseases. D) OTHER TYPES OF CEREBRAL INJURY. Traumatic brain injury (TBI), the most common cause of death in developed countries, increases cell proliferation in the SGZ (as well as in the SVZ and the cortex; Refs. 107, 319, 459). The number of newly born cells increases as early as 24 h post-TBI; the cells accumulate over time and express TOAD-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 day after TBI) to rats subjected to TBI signicantly increases proliferation, survival, migration, and differentiation of neural progenitors in the DG (as well as other brain structures) and signicantly improves neurological functional outcome (319). 2. Pathologies associated with a downregulation of neurogenesis
A) AFFECTIVE DISORDERS. In unipolar major depression, bipolar mood disorders, and other chronic diseases associated with affective disorders [posttraumatic stress disorder (PTSD), Cushings disease], brain imaging studies have consistently described hippocampal atrophy (60, 195, 329, 504, 518, 519, 550). Although a role for neuro-
genesis in mood disorders is speculative, it has been suggested that a fall in neurogenesis in the DG contributes, together with atrophy and death of hippocampal neurons, to hippocampal attrition. I) Antidepressants. It has been suggested that biogenic amine deciency underlies mood disorders, and indeed, treatments increasing extracellular levels of serotonin or norepinephrine are effective in the remediation of depressive symptoms. Because serotonin and norepinephrine stimulate cell genesis (see sect. IID2B and Table 1), and given that it takes weeks for antidepressants to take effect, it has been proposed that they may exert their action via a remodeling of neuronal networks by promoting either neurogenesis or the survival of hippocampal neurons believed to be endangered (131). Chronic (and not acute) treatments with different classes of antidepressants such as a selective serotonin reuptake inhibitor (uoxetine, 5 or 10 mg kg1 day1 for 1128 days), a selective norepinephrine reuptake inhibitor (reboxetine, mg kg1 day1 for 21 days), a monoamine oxidase inhibitor (tranylcypromine, 7.5 mg kg1 day1 the rst week and 10 mg kg1 day1 the second week), and tricyclic antidepressants (TCAs, imipramine and desipramine: 20 mg kg1 day1 for 28 days) increase hippocampal cell proliferation evaluated 2 or 24 h after the last BrdU pulse (1 75 mg/kg or 4 75 mg/kg every 2 h) performed on the nal day or 4 days after the treatment (335, 483). Three weeks after labeling, most of the newly born cells express NeuN (70%), independently of the classes of antidepressants (335, 483). It was further shown that a uoxetine- but not an imipramine-induced increase in cell proliferation is mediated by 5HT1A receptors, since it is abolished in mice lacking 5HT1A receptors (483). To determine effects of uoxetine on cell survival, BrdU (4 75 mg/kg spaced by 2 h) was administered before intitiation of the chronic treatment (5 mg/kg for 14 days). Neither survival nor maturation of the cells, evaluated 28 days after the last BrdU injection, was inuenced by uoxetine treatment (335). The preclinical contribution of hippocampal neurogenesis has been examined in the learned helplessness paradigm, a classical animal model for depression, and it was reported that inescapable stress induced a decrease in cell proliferation that was reversed, together with behavioral despair, by a 7-day course of uoxetine (10 mg/kg) (334). A strongest link between depression and neurogenesis was evidenced following X-irradiation that blocked the effects of uoxetine and 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 genetic vulnerability, several lines of evidence suggest that stress-induced cellular changes in the adult HF, mediated
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by an upregulation of the HPA axis, contribute to the pathophysiology of these disorders, at least in animal models. The impact of antidepressants on neurogenesis was therefore tested in various stress models. In adult male tree shrews exposed to chronic psychosocial stress (see sect. IIIB1), chronic treatment with tianeptine (50 mg kg1 day1 for 28 days), a modied TCA, reversed the stress-induced decline in hippocampal volume, hippocampal activity, and hippocampal neurogenesis (104). In rat pups, uoxetine treatment (5 mg/kg for 7 days concurrent with 50 mg/kg BrdU) counteracted the downregulation of cell proliferation observed in the DG of 2-wk-old maternally separated pups (300). In a chronic mild stress model (CMS; see sect. IIIB1), chronic treatment with the antidepressant uoxetine (10 mg/kg for 28 days starting 3 wk after the beginning of the CMS) reversed the stress-induced reduction of cell proliferation and prevented the stress-induced reduction of neurogenesis and hippocampal atrophy (10). II) Electroconvulsive therapy. Electroconvulsive therapy (ECT) is one of the most effective treatments for major depression, especially in subjects who do not respond to antidepressants, but its mechanisms of action remain largely unknown. Electroconvulsive seizure (ECS) differs from kindling and chemoconvulsant treatments in that it does not lead to an epileptiform state and does not cause cell death. ECS (one daily for 10 days) enhances (2 or 24 h after a BrdU pulse) cell proliferation in the DG, and the newly born cells survive for at least 3 mo, a time point when most of them express NeuN (75%) and few GFAP (13%) (331, 335). This proliferative effect is dosedependent as a series of seizures further increases neurogenesis (331). The neurogenic efcacy of ECS has been investigated in conditions mimicking stress-induced depression, i.e., in animals with high corticosterone levels. The downregulation of neurogenesis (75%) in the GCL of rats chronically treated with corticosterone was eliminated by ECS performed at the end of the treatment (212). Because ECS upregulates several factors described as stimulating neurogenesis, such as bFGF, neuropeptide Y, VEGF, BDNF, and Cox-2 (404, 406), these factors are likely mediators of the proliferative effect of ECS. Among them, BDNF deserves special mention as ECS-induced MFS is diminished in BDNF knockout mice (549). III) Mood stabilizers. Chronic treatment with lithium can reverse the hippocampal attrition in sufferers of manicdepressive illness (MDI) and enhance the levels of Nacetylaspartate, 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 BrdUlabeled cells by 25% 1 day after BrdU treatment (1 50 mg/kg over 12 days), two-thirds of which coexpress NeuN. Interestingly, the expression of bcl-2, an antiapoptotic regulator, is also increased suggesting that survival of the newly born neurons might be enhanced (84).
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IV) Summary. These results suggest that antidepressants, ECT, and mood stabilizers may exert some of their therapeutic effects on mood disorders by stimulating neurogenesis. They also suggest that alternative strategies for stimulating neurogenesis may provide new avenues for the treatment of mood disorders. Since a fall in neurogenesis has been associated with an alteration in cognitive functions, further studies are needed to clarify the involvement of neurogenesis, and hippocampal function, in the development of cognitive decits observed in depression in young and elderly patients. B) SCHIZOPHRENIA AND NEUROLEPTICS. Developmental dysfunction of the HF is thought to play a major role in the pathogenesis of schizophrenia (206, 488), and defects such as a reduction in hippocampal volume (53, 400, 558), hippocampal shape deformations (101), abnormalities in the GCL (357), the MF pathway (170), the hippocampal cell density (41, 150, 233) and orientation (93, 288), and in several cellular markers (203, 313) have been reported. These changes are believed to underlie the progressive decit in cognition that is a hallmark of schizophrenia. Interestingly, models of aberrant neurogenesis (prenatal stress, X-rays, or MAM manipulations) are thought to reproduce some of the behavioral characteristics associated with schizophrenia (313). The inuence on neurogenesis of chronic treatment with the typical neuroleptic haloperidol, a mainstay in the treatment of schizophrenia, has been evaluated, leading to controversial results. Indeed, haloperidol has been shown to increase (110) or to have no effect (199, 335, 483, 562) on neurogenesis in the rodent DG. Differences in dosage, time course of drug treatment, species and age of the animals, and BrdU labeling protocol could account for the observed discrepancy. On the other hand, chronic treatment with atypical neuroleptics such as risperidone (0.5 mg kg1 day1 for 21 days) or olanzapine (2 mg kg1 day1 for 21 days) increases cell proliferation (24 h after 1 100 mg/kg BrdU on the 20th day of neuroleptic treatment) in the SVZ but not in the DG (562). A low dose of clozapine (0.5 mg kg1 day1 for 4 wk before a single injection of BrdU at 200 mg/kg) enhances the number of BrdU-IR cells in the DG; however, this effect is transient as the newly born cells do not survive 3 wk after labeling. Although these data clearly show that further work is required to sort out discrepancies in results, they also suggest that schizophrenia may be associated with reduced neurogenesis in the DG, where normal levels could be reestablished by neuroleptic treatment, a hypothesis that awaits conrmation. C) ADDICTION TO DRUGS OF ABUSE. Long-term neuroadaptive changes in the mesolimbic dopaminergic system have classically been observed in drug abuse (283, 402). A potential role of the HF in addiction has been suggested based on the observation that both a reduction in hippocampal volume and structural abnormalities are obwww.prv.org
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served in patients with chronic alcoholism (4, 112, 357, 524) and in psychostimulant addicts (33). In animals, chronic treatment with different drugs of abuse leads to structural changes in the HF (308, 432, 461, 463), to cell loss (563), and to LTP alterations (109, 158, 191, 200, 202, 449). The possible involvement of the HF in addiction is supported by the observation that 1) inhibiting the activity of the calcium/calmodulin-dependent protein kinase II impairs drug conditioning (321, 535) and attenuates the dependence on morphine and relapse (321), 2) dorsal hippocampal lesions disrupt acquisition of cocaine conditioning (365), 3) electrical stimulation of the glutamatergic efferent pathway of the HF to the nucleus accumbens reinstates cocaine-seeking behavior (561) and Damphetamine self-administration behavior (533), and 4) inactivation of the ventral subiculum decreases reinstatement of cocaine-seeking behavior (525). These results suggest that memory traces of the association between a specic context and the availability of the drug could be stored in the HF, and the hypothesis that drug addiction is an aberrant form of learning mediated by maladaptive recruitments of hippocampal-dependent memory system has recently gained interest (45, 147, 401, 462, 571). In this context, the involvement of neurogenesis in addiction has been studied by examining the inuence of several drugs of abuse on adult hippocampal neurogenesis and by comparing neurogenesis in animals that differ in their vulnerability to developing drug abuse. I) Opiates. Among the multiple actions of opiates in the brain, their inuence on cognition and reward is without a doubt the most relevant parameter with regard to opiate addiction. Eisch et al. (137) were the rst to demonstrate that the exogenous chronic (daily implantation of subcutaneous pellets containing 75 mg morphine during 5 days) and not acute (10 mg/kg) administration of morphine decreases cell proliferation in the GCL by 28% (measured 2 h after an injection of BrdU, 100 mg/kg, on day 6). When cells are allowed to mature for 4 wk, survival of BrdU-labeled cells is halved and 90% of the newly born cells differentiate into neurons. More relevant to addiction, the inuence of heroin self-administration has been investigated. After 26 days of heroin intake (60 g kg1 injection1), a downregulation of cell proliferation (30%) is observed in both the GCL and the hilus while cell death is unaffected. The downregulation of cell proliferation is independent of corticosterone secretion (137), a hormone known to have a major inuence in addiction (343). Finally, it was recently reported that in vitro reduced signaling through - and -opioid receptors present on adult hippocampal progenitors, although decreasing cell proliferation, leads to a net increase in the number of newly generated neurons (437). II) Nicotine. The neuroactive compound nicotine is considered to be responsible for the development and the maintenance of tobacco addiction. To analyze the effects
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of nicotine abuse on hippocampal neurogenesis, rats were trained to self-administer nicotine (0.02, 0.04, and 0.08 mg kg1 infusion1) for 42 days. A profound decrease in hippocampal cell proliferation was observed for the two highest doses of nicotine 1 day after BrdU pulse (4 50 mg/kg on days 39 41). This effect is not simply due to a difference in blood ow leading to a decrease in BrdU availability, since nicotine intake does not affect cell proliferation in the SVZ. Half of the newly born cells in the DG were found to express NeuN. In parallel with the decrease in cell proliferation, cell death, measured by the number of pyknotic cells, was increased by the two highest nicotine doses (3). Similar results were obtained following imposed administration of nicotine (1 mg kg1 day1 for 3 days concurrent with 50 mg/kg BrdU) to adolescent rats (230). Although the mechanisms involved in the effects of nicotine have not yet been investigated, nicotine could act directly on nicotinic acetylcholine receptors that are present on immortalized hippocampal progenitor cells (44), or indirectly through an upregulation of the HPA axis (67) and/or a downregulation of the serotoninergic system (43). III) Alcohol. The possibility that alcohol brings about damage in the adult brain by disrupting neurogenesis has been examined. Thus both acute (gavage with 5 g/kg ethanol) and chronic (ethanol infusion 3 times/day over 4 days for a mean dose of 9.3 g kg1 day1) binge alcohol treatments halve cell proliferation in the SGZ of the DG within 5 h (409). Furthermore, after 28 days, chronic binge treatment decreases the survival rate of the newly born cells (409). In contrast, in animals fed for 6 wk with a moderate dose of ethanol (6.4% vol/vol), the number of newly born cells (labeled by 7 BrdU injections at 2-h intervals) is not reduced when animals are killed 1 h after the last BrdU injection (218). In fact, the number of nascent cells decreases only after 2 wk suggesting that, in this experimental model, cell survival, rather than cell proliferation, is affected by ethanol exposure, a hypothesis that was conrmed by showing that cell death was dramatically increased in the DG. Finally, these effects are specic to the DG as bulbar neurogenesis is not inuenced by chronic alcoholism. Similar results were obtained with imposed injections of alcohol to adolescent rats (1 mg kg1 day1 for 3 days concurrent with 50 mg kg1 day1 BrdU), which led to a downregulation of hippocampal cell proliferation and increased cell death (230). Furthermore, coadministration of alcohol with nicotine reduces cell proliferation and cell death more potently than treatment with either one of the agents (230). Although these effects of ethanol could be mediated by NMDA or GABAA receptors (224), oxidative stress might also play a role since the antioxidant ebselen, used in the treatment of cognitive disorders of alcoholic patients, prevents ethanol effects on hippocampal neurogenesis (218).
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IV) Cannabinoid. Derivatives of cannabis sativa such as marijuana are acknowledged to be the most commonly used illicit drugs (336). The structure of their active components, the cannabinoids, the identication in the brain of the cannabinoid-1 (CB1) receptors, and the isolation of an endogenous substance acting on these receptors, the endocannabinoid anandamide, have been reported only recently. It has been suggested that the CB1 receptors that are expressed in the HF by the GABAergic interneurons are important in learning and memory (109). Chronic treatment with anandamide (5 mg kg1 day1 for 4 days) inhibits neurogenesis in the DG by decreasing the number of newly born cells that differentiate into granule neurons 12 days after the cessation of the treatment (100 mg/kg BrdU on day 2). Conversely, blocking the endogenous cannabinoid tone with SR14716 (1 mg kg1 day1 together with anandamide), an antagonist of the CB1 receptors, increases hippocampal neurogenesis by favoring neuronal differentiation (476). These effects are in accordance with a potentiality to modulate neural cell fate (197) in particular through the ERK signaling pathway (476). In addition to showing that endocannabinoids constitute a physiological system regulating neurogenesis, these data raise the possibility that cannabinoid addiction could be associated with an alteration in hippocampal neurogenesis. V) Neurogenesis as a substrate for vulnerability to addiction. The high responder rats (see sect. IIIB2) and the prenatally stressed rats (see sect. IIIB3) characterized by curtailed neurogenesis share some similarities that are relevant to drug addiction. Indeed, the HRs spontaneously develop amphetamine (443, 445) or nicotine (528) selfadministration behavior, and prenatally stressed rats exhibit greater sensitivity to the psychomotor-stimulant effects of nicotine (279) and amphetamine (215) and are more vulnerable to drug addictive effects as they develop intravenous amphetamine self-administration (116). Thus subjects starting off with the lowest neurogenesis may be most vulnerable to the development of addictive behavior. It is noteworthy that there is high comorbidity between drug abuse and many psychiatric illness, among which depression and schizophrenia (34, 152). Because hippocampal neurogenesis is reduced in preclinical models of these pathologies, it may be hypothesized that impaired hippocampal neurogenesis may constitute a potential substrate for vulnerability to drug abuse, depression, and schizophrenia (see also Fig. 8). VI) Conclusions. The downregulation of hippocampal neurogenesis, together with other maladaptive plasticity processes, i.e., dendritic remodeling and synaptic plasticity modications, are associated with permanent functional alterations in behavioral inhibition and learning, hallmarks of addiction. An alteration in hippocampal plasticity could be responsible for the cognitive decits that appear in the course of the illness (88, 109, 133, 194)
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or during drug withdrawal (211). Because drug-seeking and -taking behaviors are sensitive to the presence of drug-associated stimuli (contextual cues), initially low hippocampal plasticity and a drug-induced decrease in hippocampal plasticity may be involved in the vulnerability and the maintenance of drug abuse. Changes in hippocampal activity could lead to a dysregulation of the dopaminergic mesoaccumbens reward system (283, 402) through the hippocampal glutamatergic output that gates information in the nucleus accumbens (173) and/or through the hippocampal glutamatergic output to the mesencephalic dopaminergic cell bodies. Indeed, stimulation of the ventral subiculum increases the ring of dopaminergic neurons (51) and enhances dopamine release within the nucleus accumbens (302). Finally, drugtaking in subjects vulnerable to drug addiction most probably further increases corticosterone secretion, stimulates the dopaminergic reward system, and decreases hippocampal neurogenesis, thereby constituting a pathophysiological loop. IV. CONCLUSION The discovery of neoneurogenesis in discrete areas of the adult brain has opened up an extremely interesting eld of research in itself. Indeed, although it was initially confronted with the universal belief that after a certain period of development neither neural cell genesis nor divisions were any longer possible, it now constitutes a prototypic model of developmental neuroscience. The study of the mechanisms that preside over cell proliferation, migration, differentiation, and survival is essentially performed in the SVZ-OB paradigm as these phenomena occur in distinct compartments (cell proliferation in the SVZ, migration in the RMS, differentiation in the OB) thus rendering their analysis easier. However, the evaluation of their behavioral consequences is most frequently examined in relation to the HF (with the exception of Ref. 464). To conclude, the main issues raised by neurogenesis are as follows. 1) From a cellular point of view, a true characterization, and thus denition of stemlike and progenitor cells in the adult brain is still lacking. Although immense progress has been achieved in the description of different cell types (and their properties) in the SVZ, no consensus has been reached. Furthermore, although it has been suggested that adult neural stemlike cells could behave similarly to embryonic stem cells as far as the generation of neurons and differentiation into any neuronal type are concerned, little is known regarding their intrinsic properties and the nature of the signals that lead to the generation of neurons in the adult brain. It is expected that functional genomic technologies may help in dening the
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transcriptional program of neural progenitors and the changes in gene expression in progenitors over time (105, 323). 2) Future studies will have to better characterize the early development of adult-born neurons to dissect the steps that are inuenced by experience and vulnerable to traumatic conditions (stress, drug, epilepsy. . .). This raises the problem of tracking the fate of adult-born cells using BrdU, [3H]dT, or a retrovirus, which may alter the functioning of the adult-born neurons under investigation. 3) Undoubtedly one of the most interesting sets of data accumulated concerns the factors that powerfully regulate neurogenesis. However, the mechanisms by which these regulations are exerted in the normal and pathological brain remain obscure. 4) Although most work is focused on the generation of glutamatergic excitatory granule neurons in the adult DG, the recent discovery that GABAergic inhibitory neurons are also produced raises the important possibility that external factors (from molecules to modications in animals environments) might diversely affect the genesis of either type of neurons and thus have distinct functional consequences. 5) Functional studies are too often restricted to the evaluation of a single parameter; they should be extended to the different components of neurogenesis (basal neu-
rogenesis and experimentally induced cell proliferation, cell death, and cell survival) and to other parameters related to the anatomical (e.g., the presence of synaptic contacts) and functional (electrophysiological properties, ERK phosphorylation, immediate early gene activation . . .) integration of new neurons into the preexisting networks. Finally, the contribution of newly born neurons to the functioning of the HF and its output should be evaluated as well as their inuence on the activity of other related structures (e.g., the frontal cortex). 6) Functional evaluation of hippocampal neurogenesis has, in fact, been the object of relatively few studies that have been restricted to a limited number of behavioral tasks (mainly the Morris water maze). A more complete diversied behavioral analysis is therefore necessary to understand the contribution of neurogenesis to hippocampal functioning. 7) Except for the elegant work of Shors et al. (509), which relies on the use of MAM which is unfortunately a highly toxic compound, most studies correlate changes in rates of neuron addition with behavioral changes, in particular cognitive functions. Thus it is not clear whether these changes are coincidental or coregulated. A more direct approach to address the existence of a causal relationship between behavioral changes and neurogenesis will probably depend on the development of inducible
FIG. 7. Variation of hippocampal functioning as a function of hippocampal neurogenesis and associated pathological states.
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FIG. 8. Is impaired neurogenesis a cause or a consequence of affective and cognitive disorders? Based on the reciprocal inuences of neurogenesis on affective and cognitive states, two models can be proposed. In the rst model, impairment in neurogenesis processes resulting from both genetic and environmental inuences would predispose the individual (vulnerable phenotype) to developing affective and cognitive disorders in response to environmental challenges. In the second model, genetic and environmental inuences may orient brain functions toward deleterious developments resulting in affective and cognitive disorders that would, in turn, impair the normal course of neurogenesis.
transgenic models allowing a structure-specic blockade of neurogenesis at a given time during behavioral testing. However, this approach is a real challenge since it is based on the invalidation of the crucial genes controlling neurogenesis site specically, which have not yet been identied. 8) From a phylogenetic point of view, the apparent reduction in neuropoiesis, when moving from rodents to primates, raises the question of the associated evolutionary advantage. 9) From studies that have correlated changes in rates of neuron addition with hippocampal functioning, an inverted U curve shape can be proposed (see Fig. 7). Thus adult neurogenesis may be benecial for adult brain functioning only within a physiological adaptive range. Beyond a critical level of neurogenesis, which is over passed by stressful life events, aging, and drug abuse, dysfunction appears. On the other hand, the addition of adult-born neurons above a critical set point (i.e., following epileptiform status) may lead to pathological states and behavioral impairments most probably by introducing noise in the networks, as a consequence of ectopic connectivity. 10) Within this framework, it is not known whether an alteration in neurogenesis is the cause or the result of psychiatric illness (Fig. 8). Indeed, in preclinical studies it has been shown that phenotypes vulnerable to the development of affective or cognitive disorders are characterized by lower hippocampal neurogenesis. It may be hypothesized that these subjects who start off with impaired neurogenesis may be predisposed to the development of affective disorders, addictive behavior, and age-related
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cognitive disorders. Alternatively, the onset of pathology could produce changes in brain plasticity by acting through several mechanisms (for example, stress and HPA activity are important mediators in the genesis of cognitive impairment, depression, addiction). Repeated traumatic episodes, together with a genetic predisposition, may lead to reduced neurogenesis and participate in the worsening of the symptoms. Although these propositions are highly speculative, they highlight the fact that treatments that increase neurogenesis may help to cure or prevent the development of affective and/or cognitive disorders.
Address for reprint requests and other correspondence: D. N. Abrous, INSERM U588, Univ. of Bordeaux 2, Institut Franc ois Magendie, 146 rue Le o Saignat, 33077 Bordeaux Cedex, France (E-mail: abrous@bordeaux.inserm.fr).
REFERENCES
1. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, and Eriksson PS. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 20: 2896 2903, 2000. 2. Aberg MA, Aberg ND, Palmer TD, Alborn AM, CarlssonSkwirut C, Bang P, Rosengren LE, Olsson T, Gage FH, and Eriksson PS. IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci 24: 23 40, 2003. 3. Abrous DN, Adriani W, Montaron MF, Aurousseau C, Rougon G, Le Moal M, and Piazza PV. Nicotine self-administration impairs hippocampal plasticity. J Neurosci 22: 3656 3662, 2002. 4. Agartz I, Momenan R, Rawlings RR, Kerich MJ, and Hommer DW. Hippocampal volume in patients with alcohol dependence. Arch Gen Psychiatry 56: 356 363, 1999. www.prv.org
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556
ABROUS, KOEHL, AND LE MOAL 26. Azmitia EC. Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis. Brain Res Bull 56: 413 424, 2001. 27. Bai F, Bergeron M, and Nelson DL. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 44: 10131021, 2003. 28. Bailey CH and Kandel ER. Structural changes accompanying memory storage. Annu Rev Physiol 55: 397 426, 1993. 29. Banasr M, Hery M, Brezun JM, and Daszuta A. Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus. Eur J Neurosci 14: 14171424, 2001. 30. Banasr M, Hery M, Printemps R, and Daszuta A. Serotonininduced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29: 450 460, 2004. 31. Barami K, Iversen K, Furneaux H, and Goldman SA. Hu protein as an early marker of neuronal phenotypic differentiation by subependymal zone cells of the adult songbird forebrain. J Neurobiol 28: 82101, 1995. 32. Baron M. An overview of the Notch signalling pathway. Semin Cell Dev Biol 14: 113119, 2003. 33. Bartzokis G, Beckson M, Lu PH, Edwards N, Rapoport R, Wiseman E, and Bridge P. Age-related brain volume reductions in amphetamine and cocaine addicts and normal controls: implications for addiction research. Psychiatry Res 98: 93102, 2000. 34. Batel P. Addiction and schizophrenia. Eur Psychiatry 15: 115122, 2000. 35. Bauer S, Moyse E, Jourdan F, Colpaert F, Martel JC, and Marien M. Effects of the alpha(2)-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death. Neuroscience 117: 281291, 2003. 36. Baulieu EE and Robel P. Neurosteroids: a new brain function. J Steroid Biochem Mol Biol 37: 395 403, 1997. 37. Bayer SA, Brunner RL, Hine R, and Altman J. Behavioural effects of interference with the postnatal acquisition of hippocampal granule cells. Nature New Biol 242: 222224, 1973. 38. Belluzzi O, Benedusi M, Ackman J, and LoTurco JJ. Electrophysiological differentiation of new neurons in the olfactory bulb. J Neurosci 23: 1041110418, 2003. 39. Belvindrah R, Rougon G, and Chazal G. Increased neurogenesis in adult mCD24-decient mice. J Neurosci 22: 3594 3607, 2002. 40. Bendotti C, Pende M, Guglielmetti F, and Samanin R. Cycloheximide inhibits kainic acid-induced GAP-43 mRNA in dentate granule cells in rats. Neuroreport 7: 2539 2542, 1996. 41. Benes FM, Kwok EW, Vincent SL, and Todtenkopf MS. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44: 88 97, 1998. 42. Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, and Lindvall O. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci USA 94: 1043210437, 1997. 43. Benwell ME, Balfour DJ, and Anderson JM. Smoking-associated changes in the serotonergic systems of discrete regions of human brain. Psychopharmacology 102: 68 72, 1990. 44. Berger F, Gage FH, and Vijayaraghavan S. Nicotinic receptorinduced apoptotic cell death of hippocampal progenitor cells. J Neurosci 18: 6871 6881, 1998. 45. Berke JD and Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25: 515532, 2000. 46. Bernabeu R and Sharp FR. NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab 20: 1669 1680, 2000. 47. Bernier PJ, Vinet J, Cossette M, and Parent A. Characterization of the subventricular zone of the adult human brain: evidence for the involvement of Bcl-2. Neurosci Res 37: 6778, 2000. 48. Berridge MJ. Calcium signalling and cell proliferation. Bioessays 17: 491500, 1995. 49. Bertrand N, Castro DS, and Guillemot F. Proneural genes and the specication of neural cell types. Nat Rev Neurosci 3: 517530, 2002. www.prv.org
5. Agnati LF, Zoli M, Biagini G, and Fuxe K. Neuronal plasticity and ageing processes in the frame of the Red Queen Theory. Acta Physiol Scand 145: 301309, 1992. 6. Ahmed S, Reynolds BA, and Weiss S. BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors. J Neurosci 15: 57655778, 1995. 7. Akamatsu W, Okano HJ, Osumi N, Inoue T, Nakamura S, Sakakibara Si Miura M, Matsuo N, Darnell RB, and Okano H. Mammalian ELAV-like neuronal RNA-binding proteins HuB and HuC promote neuronal development in both the central and the peripheral nervous systems. Proc Natl Acad Sci USA 96: 98859890, 1999. 8. Alderton WK, Cooper CE, and Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J 357: 593 615, 2001. 9. Alonso G, Prieto M, and Chauvet N. Tangential migration of young neurons arising from the subventricular zone of adult rats is impaired by surgical lesions passing through their natural migratory pathway. J Comp Neurol 405: 508 528, 1999. 10. Alonso R, Griebel G, Pavone G, Stemmelin J, Le Fur G, and Soubrie P. Blockade of CRF1 or V1B receptors reverses stressinduced suppression of neurogenesis in a mouse model of depression. Mol Psychiatry 9: 224, 2004. 11. Altman J. Are new neurones formed in the brains of adult mammals? Science 135: 11271128, 1962. 12. Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec 145: 573592, 1963. 13. Altman J and Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124: 319 336, 1965. 14. Altman J and Das GD. Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol 126: 337389, 1966. 15. Alvarez-Buylla A, Seri B, and Doetsch F. Identication of neural stem cells in the adult vertebrate brain. Brain Res Bull 57: 751758, 2002. 16. Amaral DG and Witter MP. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31: 571591, 1989. 17. Ambrogini P, Orsini L, Mancini C, Ferri P, Barbanti I, and Cuppini R. Persistently high corticosterone levels but not normal circadian uctuations of the hormone affect cell proliferation in the adult rat dentate gyrus. Neuroendocrinology 76: 366 372, 2002. 18. Ambrogini P, Orsini L, Mancini C, Ferri P, Ciaroni S, and Cuppini R. Learning may reduce neurogenesis in adult rat dentate gyrus. Neurosci Lett 359: 1316, 2004. 19. Anagnostaras SG, Maren S, and Fanselow MS. Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J Neurosci 19: 1106 1114, 1999. 20. Anderson MF, Aberg MAI, Nilsson M, and Eriksson PS. Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Dev Brain Res 134: 115122, 2002. 21. Antonopoulos J, Pappas IS, and Parnavelas JG. Activation of the GABAA receptor inhibits the proliferative effects of bFGF in cortical progenitor cells. Eur J Neurosci 9: 291298, 1997. 22. Arsenijevic Y and Weiss S. Insulin-like growth factor-I is a differentiation factor for postmitotic CNS stem cell-derived neuronal precursors: distinct actions from those of brain-derived neurotrophic factor. J Neurosci 18: 2118 2128, 1998. 23. Artavanis-Tsakonas S, Rand MD, and Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 284: 770 776, 1999. 24. Arvidsson A, Collin T, Kirik D, Kokaia Z, and Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8: 963970, 2002. 25. Arvidsson A, Kokaia Z, and Lindvall O. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci 14: 10 18, 2001. Physiol Rev VOL
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN 50. Biebl M, Cooper CM, Winkler J, and Kuhn HG. Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci Lett 291: 1720, 2000. 51. Blaha CD, Yang CR, Floresco SB, Barr AM, and Phillips AG. Stimulation of the ventral subiculum of the hippocampus evokes glutamate receptor-mediated changes in dopamine efux in the rat nucleus accumbens. Eur J Neurosci 9: 902911, 1997. 52. Blanchard RJ and Blanchard DC. Effects of hippocampal lesions on the rats reaction to a cat. J Comp Physiol Psychol 78: 77 82, 1972. 53. Bogerts B, Meertz E, and Schonfeldt-Bausch R. Basal ganglia and limbic system pathology in schizophrenia. A morphometric study of brain volume and shrinkage. Arch Gen Psychiatry 42: 784 791, 1985. 54. Bondol L, Ermini F, Long JM, Ingram DK, and Jucker M. Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice. Neurobiol Aging 25: 333340, 2004. 55. Bonfanti L and Theodosis DT. Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb. Neuroscience 62: 291305, 1994. 56. Bontempi B, Laurent-Demir C, Destrade C, and Jaffard R. Time-dependent reorganization of brain circuitry underlying longterm memory storage. Nature 400: 671 675, 1999. 57. Bouchet C and Cazauvieilh G. Epilepsie et lalie nation mentale. Arch Gen Med 9: 510 542, 1825. 58. Brandt MD, Jessberger S, Steiner B, Kronenberg G, Reuter K, Bick-Sander A, von der BW, and Kempermann G. Transient calretinin expression denes early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice. Mol Cell Neurosci 24: 603 613, 2003. 59. Breitner JC, Gau BA, Welsh KA, Plassman BL, McDonald WM, Helms MJ, and Anthony JC. Inverse association of anti-inammatory treatments and Alzheimers disease: initial results of a co-twin control study. Neurology 44: 227232, 1994. 60. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, Delaney RC, McCarthy G, Charney DS, and Innis RB. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 152: 973981, 1995. 61. Brezun JM and Daszuta A. Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89: 999 1002, 1999. 62. Brezun JM and Daszuta A. Serotonergic reinnervation reverses lesion-induced decreases in PSA-NCAM labeling and proliferation of hippocampal cells in adult rats. Hippocampus 10: 37 46, 2000. 63. Brezun JM and Daszuta A. Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 12: 391396, 2000. 64. Brizze KR and Ordy JM. Age pigments, cell loss and hippocampal function. Mech Ageing Dev 9: 143162, 1979. 65. Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, and Kuhn HG. Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467: 110, 2003. 66. Brunner RL. A cross-sectional study of behavior at three ages after neonatal X irradiation of the hippocampus. Behav Biol 22: 211218, 1978. 67. Caggiula AR, Donny EC, Epstein LH, Sved AF, Knopf S, Rose C, McAllister CG, Antelman SM, and Perkins KA. The role of corticosteroids in nicotines physiological and behavioral effects. Psychoneuroendocrinology 23: 143159, 1998. 68. Cahill L and McGaugh JL. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 21: 294 299, 1998. 69. Callaghan DA, Dong L, Callaghan SM, Hou YX, Dagnino L, and Slack RS. Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity. Dev Biol 207: 257270, 1999. 70. Calza L, Giardino L, Pozza M, Bettelli C, Micera A, and Aloe L. Proliferation and phenotype regulation in the subventricular zone during experimental allergic encephalomyelitis: in vivo evidence of a role for nerve growth factor. Proc Natl Acad Sci USA 95: 3209 3214, 1998. Physiol Rev VOL
557
71. Cameron HA and Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61: 203209, 1994. 72. Cameron HA and Gould E. Distinct populations of cells in the adult dentate gyrus undergo mitosis or apoptosis in response to adrenalectomy. J Comp Neurol 369: 56 63, 1996. 73. Cameron HA, McEwen BS, and Gould E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 15: 4687 4692, 1995. 74. Cameron HA and McKay RD. Restoring production of hippocampal neurons in old age. Nat Neurosci 2: 894 897, 1999. 75. Cameron HA and McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435: 406 417, 2001. 76. Cameron HA, Tanapat P, and Gould E. Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience 82: 349 354, 1997. 77. Cameron HA, Woolley CS, and Gould E. Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus. Brain Res 611: 342346, 1993. 78. Cameron HA, Woolley CS, McEwen BS, and Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56: 337344, 1993. 79. Capela A and Temple S. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35: 865 875, 2002. 80. Carlen M, Cassidy RM, Brismar H, Smith GA, Enquist LW, and Frisen J. Functional integration of adult-born neurons. Curr Biol 12: 606 608, 2002. 81. Carleton A, Petreanu LT, Lansford R, Alvarez-Buylla A, and Lledo PM. Becoming a new neuron in the adult olfactory bulb. Nat Neurosci 6: 507518, 2003. 82. Cavallaro S, DAgata V, Manickam P, Dufour F, and Alkon DL. Memory-specic temporal proles of gene expression in the hippocampus. Proc Natl Acad Sci USA 99: 16279 16284, 2002. 83. Cecchini T, Ciaroni S, Ferri P, Ambrogini P, Cuppini R, Santi S, and Del Grande P. Alpha-tocopherol, an exogenous factor of adult hippocampal neurogenesis regulation. J Neurosci Res 73: 447 455, 2003. 84. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, and Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochem 75: 1729 1734, 2000. 85. Chiasson BJ, Tropepe V, Morshead CM, and van der Kooy D. Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci 19: 4462 4471, 1999. 86. Ciaroni S, Cecchini T, Ferri P, Cuppini R, Ambrogini P, Santi S, Benedetti S, Del Grande P, and Papa S. Neural precursor proliferation and newborn cell survival in the adult rat dentate gyrus are affected by vitamin E deciency. Neurosci Res 44: 369 377, 2002. 87. Ciaroni S, Cuppini R, Cecchini T, Ferri P, Ambrogini P, Cuppini C, and Del Grande P. Neurogenesis in the adult rat dentate gyrus is enhanced by vitamin E deciency. J Comp Neurol 411: 495502, 1999. 88. Ciopolli C and Galliani L. Addiction time and intellectual impairment in heroin users. Psychol Rep 60: 1099 1105, 1987. 89. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A, and te Riele H. Requirement for a functional Rb-1 gene in murine development. Nature 359: 328 330, 1992. 90. Cohen P, Ocrant I, Fielder PJ, Neely EK, Gargosky SE, Deal CI, Ceda GP, Youngman O, Pham H, Lamson G, Giudice LC, and Rosenfeld RG. Insulin-like growth factors (IGFs): implications for aging. Psychoneuroendocrinology 17: 335342, 1992. 91. Coleman P. How old is old? Neurobiol Aging 25: 1, 2004. 92. Coleman P, Finch C, and Joseph J. The need for multiple time points in aging studies. Neurobiol Aging 25: 3 4, 2004. 93. Conrad AJ, Abebe T, Austin R, Forsythe S, and Scheibel AB. Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry 48: 413 417, 1991. www.prv.org
85 APRIL 2005
558
ABROUS, KOEHL, AND LE MOAL tion and differentiation: combined effects of PSA residues, growth factors, and substrates. Mol Cell Neurosci 16: 422 439, 2000. Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, and Malenka RC. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42: 535552, 2004. Dellu F, Mayo W, Vallee M, Maccari S, Piazza PV, Le Moal M, and Simon H. Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly: a life-span study in rats. Psychoneuroendocrinology 21: 441 453, 1996. Deminie ` re JM, Piazza PV, Guegan G, Abrous N, Maccari S, Le Moal M, and Simon H. Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers. Brain Res 586: 135139, 1992. Dempsey RJ, Sailor KA, Bowen KK, Tureyen K, and Vemuganti R. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-I and GDNF. J Neurochem 87: 586 597, 2003. Derrick BE, York AD, and Martinez JL Jr. Increased granule cell neurogenesis in the adult dentate gyrus following mossy ber stimulation sufcient to induce long-term potentiation. Brain Res 857: 300 307, 2000. Diaz-Granados JL, Greene PL, and Amsel A. Memory-based learning in preweanling and adult rats after infantile x-irradiationinduced hippocampal granule cell hypoplasia. Behav Neurosci 106: 940 946, 1992. Dickson DW. Neuropathology of Alzheimers disease and other dementias. Clin Geriatr Med 17: 209 228, 2001. Do bro ssy MDE, Aurousseau C, Le Moal M, Piazza PV and Abrous DN. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol Psychiatry 8: 974 982, 2003. Doetsch F and Alvarez-Buylla A. Network of tangential pathways for neuronal migration in adult mammalian brain. Proc Natl Acad Sci USA 93: 1489514900, 1996. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, and AlvarezBuylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703716, 1999. Doetsch F, Garcia-Verdugo JM, and Alvarez-Buylla A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17: 5046 5061, 1997. Doetsch F, Garcia-Verdugo JM, and Alvarez-Buylla A. Regeneration of a germinal layer in the adult mammalian brain. Proc Natl Acad Sci USA 96: 11619 11624, 1999. Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, and Alvarez-Buylla A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36: 10211034, 2002. Doetsch F, Verdugo JMG, Caille I, Alvarez-Buylla A, Chao MV, and Casaccia-Bonnel P. Lack of the cell-cycle inhibitor p27Kip1 results in selective increase of transit-amplifying cells for adult neurogenesis. J Neurosci 22: 22552264, 2002. Dong H, Csernansky CA, Goico B, and Csernansky JG. Hippocampal neurogenesis follows kainic acid-induced apoptosis in neonatal rats. J Neurosci 23: 17421749, 2003. Drapeau E, Do bro ssy M, Aurousseau C, Le Moal M, Piazza PV, and Abrous DN. Learning in rats induces cell death and cell proliferation in the hippocampus. Proc Soc Neurosci New Orleans LA 2003. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, and Abrous DN. Spatial memory performances of aged rats in the water maze predict levels of hipppocampal neurogenesis. Proc Natl Acad Sci USA 100: 1438514390, 2003. Duman RS, Nakagawa S, and Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 25: 836 844, 2001. Dunaevsky A and Mason CA. Spine motility: a means towards an end? Trends Neurosci 26: 155160, 2003. Eckardt MJ and Martin PR. Clinical assessment of cognition in alcoholism. Alcohol Clin Exp Res 10: 123127, 1986. Ehninger D and Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia www.prv.org
94. Cooper-Kuhn CM, Vroemen M, Brown J, Ye H, Thompson MA, Winkler J, and Kuhn HG. Impaired adult neurogenesis in mice lacking the transcription factor E2F1. Mol Cell Neurosci 21: 312 323, 2002. 95. Cooper-Kuhn CM and Georg Kuhn H. Is it all DNA repair? Methodological considerations for detecting neurogenesis in the adult brain. Dev Brain Res 134: 1321, 2002. 96. Corotto FS, Henegar JR, and Maruniak JA. Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse. Neuroscience 61: 739 744, 1994. 97. Covolan L, Ribeiro LT, Longo BM, and Mello LE. Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus. Hippocampus 10: 169 180, 2000. 98. Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, and van der Kooy D. In vivo growth factor expansion of endogeneous subependymal neural precursor cell populations in the adult mouse. J Neurosci 16: 2649 2658, 1996. 99. Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, and McCaffery P. 13-Cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci USA 101: 51115116, 2004. 100. Cremer H, Lange R, Christoph A, Plomann M, Vopper G, Roes J, Brown R, Baldwin S, Kraemer P, Scheff S, Barthels D, Rajewsky K, and Wille W. Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and decits in spatial learning. Nature 367: 455 459, 1994. 101. Csernansky JG, Joshi S, Wang L, Haller JW, Gado M, Miller JP, Grenander U, and Miller MI. Hippocampal morphometry in schizophrenia by high dimensional brain mapping. Proc Natl Acad Sci USA 95: 11406 11411, 1998. 102. Cuppini R, Ciaroni S, Cecchini T, Ambrogini P, Ferri P, Cuppini C, Ninfali P, and Del Grande P. Tocopherols enhance neurogenesis in dentate gyrus of adult rats. Int J Vitam Nutr Res 72: 170 176, 2002. 103. Curtis MA, Penney EB, Pearson AG, Roon-Mom WM, Butterworth NJ, Dragunow M, Connor B, and Faull RL. Increased cell proliferation and neurogenesis in the adult human Huntingtons disease brain. Proc Natl Acad Sci USA 100: 90239027, 2003. 104. Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, and Fuchs E. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 98: 12796 12801, 2001. 105. DAmour KA and Gage FH. Genetic and functional differences between multipotent neural and pluripotent embryonic stem cells. Proc Natl Acad Sci USA 100 Suppl: 11866 11872, 2003. 106. Dash PK, Blum S, and Moore AN. Caspase activity plays an essential role in long-term memory. Neuroreport 11: 28112814, 2000. 107. Dash PK, Mach SA, and Moore AN. Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res 63: 313319, 2001. 108. Dashtipour K, Tran PH, Okazaki MM, Nadler JV, and Ribak CE. Ultrastructural features and synaptic connections of hilar ectopic granule cells in the rat dentate gyrus are different from those of granule cells in the granule cell layer. Brain Res 890: 261271, 2001. 109. Davies SN, Pertwee RG, and Riedel G. Functions of cannabinoid receptors in the hippocampus. Neuropharmacology 42: 9931007, 2002. 110. Dawirs RR, Hildebrandt K, and Teuchert-Noodt G. Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J Neural Transm 105: 317327, 1998. 111. Dayer AG, Ford AA, Cleaver KM, Yassaee M, and Cameron HA. Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol 460: 563572, 2003. 112. De Bellis MD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, and Keshavan MS. Hippocampal volume in adolescent-onset alcohol use disorders. Am J Psychiatry 157: 737744, 2000. 113. Decker L, Avellana-Adalid V, Nait-Oumesmar B, Durbec P, and Baron-Van Evercooren A. Oligodendrocyte precursor migraPhysiol Rev VOL
114.
115.
116.
117.
118.
119.
120. 121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132. 133. 134.
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN proliferation in the adult murine neocortex. Cereb Cortex 13: 845 851, 2003. Eichenbaum H. A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1: 4150, 2000. Eichenbaum H. The hippocampus and declarative memory: cognitive mechanisms and neural codes. Behav Brain Res 127: 199 207, 2001. Eisch AJ, Barrot M, Schad CA, Self DW, and Nestler EJ. Opiates inhibit neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci USA 97: 7579 7584, 2000. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, and Lindvall O. Inammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 100: 1363213637, 2003. Ekstrom AD, Kahana MJ, Caplan JB, Fields TA, Isham EA, Newman EL, and Fried I. Cellular networks underlying human spatial navigation. Nature 425: 184 188, 2003. Elliott RC, Khademi S, Pleasure SJ, Parent JM, and Lowenstein DH. Differential regulation of basic helix-loop-helix mRNAs in the dentate gyrus following status epilepticus. Neuroscience 106: 79 88, 2001. Emsley JG and Hagg T. Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Exp Neurol 183: 298 310, 2003. Endl E, Hollmann C, and Gerdes J. Antibodies against the Ki-67 protein: assessment of the growth fraction and tools for cell cycle analysis. In: Methods in Cell Biology. Orlando, FL: Academic, 2001, p. 399 418. Engert F and Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399: 66 70, 1999. Eriksson PS, Perlieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, and Gage FH. Neurogenesis in the adult human hippocampus. Nat Med 4: 13131317, 1998. Ernfors P, Bengzon J, Kokaia Z, Persson H, and Lindvall O. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron 7: 165176, 1991. Ettlin RA, Perentes E, Kolopp M, Lardelli P, Arnold J, Karamitopoulou E, and Oberholzer M. Overview of quantitative methods in toxicologic pathology. In Vivo 7: 315324, 1993. Everitt BJ and Wolfe ME. Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22: 33123320, 2002. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, and Palmer TD. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18: 28032812, 2003. Falconer EM and Galea LA. Sex differences in cell proliferation, cell death and defensive behavior following acute predator odor stress in adult rats. Brain Res 975: 2236, 2003. Falkai P and Bogerts B. Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236: 154 161, 1986. Falkenberg T, Mohammed AK, Henriksson B, Persson H, Winblad B, and Lindefors N. Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci Lett 138: 153156, 1992. Farrell M, Howes S, Bebbington P, Brugha T, Jenkins R, Lewis G, Marsden J, Taylor C, and Meltzer H. Nicotine, alcohol and drug dependence and psychiatric comorbidity: results of a national household survey. Br J Psychiatry 179: 432 437, 2001. Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Martin GM, Kim SH, and Langdon RB. Decient neurogenesis in forebrain-specic presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32: 911926, 2001. Filippov V, Kronenberg G, Pivneva T, Reuter K, Steiner B, Wang LP, Yamaguchi M, Kettenmann H, and Kempermann G. Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol Cell Neurosci 23: 373382, 2003. Francis F, Koulakoff A, Boucher D, Chafey P, Schaar B, Vinet MC, Friocourt G, McDonnell N, Reiner O, Kahn A, McConnell SK, Berwald-Netter Y, Denoulet P, and Chelly J. Doublecortin is a developmentally regulated, microtubule-associated protein exPhysiol Rev VOL
559
135. 136.
156.
157.
137.
138.
158.
139.
159.
140.
160. 161. 162.
141.
142.
163.
143.
164.
144.
165.
145.
166.
146.
167.
147. 148.
168.
149.
169.
150. 151.
170.
171.
152.
172.
153.
173. 174.
154.
175.
176.
155.
177.
pressed in migrating and differentiating neurons. Neuron 23: 247 256, 1999. Frederiksen K and McKay RD. Proliferation and differentiation of rat neuroepithelial precursor cells in vivo. J Neurosci 8: 1144 1151, 1988. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Wineld H, Culver S, Trojanowski JQ, Eidelberg D, and Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinsons disease. N Engl J Med 344: 710 719, 2001. Fujii S, Ji Z, Morita N, and Sumikawa K. Acute and chronic nicotine exposure differentially facilitate the induction of LTP. Brain Res 846: 137143, 1999. Fukuda S, Kato F, Tozuka Y, Yamaguchi M, Miyamoto Y, and Hisatsune T. Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus. J Neurosci 23: 93579366, 2003. Gage FH. Stem cells of the central nervous system. Curr Opin Neurobiol 8: 671 676, 1998. Gaiano N and Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 25: 471 490, 2002. Galand P and Degraef C. Cyclin/PCNA immunostaining as an alternative to tritiated thymidine pulse labelling for marking S phase cells in parafn sections from animal and human tissues. Cell Tissue Kinet 22: 383392, 1989. Galea LA and McEwen BS. Sex and seasonal differences in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles. Neuroscience 89: 955964, 1999. Gall CM and Isackson PJ. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245: 758 761, 1989. Gallo V, Pende M, Scherer S, Molne M, and Wright P. Expression and regulation of kainate and AMPA receptors in uncommitted and committed neural progenitors. Neurochem Res 20: 549 560, 1995. Garcia-Verdugo JM, Doetsch F, Wichterle H, Lim DA, and Alvarez-Buylla A. Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol 36: 234 248, 1998. Geuna S, Borrione P, Fornaro M, and Giacobini-Robecchi MG. Adult stem cells and neurogenesis: historical roots and state of the art. Anat Rec 265: 132141, 2001. Gleeson JG, Lin PT, Flanagan LA, and Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23: 257271, 1999. Goldman SA, Kirschenbaum B, Harrison-Restelli C, and Thaler HT. Neuronal precursors of the adult rat subependymal zone persist into senescence, with no decline in spatial extent or response to BDNF. J Neurobiol 32: 554 566, 1997. Goldsmith SK and Joyce JN. Alterations in hippocampal mossy ber pathway in schizophrenia and Alzheimers disease. Biol Psychiatry 37: 122126, 1995. Gomez-Pinilla F, So V, and Kesslak JP. Spatial learning and physical activity contribute to the induction of broblast growth factor: neural substrates for increased cognition associated with exercise. Neuroscience 85: 53 61, 1998. Gomez-Pinilla F, van der Wal EA, and Cotman CW. Possible coordinated gene expressions for FGF receptor, FGF-5, and FGF-2 following seizures. Exp Neurol 133: 164 174, 1995. Goto Y and ODonnell P. Synchronous activity in the hippocampus and nucleus accumbens in vivo. J Neurosci 21: RC131, 2001. Gotz M. Glial cells generate neuronsmaster control within CNS regions: developmental perspectives on neural stem cells. Neuroscientist 9: 379 397, 2003. Gould E, Beylin A, Tanapat P, Reeves A, and Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2: 260 265, 1999. Gould E, Cameron HA, Daniels DC, Woolley CS, and McEwen BS. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J Neurosci 12: 36423650, 1992. Gould E, McEwen BS, Tanapat P, Galea LA, and Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 17: 24922498, 1997. www.prv.org
85 APRIL 2005
560
ABROUS, KOEHL, AND LE MOAL 201. Hampson RE, Simeral JD, and Deadwyler SA. Distribution of spatial and nonspatial information in dorsal hippocampus. Nature 402: 610 614, 1999. 202. Harrison JM, Allen RG, Pellegrino MJ, Williams JT, and Manzoni OJ. Chronic morphine treatment alters endogenous opioid control of hippocampal mossy ber synaptic transmission. J Neurophysiol 87: 2464 2470, 2002. 203. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122: 593 624, 1999. 204. Hastings NB and Gould E. Rapid extension of axons into the CA3 region by adult-generated granule cells. J Comp Neurol 413: 146 154, 1999. 205. Heale VR, Vanderwolf CH, and Kavaliers M. Components of weasel and fox odors elicit fast wave bursts in the dentate gyrus of rats. Behav Brain Res 63: 159 165, 1994. 206. Heckers S. Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 11: 520 528, 2001. 207. Heim C and Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49: 10231039, 2001. 208. Heine VM, Maslam S, Joels M, and Lucassen PJ. Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation. Neurobiol Aging 25: 361 375, 2004. 209. Heine VM, Maslam S, Zareno J, Joels M, and Lucassen PJ. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur J Neurosci 19: 131144, 2004. 210. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, and Gotz M. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5: 308 315, 2002. 211. Heishman SJTRC and Henningled JE. Nicotine and smoking: a review of effects on human performance. Exp Clin Psychopharmacol 2: 345395, 1994. 212. Hellsten J, Wennstro m M, Mohapel P, Ekdahl CT, Bengzon J, and Tingstro m A. Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment. Eur J Neurosci 16: 283290, 2002. 213. Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein RA, Hake AM, and Farlow MR. Estrogen for Alzheimers disease in women: randomized, double-blind, placebo-controlled trial. Neurology 54: 295301, 2000. 214. Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP, and Allis CD. Mitosis-specic phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106: 348 360, 1997. 215. Henry C, Guegant G, Cador M, Arnauld E, Arsaut J, Le Moal M, and Demotes-Mainard J. Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens. Brain Res 685: 179 186, 1995. 216. Hering H and Sheng M. Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2: 880 888, 2001. 217. Herman JP and Abrous DN. Dopaminergic neural grafts after fteen years: results and perspectives. Prog Neurobiol 44: 135, 1994. 218. Herrera DG, Yague AG, Johnsen-Soriano S, Bosch-Morell F, Collado-Morente L, Muriach M, Romero FJ, and Garcia-Verdugo JM. Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proc Natl Acad Sci USA 100: 7919 7924, 2003. 219. Holmes MM and Galea LA. Defensive behavior and hippocampal cell proliferation: differential modulation by naltrexone during stress. Behav Neurosci 116: 160 168, 2002. 220. Hu H, Tomasiewicz H, Magnuson T, and Rutishauser U. The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 16: 735743, 1996. www.prv.org
178. Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, and Fuchs E. Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci USA 96: 52635267, 1999. 179. Gould E, Reeves AJ, Graziano MS, and Gross CG. Neurogenesis in the neocortex of adult primates. Science 286: 548 552, 1999. 180. Gould E and Tanapat P. Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rats. Neuroscience 80: 427 436, 1997. 181. Gould E, Tanapat P, McEwen BS, Flugge G, and Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 95: 3168 3171, 1998. 182. Gould E, Vail N, Wagers M, and Gross CG. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence. Proc Natl Acad Sci USA 98: 10910 10917, 2001. 183. Gould E, Woolley CS, and McEwen BS. Adrenal steroids regulate postnatal development of the rat dentate gyrus. I. Effects of glucocorticoids on cell death. J Comp Neurol 313: 479 485, 1991. 184. Gould MN and Yatvin MB. The effects of x-irradiation on the early stages of the memory system in rats. Physiol Behav 11: 177179, 1973. 185. Graham YP, Heim C, Goodman SH, Miller AH, and Nemeroff CB. The effects of neonatal stress on brain development: implications for psychopathology. Dev Psychopathol 11: 545565, 1999. 186. Grandbarbe L, Bouissac J, Rand M, Hrabe DA, ArtavanisTsakonas S, and Mohier E. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development 130: 13911402, 2003. 187. Gray JA and McNaughton N. Comparison between the behavioral effects of septal and hippocampal lesions: a review. Neurosci Biobehav Rev 7: 119 188, 1982. 188. Gray WP and Sundstrom LE. Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790: 5259, 1998. 189. Gross CG. Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1: 6773, 2000. 190. Gross RE, Mehler MF, Mabie PC, Zang Z, Santschi L, and Kessler JA. Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 17: 595 606, 1996. 191. Grover CA and Frye GD. Ethanol effects on synaptic neurotransmission and tetanus-induced synaptic plasticity in hippocampal slices of chronic in vivo lead-exposed adult rats. Brain Res 734: 6171, 1996. 192. Grutzendler J, Kasthuri N, and Gan WB. Long-term dendritic spine stability in the adult cortex. Nature 420: 812 816, 2002. 193. Gu W, Brannstrom T, and Wester P. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J Cereb Blood Flow Metab 20: 1166 1173, 2000. 194. Guerra D, Sole A, Cami J, and Tobena A. Neuropsychological performance in opiate addicts after rapid detoxication. Drug Alcohol Dependence 20: 261270, 1987. 195. Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, Orr SP, Kikinis R, Jolesz FA, McCarley RW, and Pitman RK. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 40: 10911099, 1996. 196. Gutie rrez R. The GABAergic phenotype of the glutamatergic granule cells of the dentate gyrus. Prog Neurobiol 71: 337358, 2003. 197. Guzman M, Galve-Roperh I, and Sanchez C. Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol Sci 22: 19 22, 2001. 198. Hack I, Bancila M, Loulier K, Carroll P, and Cremer H. Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nat Neurosci 5: 939 945, 2002. 199. Halim ND, Weickert CS, McClintock BW, Weinberger DR, and Lipska BK. Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 29: 10631069, 2004. 200. Hamid S, Dawe GS, Gray JA, and Stephenson JD. Nicotine induces long-lasting potentiation in the dentate gyrus of nicotineprimed rats. Neurosci Res 29: 81 85, 1997. Physiol Rev VOL
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN 221. Huang L and Bittman EL. Olfactory bulb cells generated in adult male golden hamsters are specically activated by exposure to estrous females. Horm Behav 41: 343350, 2002. 222. Hughes P and Dragunow M. Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol Rev 47: 133178, 1995. 223. Huttmann K, Sadgrove M, Wallraff A, Hinterkeuser S, Kirchhoff F, Steinhauser C, and Gray WP. Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur J Neurosci 18: 2769 2778, 2003. 224. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Horster F, Tenkova T, Dikranian K, and Olney JW. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287: 1056 1060, 2000. 225. Imura T, Kornblum HI, and Sofroniew MV. The predominant neural stem cell isolated from postnatal and adult forebrain but not early embryonic forebrain expresses GFAP. J Neurosci 23: 2824 2832, 2003. 226. Iso T, Kedes L, and Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194: 237255, 2003. 227. Izquierdo I and Medina JH. Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Memory 68: 285 316, 1997. 228. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, and Weinberg RA. Effects of an Rb mutation in the mouse. Nature 359: 295300, 1992. 229. Jacobs LF and Schenk F. Unpacking the cognitive map: the parallel map theory of hippocampal function. Psychol Rev 110: 285315, 2003. 230. Jang MH, Shin MC, Jung SB, Lee TH, Bahn GH, Kwon YK, Kim EH, and Kim CJ. Alcohol and nicotine reduce cell proliferation and enhance apoptosis in dentate gyrus. Neuroreport 13: 1509 1513, 2002. 231. Jankovski A, Garcia C, Soriano E, and Sotelo C. Proliferation, migration and differentiation of neuronal progenitor cells in the adult mouse subventricular zone surgically separated from its olfactory bulb. Eur J Neurosci 10: 38533868, 1998. 232. Jessberger S and Kempermann G. Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur J Neurosci 18: 27072712, 2003. 233. Jeste DV and Lohr JB. Hippocampal pathologic ndings in schizophrenia. A morphometric study. Arch Gen Psychiatry 46: 1019 1024, 1989. 234. Jiang W, Wang JC, Zhang Z, Sheerin AH, and Zhang X. Response of seizure-induced newborn neurons in the dentate gyrus of adult rats to second episode of seizures. Brain Res 1006: 248 252, 2004. 235. Jin K, Mao XO, Sun Y, Xie L, and Greenberg DA. Stem cell factor stimulates neurogenesis in vitro and in vivo. J Clin Invest 110: 311319, 2003. 236. Jin K, Mao XO, Sun Y, Xie L, Jin L, Nishi E, Klagsbrun M, and Greenberg DA. Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J Neurosci 22: 53655373, 2002. 237. Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, and Greenberg DA. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 98: 4710 4715, 2001. 238. Jin K, Sun Y, Xie L, Batteur S, Mao XO, Smelick C, Logvinova A, and Greenberg DA. Neurogenesis and aging: FGF-2 and HBEGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell 2: 175183, 2003. 239. Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, and Greenberg DA. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 24: 171189, 2003. 240. Jin K, Xie L, Childs J, Sun Y, Mao XO, Logvinova A, and Greenberg DA. Cerebral neurogenesis is induced by intranasal administration of growth factors. Ann Neurol 53: 405 409, 2003. Physiol Rev VOL
561
241. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, and Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99: 11946 11950, 2002. 242. Johansson CB, Svensson M, Wallstedt L, Janson AM, and Frisen J. Neural stem cells in the adult human brain. Exp Cell Res 253: 733736, 1999. 243. Junier MP. What role(s) for TGFalpha in the central nervous system? Prog Neurobiol 62: 443 473, 2000. 244. Justice NJ and Jan YN. Variations on the Notch pathway in neural development. Curr Opin Neurobiol 12: 64 70, 2002. 245. Kamiguchi H, Yoshida K, Wakamoto H, Inaba M, Sasaki H, Otani M, and Toya S. Cytokine-induced selective increase of high-molecular-weight bFGF isoforms and their subcellular kinetics in cultured rat hippocampal astrocytes. Neurochem Res 21: 701706, 1996. 246. Kaneko Y, Sakakibara S, Imai T, Suzuki A, Nakamura Y, Sawamoto K, Ogawa Y, Toyama Y, Miyata T, and Okano H. Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev Neurosci 22: 139 153, 2000. 247. Kaplan MS. Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol 195: 323338, 1981. 248. Kaplan MS. Formation and turnover of neurons in young and senescent animals: an electronmicroscopic and morphometric analysis. Ann NY Acad Sci 457: 173192, 1985. 249. Kaplan MS. Environment complexity stimulates visual cortex neurogenesis: death of a dogma and a research career. Trends Neurosci 24: 617 620, 2001. 250. Kaplan MS and Bell DH. Neuronal proliferation in the 9-monthold rodent-radioautographic study of granule cells in the hippocampus. Exp Brain Res 52: 15, 1983. 251. Kaplan MS and Bell DH. Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus. J Neurosci 4: 1429 1441, 1984. 252. Kaplan MS and Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 197: 1092 1094, 1977. 253. Kaplan MS, McNelly NA, and Hinds JW. Population dynamics of adult-formed granule neurons of the rat olfactory bulb. J Comp Neurol 239: 117125, 1985. 254. Karishma KK and Herbert J. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosteroneinduced suppression. Eur J Neurosci 16: 445 453, 2002. 255. Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, and Nakahara H. Structure-stability-function relationships of dendritic spines. Trends Neurosci 26: 360 368, 2003. 256. Kato T, Yokouchi K, Fukushima N, Kawagishi K, Li Z, and Moriizumi T. Continual replacement of newly-generated olfactory neurons in adult rats. Neurosci Lett 307: 1720, 2001. 257. Katoh-Semba R, Asano T, Ueda H, Morishita R, Takeuchi IK, Inaguma Y, and Kato K. Riluzole enhances expression of brainderived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. FASEB J 16: 1328 1330, 2002. 258. Kawai T, Takagi N, Miyake-Takagi K, Okuyama N, Mochizuki N, and Takeo S. Characterization of BrdU-positive neurons induced by transient global ischemia in adult hippocampus. J Cereb Blood Flow Metab 24: 548 555, 2004. 259. Kee N, Sivalingam S, Boonstra R, and Wojtowicz JM. The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods 115: 97105, 2002. 260. Kee NJ, Preston E, and Wojtowicz JM. Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat. Exp Brain Res 136: 313320, 2001. 261. Kempermann G, Brandon EP, and Gage FH. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr Biol 8: 939 942, 1998. 262. Kempermann G and Gage FH. Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal. Hippocampus 9: 321332, 1999. 263. Kempermann G, Gast D, Kronenberg G, Yamaguchi M, and Gage FH. Early determination and long-term persistence of adultwww.prv.org
85 APRIL 2005
562
ABROUS, KOEHL, AND LE MOAL generated new neurons in the hippocampus of mice. Development 130: 391399, 2003. Kempermann G, Gast D, and Gage FH. Neuroplasticity in old age: sustained vefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 52: 135143, 2002. Kempermann G, Jessberger S, Steiner B, and Kronenberg G. Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27: 447 452, 2004. Kempermann G and Gage FH. Genetic inuence on phenotypic differentiation in adult hippocampal neurogenesis. Dev Brain Res 134: 112, 2002. Kempermann G, Kuhn HG, and Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature 386: 493 495, 1997. Kempermann G, Kuhn HG, and Gage FH. Genetic inuence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94: 10409 10414, 1997. Kempermann G, Kuhn HG, and Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18: 3206 3212, 1998. Kesner RP, Gilbert PE, and Wallenstein GV. Testing neural network models of memory with behavioral experiments. Curr Opin Neurobiol 10: 260 265, 2000. Kesslak JP, So V, Choi J, Cotman CW, and Gomez-Pinilla F. Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance? Behav Neurosci 112: 10121019, 1998. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, and Glaser R. Chronic stress and age-related increases in the proinammatory cytokine IL-6. Proc Natl Acad Sci USA 100: 9090 9095, 2003. Kim JJ, Clark RE, and Thompson RF. Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses. Behav Neurosci 109: 195203, 1995. Kim JJ and Fanselow MS. Modality-specic retrograde amnesia of fear. Science 256: 675 677, 1992. Kirschenbaum B, Doetsch F, Lois C, and Alvarez-Buylla A. Adult subventricular zone neuronal precursors continue to proliferate and migrate in the absence of the olfactory bulb. J Neurosci 19: 21712180, 1999. Kirschenbaum B and Goldman SA. Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone. Proc Natl Acad Sci USA 92: 210 214, 1995. Kiss JZ and Rougon G. Cell biology of polysialic acid. Curr Opin Neurobiol 7: 640 646, 1997. Kitamura T, Mishina M, and Sugiyama H. Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit. Neurosci Res 47: 55 63, 2003. Koehl M, Bjijou Y, Le Moal M, and Cador M. Nicotine-induced locomotor activity is increased by preexposure of rats to prenatal stress. Brain Res 882: 196 200, 2000. Koehl M, Lemaire V, Mayo W, Abrous DN, Maccari S, Piazza PV, Le Moal M, and Vallee M. Individual vulnerability to substance abuse and affective disorders: role of early environmental inuences. Neurotoxicity Res 4: 281296, 2002. Koketsu D, Mikami A, Miyamoto Y, and Hisatsune T. Nonrenewal of neurons in the cerebral neocortex of adult macaque monkeys. J Neurosci 23: 937942, 2003. Kolb B, Pedersen B, Ballermann M, Gibb R, and Whishaw IQ. Embryonic and postnatal injections of bromodeoxyuridine produce age-dependent morphological and behavioral abnormalities. J Neurosci 19: 23372346, 1999. Koob GF and Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24: 97129, 2001. Kornack DR and Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA 96: 5768 5773, 1999. Kornack DR and Rakic P. Cell proliferation without neurogenesis in adult primate neocortex. Science 294: 21272130, 2001. Physiol Rev VOL 286. Kornack DR and Rakic P. The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc Natl Acad Sci USA 98: 4752 4757, 2001. 287. Kostyuk P. Plasticity in Nerve Cell Function. Oxford, UK: Clarendon, 1998. 288. Kovelman JA and Scheibel AB. A neurohistological correlate of schizophrenia. Biol Psychiatry 19: 16011621, 1984. 289. Kronenberg G, Reuter K, Steiner B, Brandt MD, Jessberger S, Yamaguchi M, and Kempermann G. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J Comp Neurol 467: 455 463, 2003. 290. Kuhn HG, Dickinson-Anson H, and Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16: 20272033, 1996. 291. Kuhn HG, Winkler J, Kempermann G, Thal LJ, and Gage FH. Epidermal growth factor and broblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 17: 5820 5829, 1997. 292. Kulkarni VA, Jha S, and Vaidya VA. Depletion of norepinephrine decreases the proliferation, but does not inuence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci 16: 2008 2012, 2002. 293. Kumihashi K, Uchida K, Miyazaki H, Kobayashi J, Tsushima T, and Machida T. Acetylsalicylic acid reduces ischemia-induced proliferation of dentate cells in gerbils. Neuroreport 12: 915917, 2001. 294. Kurki P, Vanderlaan M, Dolbeare F, Gray J, and Tan EM. Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res 166: 209 219, 1986. 295. Lai K, Kaspar BK, Gage FH, and Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6: 2127, 2003. 296. Laming PR, Kimelberg H, Robinson S, Salm A, Hawrylak N, Muller C, Roots B, and Ng K. Neuronal-glial interactions and behaviour. Neurosci Biobehav Rev 24: 295340, 2000. 297. Lamprecht R and LeDoux J. Structural plasticity and memory. Nat Rev Neurosci 5: 4554, 2004. 298. Lauder JM and Krebs H. Serotonin as a differentiation signal in early neurogenesis. Dev Neurosci 1: 1530, 1978. 299. Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, and Bradley A. Mice decient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359: 288 294, 1992. 300. Lee HJ, Kim JW, Yim SV, Kim MJ, Kim SA, Kim YJ, Kim CJ, and Chung JH. Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats. Mol Psychiatry 6: 610 728, 2001. 301. Lee J, Duan W, and Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82: 13671375, 2002. 302. Legault M, Rompre PP, and Wise RA. Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area. J Neurosci 20: 16351642, 2000. 303. Legrier ME, Ducray A, Propper A, Chao M, and Kastner A. Cell cycle regulation during mouse olfactory neurogenesis. Cell Growth Differ 12: 591 601, 2001. 304. Lemaire V and Agmo A. High and low reactivity to novelty and sexual behavior in male rats. Psychobiology 25: 241245, 1997. 305. Lemaire V, Aurousseau C, Le Moal M, and Abrous DN. Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis. Eur J Neurosci 11: 4006 4014, 1999. 306. Lemaire V, Koehl M, Le Moal M, and Abrous DN. Prenatal stress produces learning decits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA 97: 1103211037, 2000. 307. Lendahl U, Zimmerman LB, and McKay RD. CNS stem cells express a new class of intermediate lament protein. Cell 60: 585595, 1990. 308. Lescaudron L, Jaffard R, and Verna A. Modications in number and morphology of dendritic spines resulting from chronic ethanol www.prv.org
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274. 275.
276.
277. 278.
279.
280.
281.
282.
283. 284.
285.
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN consumption and withdrawal: a Golgi study in the mouse anterior and posterior hippocampus. Exp Neurol 106: 156 161, 1989. Leuner B, Mendolia-Loffredo S, Kozorovitskiy Y, Samburg D, Gould E, and Shors TJ. Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. J Neurosci 24: 74777481, 2004. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, and Riddle DR. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107: 603 613, 2001. Lim DA, Tramontin AD, Trevejo JM, Herrera DG, GarciaVerdugo JM, and Alvarez-Buylla A. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28: 713726, 2000. Linnarsson S, Willson CA, and Ernfors P. Cell death in regenerating populations of neurons in BDNF mutant mice. Brain Res 75: 61 69, 2000. Lipska BK and Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23: 223239, 2000. Liu G and Rao Y. Neuronal migration from the forebrain to the olfactory bulb requires a new attractant persistent in the olfactory bulb. J Neurosci 23: 6651 6659, 2003. Liu J, Solway K, Messing RO, and Sharp FR. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18: 7768 7778, 1998. Liu S, Wang J, Zhu D, Fu Y, Lukowiak K, and Lu YM. Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci 23: 732736, 2003. Lois C and Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science 264: 11451148, 1994. LoTurco JJ, Owens DF, Heath MJ, Davis MB, and Kriegstein AR. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15: 12871298, 1995. Lu D, Mahmood A, Zhang R, and Copp M. Upregulation of neurogenesis and reduction in functional decits following administration of DEtA/NONOate, a nitric oxide donor, after traumatic brain injury in rats. J Neurosurg 99: 351361, 2003. Lu L, Bao G, Chen H, Xia P, Fan X, Zhang J, Pei G, and Ma L. Modication of hippocampal neurogenesis and neuroplasticity by social environments. Exp Neurol 183: 600 609, 2003. Lu L, Zeng S, Liu D, and Ceng X. Inhibition of the amygdala and hippocampal calcium/calmodulin-dependent protein kinase II attenuates the dependence and relapse to morphine differently in rats. Neurosci Lett 291: 191195, 2000. Lund RD. Developement and Plasticity of the Brain. An Introduction. New York: Oxford Univ. Press, 1978. Luo Y, Cai J, Liu Y, Xue H, Chrest FJ, Wersto RP, and Rao M. Microarray analysis of selected genes in neural stem and progenitor cells. J Neurochem 83: 14811497, 2002. Lupien SJ and McEwen BS. The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res Rev 24: 127, 1997. Luskin MB. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11: 173189, 1993. Luskin MB. Neuroblasts of the postnatal mammalian forebrain: their phenotype and fate. J Neurobiol 36: 221233, 1998. Ma W, Liu QY, Maric D, Sathanoori R, Chang YH, and Barker JL. Basic FGF-responsive telencephalic precursor cells express functional GABA(A) receptor/Cl-channels in vitro. J Neurobiol 35: 277286, 1998. Mackenzie IR. Activated microglia in dementia with Lewy bodies. Neurology 55: 132134, 2000. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, and Young LT. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA 100: 13871392, 2003. Madsen TM, Kristjansen PE, Bolwig TG, and Wortwein G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119: 635 642, 2003. Physiol Rev VOL
563
309.
310.
311.
312.
313.
314.
315.
316.
317. 318.
319.
320.
321.
322. 323.
324.
325.
326. 327.
328. 329.
330.
331. Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, and Tingstrom A. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 47: 10431049, 2000. 332. Magavi SS, Leavitt BR, and Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 405: 951955, 2000. 333. Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological signicance. Prog Neurobiol 38: 379 395, 1992. 334. Malberg JE and Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by uoxetine treatment. Neuropsychopharmacology 28: 15621571, 2003. 335. Malberg JE, Eisch AJ, Nestler EJ, and Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20: 9104 9110, 2000. 336. Maldonado R. Study of cannabinoid dependence in animals. Pharmacol Ther 95: 153164, 2002. 337. Malenka RC and Nicoll RA. Long-term potentiationa decade of progress? Science 285: 1870 1874, 1999. 338. Maletic-Savatic M, Malinow R, and Svoboda K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283: 19231927, 1999. 339. Manev H, Uz T, and Manev R. Glia as a putative target for antidepressant treatments. J Affective Disorders. In press. 340. Manev H, Uz T, Manev R, and Zhang Z. Neurogenesis and neuroprotection in the adult brain. A putative role for 5-lipoxygenase? Ann NY Acad Sci 939: 4551, 2001. 341. Marczynski TJ. GABAergic deafferentation hypothesis of brain aging and Alzheimers disease revisited. Brain Res Bull 45: 341 379, 1998. 342. Maren S, Aharonov G, and Fanselow MS. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav Brain Res 88: 261274, 1997. 343. Marinelli M and Piazza PV. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci 16: 387394, 2002. 344. Markakis EA and Gage FH. Adult-generated neurons in the dentate gyrus send axonal projections to eld CA3 and are surrounded by synaptic vesicles. J Comp Neurol 406: 449 460, 1999. 345. Markowska AL, Mooney M, and Sonntag WE. Insulin-like growth factor-1 ameliorates age-related behavioral decits. Neuroscience 87: 559 569, 1998. 346. Marti E and Bovolenta P. Sonic hedgehog in CNS development: one signal, multiple outputs. Trends Neurosci 25: 89 96, 2002. 347. Matsuoka N, Nozaki K, Takagi Y, Nishimura M, Hayashi J, Miyatake S, and Hashimoto N. Adenovirus-mediated gene transfer of broblast growth factor-2 increases BrdU-positive cells after forebrain ischemia in gerbils. Stroke 34: 1519 1525, 2003. 348. Mayo W, Lemaire V, Malaterre J, Rodriguez JJ, Cayre M, Stewart MG, Kharouby M, Rougon G, Le Moal M, Piazza PV, and Abrous DN. The neurosteroid pregnenolone sulfate enhances neurogenesis in the young and senescent dentate gyrus. Neurobiol Aging 26: 103114, 2005. 349. Mayo W, Valle e M, Darnaude ry M, and Le Moal M. Neurosteroids: Behavioral Studies. Clifton, NJ: Humana, 1999. 350. McEchron MD and Disterhoft JF. Hippocampal encoding of non-spatial trace conditioning. Hippocampus 9: 385396, 1999. 351. McEwen BS. Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann NY Acad Sci 933: 265277, 2001. 352. McEwen BS. Sex, stress and the hippocampus: allostasis, allostatic load and the aging process. Neurobiol Aging 23: 921939, 2002. 353. McEwen BS. Early life inuences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev 9: 149 154, 2003. 354. McEwen BS, Cameron H, Chao HM, Gould E, Magarinos AM, Watanabe Y, and Woolley CS. Adrenal steroids and plasticity of hippocampal neurons: toward an understanding of underlying cellular and molecular mechanisms. Cell Mol Neurobiol 13: 457 482, 1993. 355. McGeer PL, Schulzer M, and McGeer EG. Arthritis and antiinammatory agents as possible protective factors for Alzheimers disease: a review of 17 epidemiologic studies. Neurology 47: 425 432, 1996. www.prv.org
85 APRIL 2005
564
ABROUS, KOEHL, AND LE MOAL 380. Morshead CM, Garcia AD, Sofroniew MV, and van der Kooy D. The ablation of glial brillary acidic protein-positive cells from the adult central nervous system results in the loss of forebrain neural stem cells but not retinal stem cells. Eur J Neurosci 18: 76 84, 2003. 381. Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, and van der Kooy D. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13: 1071 1082, 1994. 382. Morshead CM and van der Kooy D. Postmitotic death is the fate of constitutively proliferating cells in the subependymal layer of the adult mouse brain. J Neurosci 12: 249 256, 1992. 383. Moser MB. Making more synapses: a way to store information? Cell Mol Life Sci 55: 593 600, 1999. 384. Mouritzen Dam A. The density of neurons in the human hippocampus. Neuropathol Appl Neurobiol 5: 249 264, 1979. 385. Moyer JR Jr, Deyo RA, and Disterhoft JF. Hippocampectomy disrupts trace eye-blink conditioning in rabbits. Behav Neurosci 104: 243252, 1990. 386. Mullen RJ, Buck CR, and Smith AM. NeuN, a neuronal specic nuclear protein in vertebrates. Development 116: 201211, 1992. 387. Mumby DG, Astur RS, Weisend MP, and Sutherland RJ. Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations. Behav Brain Res 106: 97107, 1999. 388. Murray EA and Bussey TJ. Consolidation and the medial temporal lobe revisited: methodological considerations. Hippocampus 11: 17, 2001. 389. Nacher J, Crespo C, and McEwen BS. Doublecortin expression in the adult rat telencephalon. Eur J Neurosci 14: 629 644, 2001. 390. Nacher J, Rosell DR, Alonso-Llosa G, and McEwen BS. NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci 13: 512520, 2001. 391. Nacher J, Alonso-Llosa G, Rosell DR, and McEwen BS. NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging 24: 273284, 2003. 392. Nacher J, Rosell DR, and McEwen BS. Widespread expression of rat collapsin response-mediated protein 4 in the telencephalon and other areas of the adult rat central nervous system. J Comp Neurol 424: 628 639, 2000. 393. Nadel L and Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 7: 217227, 1997. 394. Nadel L, Pran L, Hayes SM, Gilboa A, and Moscovitch M. The role of the hippocampal complex in long-term episodic memory. Int Cong Ser 1250: 215234, 2003. 395. Nadel L, Samsonovich A, Ryan L, and Moscovitch M. Multiple trace theory of human memory: computational, neuroimaging, and neuropsychological results. Hippocampus 10: 352368, 2000. 396. Nakagawa E, Aimi Y, Yasuhara O, Tooyama I, Shimada M, McGeer PL, and Kimura H. Enhancement of progenitor cell division in the dentate gyrus triggered by initial limbic seizures in rat models of epilepsy. Epilepsia 41: 10 18, 2000. 397. Nakamura K, Kaneko T, Yamashita Y, Hasegawa H, Katoh H, and Negishi M. Immunohistochemical localization of prostaglandin EP3 receptor in the rat nervous system. J Comp Neurol 421: 543569, 2000. 398. Nakamura Y, Sakakibara S, Miyata T, Ogawa M, Shimazaki T, Weiss S, Kageyama R, and Okano H. The bHLH gene hes1 as a repressor of the neuronal commitment of CNS stem cells. J Neurosci 20: 283293, 2000. 399. Nakatomi H, Kuriu T, Okabe S, Yamamoto SI, Hatano O, Kawahara N, Tamura A, Kirino T, and Nakafuku M. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110: 429 441, 2002. 400. Nelson MD, Saykin AJ, Flashman LA, and Riordan HJ. Hippocampal volume reduction in schizophrenia as assessed by magwww.prv.org
356. McKay R. Stem cells in the central nervous system. Science 276: 66 71, 1997. 357. McLardy T and Path FRC. Hippocampal zinc and structural decit in brains from chronic alcoholics and some schizophrenics. J Orthomol Psychiatry 4: 3236, 1975. 358. Mehler MF. Mechanisms regulating lineage diversity during mammalian cerebral cortical neurogenesis and gliogenesis. Results Probl Cell Differ 39: 2752, 2002. 359. Meirer R, Gurunluoglu R, and Siemionow M. Neurogenic perspective on vascular endothelial growth factor: review of the literature. J Reconstr Microsurg 17: 625 630, 2001. 360. Memberg SP and Hall AK. Dividing neuron precursors express neuron-specic tubulin. J Neurobiol 27: 26 43, 1995. 361. Menezes JR and Luskin MB. Expression of neuron-specic tubulin denes a novel population in the proliferative layers of the developing telencephalon. J Neurosci 14: 5399 5416, 1994. 362. Mercer A, Ronnholm H, Holmberg J, Lundh H, Heidrich J, Zachrisson O, Ossoinak A, Frisen J, and Patrone C. PACAP promotes neural stem cell proliferation in adult mouse brain. J Neurosci Res 76: 205215, 2004. 363. Mercier F, Kitasako JT, and Hatton GI. Anatomy of the brain neurogenic zones revisited: fractones and the broblast/macrophage network. J Comp Neurol 451: 170 188, 2002. 364. Mesulam MM. Neuroplasticity failure in Alzheimers disease: bridging the gap between plaques and tangles. Neuron 24: 521529, 1999. 365. Meyers RA, Zavala AR, and Neisewander JL. Dorsal, but not ventral, hippocampal lesions disrupt cocaine place conditioning. Neuroreport 14: 21272131, 2003. 366. Minturn JE, Geschwind DH, Fryer HJ, and Hockeld S. Early postmitotic neurons transiently express TOAD-64, a neural specic protein. J Comp Neurol 355: 369 379, 1995. 367. Mirescu C, Peters JD, and Gould E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci. In press. 368. Mizrahi A and Katz LC. Dendritic stability in the adult olfactory bulb. Nat Neurosci 6: 12011207, 2003. 369. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, and Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 63: 4021 4027, 2003. 370. Mohammed AH, Henriksson BG, Soderstrom S, Ebendal T, Olsson T, and Seckl JR. Environmental inuences on the central nervous system and their implications for the aging rat. Behav Brain Res 57: 183191, 1993. 371. Monje ML, Mizumatsu S, Fike JR, and Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med 8: 955962, 2002. 372. Monje ML, Toda H, and Palmer TD. Inammatory blockade restores adult hippocampal neurogenesis. Science 302: 1760 1765, 2003. 373. Montaron MF, Petry KG, Rodriguez JJ, Marinelli M, Aurousseau C, Rougon G, Le Moal M, and Abrous DN. Adrenalectomy increases neurogenesis but not PSA-NCAM expression in aged dentate gyrus. Eur J Neurosci 11: 1479 1485, 1999. 374. Montaron MF, Piazza PV, Aurousseau C, Urani A, Le Moal M, and Abrous DN. Implication of corticosteroid receptors in the regulation of hippocampal structural plasticity. Eur J Neurosci 18: 31053111, 2003. 375. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, and Manji HK. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2s neurotrophic effects? Biol Psychiatry 48: 1 8, 2000. 376. Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK, and Menji HK. Lithium-induced increase in human brain grey matter. Lancet 356: 12411242, 2000. 377. Moreno-Lopez B, Noval JA, Gonzalez-Bonet LG, and Estrada C. Morphological bases for a role of nitric oxide in adult neurogenesis. Brain Res 869: 244 250, 2000. 378. Morris RG, Garrud P, Rawlins JN, and OKeefe J. Place navigation impaired in rats with hippocampal lesions. Nature 297: 681 683, 1982. 379. Morrison SJ. Neuronal potential and lineage determination by neural stem cells. Curr Opin Cell Biol 13: 666 672, 2001. Physiol Rev VOL
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN netic resonance imaging: a meta-analytic study. Arch Gen Psychiatry 55: 433 440, 1998. Nestler EJ. Molecular neurobiology of addiction. Am J Addict 10: 201217, 2001. Nestler EJ and Aghajanian GK. Molecular and cellular basis of addiction. Science 278: 58 63, 1997. Nevins JR. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 258: 424 429, 1992. Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, and Duman RS. Gene prole of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 23: 1084110851, 2003. Niblock MM, Brunso-Bechtold JK, and Riddle DR. Insulin-like growth factor I stimulates dendritic growth in primary somatosensory cortex. J Neurosci 20: 4165 4176, 2000. Nibuya M, Morinobu S, and Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15: 7539 7547, 1995. Nilsson M, Perlieva E, Johansson U, Orwar O, and Eriksson PS. Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol 39: 569 578, 1999. Nimchinsky EA, Sabatini BL, and Svoboda K. Structure and function of dendritic spines. Annu Rev Physiol 64: 313353, 2002. Nixon K and Crews FT. Binge ethanol exposure decreases neurogenesis in the adult rat hippocampus. J Neurochem 83: 1087 1093, 2002. Nottebohm F. From bird song to neurogenesis. Sci Am 260: 74 79, 1989. Nowakowski RS and Hayes NL. New neurons: extraordinary evidence or extraordinary conclusion? Science 288: 771, 2000. Nowakowski RS, Lewin SB, and Miller MW. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically dened population. J Neurocytol 18: 311318, 1989. Ohtsuka T, Sakamoto M, Guillemot F, and Kageyama R. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem 276: 30467 30474, 2001. Okano HJ and Darnell RB. A hierarchy of Hu RNA binding proteins in developing and adult neurons. J Neurosci 17: 3024 3037, 1997. Okano HJ, Pfaff DW, and Gibbs RB. RB and Cdc2 expression in brain: correlations with 3H-thymidine incorporation and neurogenesis. J Neurosci 13: 2930 2938, 1993. Okano HJ, Pfaff DW, and Gibbs RB. Expression of EGFR-, p75NGFR-, and PSTAIR (cdc2)-like immunoreactivity by proliferating cells in the adult rat hippocampal formation and forebrain. Dev Neurosci 18: 199 209, 1996. Okuyama N, Takagi N, Kawai T, Miyake-Takagi K, and Takeo S. Phosphorylation of extracellular-regulating kinase in NMDA receptor antagonist-induced newly generated neurons in the adult rat dentate gyrus. J Neurochem 88: 717725, 2004. Ono K, Tomasiewicz H, Magnuson T, and Rutishauser U. NCAM mutation inhibits tangential neuronal migration and is phenocopied by enzymatic removal of polysialic acid. Neuron 13: 595 609, 1994. Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci 14: 453501, 1991. Ormerod BK, Falconer EM, and Galea LA. N-methyl-D-aspartate receptor activity and estradiol: separate regulation of cell proliferation in the dentate gyrus of adult female meadow vole. J Endocrinol 179: 155163, 2003. Ormerod BK and Galea LAM. Reproductive status inuences cell proliferation and cell survival in the dentate gyrus of adult female meadow voles: a possible regulatory role for estradiol. Neuroscience 102: 369 379, 2001. Ormerod BK, Lee TT, and Galea LA. Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55: 247260, 2003. Oumesmar BN, Vignais L, Duhamel-Clerin E, Avellana-Adalid V, Rougon G, and Baron-Van Evercooren A. Expression of the Physiol Rev VOL
565
401. 402. 403. 404.
424. 425.
426. 427.
405.
406.
428.
407.
429.
408. 409.
430.
410. 411. 412.
431.
432.
413.
433.
414.
434.
415.
435.
416.
436.
417.
437.
418.
438.
419. 420.
439.
421.
440. 441.
422.
442.
423.
highly polysialylated neural cell adhesion molecule during postnatal myelination and following chemically induced demyelination of the adult mouse spinal cord. Eur J Neurosci 7: 480 491, 1995. Palmer TD, Willhoite AR, and Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425: 479 494, 2000. Parent JM, Janumpalli S, McNamara JO, and Lowenstein DH. Increased dentate granule cell neurogenesis following amygdala kindling in the adult rat. Neurosci Lett 247: 9 12, 1998. Parent JM and Lowenstein DH. Mossy ber reorganization in the epileptic hippocampus. Curr Opin Neurol 10: 103109, 1997. Parent JM, Tada E, Fike JR, and Lowenstein DH. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy ber synaptic reorganization in the rat. J Neurosci 19: 4508 4519, 1999. Parent JM, Valentin VV, and Lowenstein DH. Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. J Neurosci 22: 3174 3188, 2002. Parent JM, Vexler ZS, Gong C, Derugin N, and Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52: 802 813, 2002. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, and Lowenstein DH. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17: 37273738, 1997. Park HJ, Lim S, Lee HS, Lee HJ, Yoo YM, Lee HJ, Kim SA, Yin CS, Seo JC, and Chung JH. Acupuncture enhances cell proliferation in dentate gyrus of maternally-separated rats. Neurosci Lett 319: 153156, 2002. Paula-Barbosa MM, Brandao F, Madeira MD, and CadeteLeite A. Structural changes in the hippocampal formation after long-term alcohol consumption and withdrawal in the rat. Addiction 88: 237247, 1993. Peissner W, Kocher M, Treuer H, and Gillardon F. Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Mol Brain Res 71: 61 68, 1999. Pencea V, Bingaman KD, Freedman LJ, and Luskin MB. Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain. Exp Neurol 172: 116, 2001. Perez-Martin M, Azcoitia I, Trejo JL, Sierra A, and GarciaSegura LM. An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat. Eur J Neurosci 18: 923930, 2003. Perlieva E, Risedal A, Nyberg J, Johansson BB, and Eriksson PS. Gender and strain inuence on neurogenesis in dentate gyrus of young rats. J Cereb Blood Flow Metab 21: 211217, 2001. Persson AI, Thorlin T, Bull C, Zarnegar P, Ekman R, Terenius L, and Eriksson PS. Mu- and delta-opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors. Eur J Neurosci 17: 1159 1172, 2003. Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, and Arnold A. The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev 20: 501534, 1999. Petreanu L and Alvarez-Buylla A. Maturation and death of adultborn olfactory bulb granule neurons: role of olfaction. J Neurosci 22: 6106 6113, 2002. Pevny L and Rao MS. The stem-cell menagerie. Trends Neurosci 26: 351359, 2003. Pham K, Nacher J, Hof PR, and McEwen BS. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci 17: 879 886, 2003. Pham TM, Ickes B, Albeck D, Soderstrom S, Granholm AC, and Mohammed AH. Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year. Neuroscience 94: 279 286, 1999. www.prv.org
85 APRIL 2005
566
ABROUS, KOEHL, AND LE MOAL form of the neuronal cell adhesion molecule by glucocorticoids in the rat hippocampus. Eur J Neurosci 10: 2994 3006, 1998. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Coeld M, Mansukhani L, and Willson P. Clinical trial of indomethacin in Alzheimers disease. Neurology 43: 1609 1611, 1993. Rogister B, Ben Hur T, and Dubois-Dalcq M. From neural stem cells to myelinating oligodendrocytes. Mol Cell Neurosci 14: 287 300, 1999. Rolls ET. A theory of hippocampal function in memory. Hippocampus 6: 601 620, 1996. Rosenbaum RS, Winocur G, and Moscovitch M. New views on old memories: re-evaluating the role of the hippocampal complex. Behav Brain Res 127: 183197, 2001. Rosenzweig MR. Effects of environmental complexity and training on brain chemistry and anatomy: a replication and extension. J Comp Physiol Psychol 55: 429 437, 1962. Rosenzweig MR and Bennett E. Experimental Inuences on Brain Anatomy and Brain Chemistry in Rodents. New York: Academic, 1977. Rosenzweig MR and Bennett EL. Psychobiology of plasticity: effects of training and experience on brain and behaviour. Behav Brain Res 78: 57 65, 1996. Ross SE, Greenberg ME, and Stiles CD. Basic helix-loop-helix factors in cortical development. Neuron 39: 1325, 2003. Rousselot P, Lois C, and Alvarez-Buylla A. Embryonic (PSA) N-CAM reveals chains of migrating neuroblasts between the lateral ventricle and the olfactory bulb of adult mice. J Comp Neurol 351: 51 61, 1995. Roy NS, Wang S, Jiang L, Kang J, Benraiss A, HarrisonRestelli C, Fraser RA, Couldwell WT, Kawaguchi A, Okano H, Nedergaard M, and Goldman SA. In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6: 271277, 2000. Rueda D, Navarros B, martinez-Serrano A, Guzman M, and Gave-Roperh I. The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/ B-Raf/ERK pathway. J Biol Chem 277: 46645 46650, 2002. Sabbieti MG, Marchetti L, Abreu C, Montero A, Hand AR, Raisz LG, and Hurley MM. Prostaglandins regulate the expression of broblast growth factor-2 in bone. Endocrinology 140: 434 444, 1999. Saghatelyan A, De Chevigny A, Schachner M, and Lledo PM. Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain. Nat Neurosci 7: 347356, 2004. Sakakibara S, Imai T, Hamaguchi K, Okabe M, Aruga J, Nakajima K, Yasutomi D, Nagata T, Kurihara Y, Uesugi S, Miyata T, Ogawa M, Mikoshiba K, and Okano H. Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 176: 230 242, 1996. Sakakibara SI, Nakamura Y, Satoh H, and Okano H. RNAbinding protein musashi2: developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS. J Neurosci 21: 8091 8107, 2001. Sakamoto M, Hirata H, Ohtsuka T, Bessho Y, and Kageyama R. The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. J Biol Chem 278: 44808 44815, 2003. Sanchez MM, Ladd CO, and Plotsky PM. Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev Psychopathol 13: 419 449, 2001. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, and Hen R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805 809, 2003. Sapolsky RM. Stress, the Aging Brain, and the Mechanisms of Neuron Death. Cambridge, MA: MIT Press, 1992. Sasaki T, Kitagawa K, Sugiura S, Omura-Matsuoka E, Tanaka S, Yagita Y, Okano H, Matsumoto M, and Hori M. Implication of cyclooxygenase-2 on enhanced proliferation of neural progenitor cells in the adult mouse hippocampus after ischemia. J Neurosci Res 72: 461 471, 2003. www.prv.org
443. Piazza PV, Deminiere JM, Le Moal M, and Simon H. Factors that predict individual vulnerability to amphetamine self-administration. Science 245: 15111513, 1989. 444. Piazza PV, Deroche V, Deminiere JM, Maccari S, Le Moal M, and Simon H. Corticosterone in the range of stress-induced levels possesses reinforcing properties: implications for sensation-seeking behaviors. Proc Natl Acad Sci USA 90: 11738 11742, 1993. 445. Piazza PV, Deroche-Gamonent V, Rouge-Pont F, and Le Moal M. Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20: 4226 4232, 2000. 446. Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, and Simon H. Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci USA 88: 2088 2092, 1991. 447. Piazza PV, Mittleman G, Deminiere JM, Le Moal M, and Simon H. Relationship between schedule-induced polydipsia and amphetamine intravenous self-administration. Individual differences and role of experience. Behav Brain Res 55: 185193, 1993. 448. Privat A and Leblond CP. The subependymal layer and neighboring region in the brain of the young rat. J Comp Neurol 146: 277302, 1972. 449. Pu L, Bao GB, Xu NJ, Ma L, and Pei G. Hippocampal long-term potentiation is reduced by chronic opiate treatment and can be restored by re-exposure to opiates. J Neurosci 22: 1914 1921, 2002. 450. Quartz SR and Sejnowski TJ. The neural basis of cognitive development: a constructivist manifesto. Behav Brain Sci 20: 537 556, 1997. 451. Radley JJ and Jacobs BL. 5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus. Brain Res 955: 264 267, 2002. 452. Rakic P. Limits of neurogenesis in primates. Science 227: 1054 1056, 1985. 453. Rakic P. Adult neurogenesis in mammals: an identity crisis. J Neurosci 22: 614 618, 2002. 454. Rakic P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat Rev Neurosci 3: 6571, 2002. 455. Ramirez-Amaya V, Balderas I, Sandoval J, Escobar ML, and Bermudez-Rattoni F. Spatial long-term memory is related to mossy ber synaptogenesis. J Neurosci 21: 7340 7348, 2001. 456. Rao MS and Shetty AK. Efcacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur J Neurosci 19: 234 246, 2004. 457. Rapp PR and Amaral DG. Individual differences in the cognitive and neurobiological consequences of normal aging. Trends Neurosci 15: 340 345, 1992. 458. Rapp PR and Gallagher M. Preserved neuron number in the hippocampus of aged rats with spatial learning decits. Proc Natl Acad Sci USA 93: 9926 9930, 1996. 459. Rice AC, Khaldi A, Harvey HB, Salman NJ, White F, Fillmore H, and Bullock MR. Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury. Exp Neurol 183: 406 417, 2003. 460. Riddle DR, Sonntag WE, and Lichtenwalner RJ. Microvascular plasticity in aging. Ageing Res Rev 2: 149 168, 2003. 461. Riley JN and Walker DW. Morphological alterations in hippocampus after long-term alcohol consumption in mice. Science 201: 646 648, 1978. 462. Robbins TW and Everitt BJ. Limbic-striatal memory systems and drug addiction. Neurobiol Learn Memory 78: 625 636, 2002. 463. Robinson TE and Kolb B. Persistent structural modications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17: 8491 8497, 1997. 464. Rochefort C, Gheusi G, Vincent JD, and Lledo PM. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci 22: 2679 2689, 2002. 465. Rodriguez JJ, Montaron MF, Petry KG, Aurousseau C, Marinelli M, Premier S, Rougon G, Le Moal M, and Abrous DN. Complex regulation of the expression of the polysialylated Physiol Rev VOL
466.
467.
468. 469.
470.
471.
472.
473. 474.
475.
476.
477.
478.
479.
480.
481.
482.
483.
484. 485.
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN 486. Scemes E. Components of astrocytic intercellular calcium signaling. Mol Neurobiol 22: 167179, 2000. 487. Scharfman HE, Goodman JH, and Sollas AL. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci 20: 6144 6158, 2000. 488. Schmajuk NA. Hippocampal dysfunction in schizophrenia. Hippocampus 11: 599 613, 2001. 489. Schmidt W and Reymann KG. Proliferating cells differentiate into neurons in the hippocampal CA1 region of gerbils after global cerebral ischemia. Neurosci Lett 334: 153156, 2002. 490. Schmidt-Hieber C, Jonas P, and Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429: 184 187, 2004. 491. Schweisguth F. Notch signaling activity. Curr Biol 14: R129 R138, 2004. 492. Scott BW, Wang S, Burnham WM, De Boni U, and Wojtowicz JM. Kindling-induced neurogenesis in the dentate gyrus of the rat. Neurosci Lett 248: 7376, 1998. 493. Seaberg RM and van der Kooy D. Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci 22: 1784 1793, 2002. 494. Seaberg RM and van der Kooy D. Stem and progenitor cells: the premature desertion of rigorous denitions. Trends Neurosci 26: 125131, 2003. 495. Sekerkova G, Ilijic E, and Mugnaini E. Bromodeoxyuridine administered during neurogenesis of the projection neurons causes cerebellar defects in rat. J Comp Neurol 470: 221239, 2004. 496. Seki T. Expression patterns of immature neuronal markers PSANCAM, CRMP-4 and NeuroD in the hippocampus of young adult and aged rodents. J Neurosci Res 70: 327334, 2002. 497. Seki T. Hippocampal adult neurogenesis occurs in a microenvironment provided by PSA-NCAM-expressing immature neurons. J Neurosci Res 69: 772783, 2002. 498. Seki T and Arai Y. Highly polysialylated neural cell adhesion molecule (NCAM-H) is expressed by newly generated granule cells in the dentate gyrus of the adult rat. J Neurosci 13: 23512358, 1993. 499. Seki T and Arai Y. Age-related production of new granule cells in the adult dentate gyrus. Neuroreport 6: 2479 2482, 1995. 500. Seri B and Alvarez-Buylla A. Neural stem cells and the regulation of neurogenesis in the adult hippocampus. Clin Neurosci Res 2: 1116, 2002. 501. Seri B, Garcia-Verdugo JM, McEwen BS, and Alvarez-Buylla A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21: 71537160, 2001. 502. Seroogy KB, Gall CM, Lee DC, and Kornblum HI. Proliferative zones of postnatal rat brain express epidermal growth factor receptor mRNA. Brain Res 670: 157164, 1995. 503. Shastri L. Episodic memory and cortico-hippocampal interactions. Trends Cogn Sci 6: 162168, 2002. 504. Sheline YI, Sanghavi M, Mintun MA, and Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19: 5034 5043, 1999. 505. Shen Q, Goderie S, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, and Temple S. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. In press. 506. Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, Cross JC, and Weiss S. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299: 117120, 2003. 507. Shingo T, Sorokan ST, and Shimazaki TWS. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21: 97339743, 2001. 508. Shors TJ. Memory traces of trace memories: neurogenesis, synaptogenesis and awareness. Trends Neurosci 27: 250 256, 2004. 509. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, and Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410: 372376, 2001. Physiol Rev VOL
567
510. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, and Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12: 578 584, 2002. 511. Smart I. The subependymal layer of the mouse brain and its cell production as shown by radioautography after thymidine-H3 injection. J Comp Neurol 116: 325347, 1961. 512. Solomon PR, Vander Schaaf ER, Thompson RF, and Weisz DJ. Hippocampus and trace conditioning of the rabbits classically conditioned nictitating membrane response. Behav Neurosci 100: 729 744, 1986. 513. Song H, Stevens CF, and Gage FH. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci 5: 438 445, 2002. 514. Song H, Stevens CF, and Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature 417: 39 44, 2002. 515. Sousa N and Almeida OFX. Corticosteroids: sculptors of the hippocampal formation. Rev Neurosci 13: 59 84, 2002. 516. Spranger M, Lindholm D, Bandtlow C, Heumann R, Gnahn H, Njer-No M, and Thonen H. Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: comparison between the effects of interleukin-1 and various growth factors in astrocyte culture and in vivo. Eur J Neurosci 2: 69 76, 1990. 517. Staneld BB and Trice JE. Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res 72: 399 406, 1988. 518. Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, and Schteingart DE. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushings disease. Biol Psychiatry 46: 15951602, 1999. 519. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, MacFall JR, and Krishnan KR. Hippocampal volume in geriatric depression. Biol Psychiatry 48: 301 309, 2000. 520. Stein-Behrens BA, Lin WJ, and Sapolsky RM. Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63: 596 602, 1994. 521. Steiner B, Kronenberg G, Jessberger S, Brandt MD, Reuter K, and Kempermann G. Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice. Glia 46: 4152, 2004. 522. Stenvers KL, Lund PK, and Gallagher M. Increased expression of type 1 insulin-like growth factor receptor messenger RNA in rat hippocampal formation is associated with aging and behavioral impairment. Neuroscience 72: 505518, 1996. 523. Stump G, Durrer A, Klein AL, Lutolf S, Suter U, and Taylor V. Notch1 and its ligands Delta-like and Jagged are expressed and active in distinct cell populations in the postnatal mouse brain. Mech Dev 114: 153159, 2002. 524. Sullivan EV, Marsh L, Mathalon DH, Lim KO, and Pfefferbaum A. Anterior hippocampal volume decits in nonamnesic, aging chronic alcoholics. Alcohol Clin Exp Res 19: 110 122, 1995. 525. Sun W and Rebec GV. Lidocaine inactivation of ventral subiculum attenuates cocaine-seeking behavior in rats. J Neurosci 23: 10258 10264, 2003. 526. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, and Greenberg DA. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111: 18431851, 2003. 527. Sutherland RJ, Weisend MP, Mumby D, Astur RS, Hanlon FM, Koerner A, Thomas MJ, Wu Y, Moses SN, Cole C, Hamilton DA, and Hoesing JM. Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks. Hippocampus 11: 27 42, 2001. 528. Suto N, Austin JD, and Vezina P. Locomotor response to novelty predicts a rats propensity to self-administer nicotine. Psychopharmacologia 158: 175180, 2001. 529. Sutula T, Cascino G, Cavazos J, Parada I, and Ramirez L. Mossy ber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 26: 321330, 1989. 530. Sutula T, Lauersdorf S, Lynch M, Jurgella C, and Woodard A. Decits in radial arm maze performance in kindled rats: evidence for long-lasting memory dysfunction induced by repeated brief seizures. J Neurosci 15: 8295 8301, 2003. www.prv.org
85 APRIL 2005
568
ABROUS, KOEHL, AND LE MOAL 551. Valle e M, Mayo W, Darnaude ry M, Corpe chot C, Young J, Koehl M, Le Moal M, Baulieu EE, Robel P, and Simon H. Neurosteroids: decient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc Natl Acad Sci USA 94: 1486514870, 1997. 552. Vallieres L, Campbell IL, Gage FH, and Sawchenko PE. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22: 486 492, 2002. 553. Van Praag H, Christie BR, Sejnowski TJ, and Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96: 1342713431, 1999. 554. Van Praag H, Kempermann G, and Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2: 266 270, 1999. 555. Van Praag H, Kempermann G, and Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci 1: 191 198, 2000. 556. Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, and Gage FH. Functional neurogenesis in the adult hippocampus. Nature 415: 1030 1034, 2002. 557. Vazquez DM. Stress and the developing limbic-hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 23: 663700, 1988. 558. Velakoulis D, Stuart GW, Wood SJ, Smith DJ, Brewer WJ, Desmond P, Singh B, Copolov D, and Pantelis C. Selective bilateral hippocampal volume loss in chronic schizophrenia. Biol Psychiatry 50: 531539, 2001. 559. Viau V, Sharma S, and Meaney MJ. Changes in plasma adrenocorticotropin, corticosterone, corticosteroid-binding globulin, and hippocampal glucocorticoid receptor occupancy/translocation in rat pups in response to stress. J Neuroendocrinol 8: 1 8, 1996. 560. Vitry S, Avellana-Adalid V, Hardy R, Lachapelle F, and BaronVan Evercooren A. Mouse oligospheres: from pre-progenitors to functional oligodendrocytes. J Neurosci Res 58: 735751, 1999. 561. Vorel SR, Liu X, Hayes RJ, Spector JA, and Gardner EL. Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292: 11751178, 2001. 562. Wakade CG, Mahadik SP, Waller JL, and Chiu FC. Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 69: 7279, 2002. 563. Walker DW, Barnes DE, Zornetzer SF, Hunter BE, and Kubanis P. Neuronal loss in hippocampus induced by prolonged ethanol consumption in rats. Science 209: 711713, 1980. 564. Wang S, Scott BW, and Wojtowicz JM. Heterogeneous properties of dentate granule neurons in the adult rat. J Neurobiol 42: 248 257, 2000. 565. Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, and Seeman TE. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 59: 371378, 2002. 566. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 81: 323330, 1995. 567. Weinmaster G. Notch signal transduction: a real rip and more. Curr Opin Genet Dev 10: 363369, 2000. 568. Weinstein DE, Burrola P, and Kilpatrick TJ. Increased proliferation of precursor cells in the adult rat brain after targeted lesioning. Brain Res 743: 1116, 1996. 569. Weinstock M. Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 65: 427 451, 2001. 570. Weiss S, Reynolds BA, Vescovi AL, Morshead C, Craig CG, and van der Kooy D. Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 19: 387393, 1996. 571. White NM. Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction 91: 921949, 1996. 572. Winner B, Cooper-Kuhn CM, Aigner R, Winkler J, and Kuhn HG. Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur J Neurosci 16: 16811689, 2002. 573. Wittenberg GM and Tsien JZ. An emerging molecular and cellular framework for memory processing by the hippocampus. Trends Neurosci 25: 501505, 2002. 574. Wu W, Wong K, Chen J, Jiang Z, Dupuis S, Wu JY, and Rao Y. Directional guidance of neuronal migration in the olfactory system by the protein Slit. Nature 400: 331336, 1999. www.prv.org
531. Szele FG and Chesselet MF. Cortical lesions induce an increase in cell number and PSA-NCAM expression in the subventricular zone of adult rats. J Comp Neurol 368: 439 454, 1996. 532. Tada E, Parent JM, Lowenstein DH, and Fike JR. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 99: 33 41, 2000. 533. Taepavarapruk P and Phillips AG. Neurochemical correlates of relapse to D-amphetamine self-administration by rats induced by stimulation of the ventral subiculum. Psychopharmacology 168: 99 108, 2003. 534. Takasawa K, Kitagawa K, Yagita Y, Sasaki T, Tanaka S, Matsushita K, Ohstuki T, Miyata T, Okano H, Hori M, and Matsumoto M. Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 22: 299 307, 2002. 535. Tan SE. Impairing the amphetamine conditioning in rats through the inhibition of hippocampal calcium/calmodulin-dependent protein kinase II activity. Neuropharmacology 42: 540 547, 2002. 536. Tanapat P, Hastings NB, Reeves AJ, and Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 19: 57925801, 1999. 537. Tanapat P, Hastings NB, Rydel TA, Galea LA, and Gould E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol 437: 496 504, 2001. 538. Teyler TJ and DiScenna P. The hippocampal memory indexing theory. Behav Neurosci 100: 147154, 1986. 539. Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, and Nomura Y. Changes in expressions of proinammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885: 2531, 2000. 540. Tomasiewicz H, Ono K, Yee D, Thompson C, Goridis C, Rutishauser U, and Magnuson T. Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system. Neuron 11: 11631174, 1993. 541. Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, and Svoboda K. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420: 788 794, 2002. 542. Trejo JL, Carro E, and Torres-Aleman I. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21: 1628 1634, 2001. 543. Tropepe V, Craig CG, Morshead CM, and van der Kooy D. Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci 17: 7850 7859, 1997. 544. Tsai G and Coyle JT. N-aspartate in neuropsychiatric disorders. Prog Neurobiol 46: 531540, 1995. 545. Tzeng SF. Inhibitors of DNA binding in neural cell proliferation and differentiation. Neurochem Res 28: 4552, 2003. 546. Tzeng SF and Wu JP. Responses of microglia and neural progenitors to mechanical brain injury. Neuroreport 10: 22872292, 1999. 547. Uchida K, Kumihashi K, Kurosawa S, Kobayashi T, Itoi K, and Machida T. Stimulatory effects of prostaglandin E2 on neurogenesis in the dentate gyrus of the adult rat. Zool Sci 19: 12111216, 2002. 548. Ueki T, Tanaka M, Yamashita K, Mikawa S, Qiu Z, Maragakis NJ, Hevner RF, Miura N, Sugimura H, and Sato K. A novel secretory factor, Neurogenesin-1, provides neurogenic environmental cues for neural stem cells in the adult hippocampus. J Neurosci 23: 1173211740, 2003. 549. Vaidya VA, Siuciak JA, Du F, and Duman RS. Hippocampal mossy ber sprouting induced by chronic electroconvulsive seizures. Neuroscience 89: 157166, 1999. 550. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, BonelloCintron CM, and Yurgelun-Todd DA. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry 47: 10871090, 2000. Physiol Rev VOL
85 APRIL 2005
NEUROGENESIS IN THE ADULT BRAIN 575. Yagita Y, Kitagawa K, Ohtsuki T, Takasawa K, Miyata T, Okano H, Hori M, and Matsumoto M. Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Stroke 32: 1890 1896, 2001. 576. Yagita Y, Kitagawa K, Sasaki T, Miyata T, Okano H, Hori M, and Matsumoto M. Differential expression of Musashi1 and nestin in the adult rat hippocampus after ischemia. J Neurosci Res 69: 750 756, 2002. 577. Yamaguchi M, Saito H, Suzuki M, and Mori K. Visualization of neurogenesis in the central nervous system using nestin promoterGFP transgenic mice. Neuroreport 11: 19911996, 2000. 578. Yanagisawa M, Takizawa T, Ochiai W, Uemura A, Nakashima K, and Taga T. Fate alteration of neuroepithelial cells from neurogenesis to astrocytogenesis by bone morphogenetic proteins. Neurosci Res 41: 391396, 2001. 579. Yoshida K, Kakihana M, Chen LS, Ong M, Baird A, and Gage FH. Cytokine regulation of nerve growth factor-mediated cholinergic neurotrophic activity synthesized by astrocytes and broblasts. J Neurochem 59: 919 931, 1992. 580. Yoshikawa K. Cell cycle regulators in neural stem cells and postmitotic neurons. Neurosci Res 37: 114, 2000. 581. Yoshimizu T and Chaki S. Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotropic glutamate receptor antagonist, MGS0039. Biochem Biophys Res Commun 315: 493 496, 2004. 582. Yoshimura S, Takagi Y, Harada J, Teramoto T, Thomas SS, Waeber C, Bakowska JC, Breakeeld XO, and Moskowitz MA. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci USA 98: 5874 5879, 2001. 583. Young D and Dragunow M. Neuronal injury following electrically induced status epilepticus with and without adenosine receptor antagonism. Exp Neurol 133: 125137, 1995. 584. Young D, Lawlor PA, Leone P, Dragunow M, and During MJ. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 5: 448 453, 1999. 585. Yu IT, Lee SH, Lee YS, and Son H. Differential effects of corticosterone and dexamethasone on hippocampal neurogenesis in vitro. Biochem Biophys Res Commun 317: 484 490, 2004.
569
586. Yuste R and Bonhoeffer T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24: 10711089, 2001. 587. Zhang R, Zhang L, Zhang Z, Wang Y, Lu M, Lapointe M, and Chopp M. A nitric oxide donor induces neurogenesis and reduces functional decits after stroke in rats. Ann Neurol 50: 602 611, 2001. 588. Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C, and Chopp M. Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab 24: 441 448, 2004. 589. Zhang RL, Zhang ZG, Zhang L, and Chopp M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105: 33 41, 2001. 590. Zhu DY, Liu SH, Sun HS, and Lu YM. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 23: 223229, 2003. 591. Zhu Y, Jin K, Mao XO, and Greenberg DA. Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J 17: 186 193, 2003. 592. Zhu Z, Jiang W, and Thompson HJ. Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas. Carcinogenesis 24: 12251231, 2003. 593. Zigova T, Pencea V, Wiegand SJ, and Luskin MB. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 11: 234 245, 1998. 594. Zucconi GG and Giuditta A. Is it only neurogenesis? Rev Neurosci 13: 375382, 2002. 595. Zwain IH and Yen SS. Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain. Endocrinology 140: 38433852, 1999.
Physiol Rev VOL
85 APRIL 2005
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Adult Neurogenesis: From Precursors to Network and Physiology

Djoher Nora Abrous, Muriel Koehl and Michel Le Moal
Physiol Rev 85:523-569, 2005. doi:10.1152/physrev.00055.2003 You might find this additional info useful... This article cites 585 articles, 150 of which can be accessed free at: http://physrev.physiology.org/content/85/2/523.full.html#ref-list-1 This article has been cited by 50 other HighWire hosted articles, the first 5 are: IDH Mutation and Neuroglial Developmental Features Define Clinically Distinct Subclasses of Lower Grade Diffuse Astrocytic Glioma Daniel Gorovets, Kasthuri Kannan, Ronglai Shen, Edward R. Kastenhuber, Nasrin Islamdoust, Carl Campos, Elena Pentsova, Adriana Heguy, Suresh C. Jhanwar, Ingo K. Mellinghoff, Timothy A. Chan and Jason T. Huse Clin Cancer Res, May 1, 2012; 18 (9): 2490-2501. [Abstract] [Full Text] [PDF] Long-Lasting Plasticity of Hippocampal Adult-Born Neurons Valrie Lemaire, Sophie Tronel, Marie-Franoise Montaron, Annabelle Fabre, Emilie Dugast and Djoher Nora Abrous J. Neurosci., February 29, 2012; 32 (9): 3101-3108. [Abstract] [Full Text] [PDF] Risperidone Administered During Asymptomatic Period of Adolescence Prevents the Emergence of Brain Structural Pathology and Behavioral Abnormalities in an Animal Model of Schizophrenia Yael Piontkewitz, Michal Arad and Ina Weiner Schizophr Bull, November , 2011; 37 (6): 1257-1269. [Abstract] [Full Text] [PDF] ApoE is required for maintenance of the dentate gyrus neural progenitor pool Cui-Ping Yang, Jennifer A. Gilley, Gui Zhang and Steven G. Kernie Development, October 15, 2011; 138 (20): 4351-4362. [Abstract] [Full Text] [PDF] EphB2 Tyrosine Kinase-Dependent Forward Signaling in Migration of Neuronal Progenitors That Populate and Form a Distinct Region of the Dentate Niche Timothy Catchpole and Mark Henkemeyer J. Neurosci., August 10, 2011; 31 (32): 11472-11483. [Abstract] [Full Text] [PDF] Updated information and services including high resolution figures, can be found at: http://physrev.physiology.org/content/85/2/523.full.html Additional material and information about Physiological Reviews can be found at: http://www.the-aps.org/publications/prv
Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2005 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at http://www.the-aps.org/.
This information is current as of May 26, 2012.
Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2005 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at http://www.the-aps.org/.

Adult Neurogenesis - From Precursors To Network and Physiology (2005)

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Physiol Rev 85: 523569, 2005; doi:10.1152/physrev.00055.2003.

Adult Neurogenesis: From Precursors to Network and Physiology

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0031-9333/05 $18.00 Copyright 2005 the American Physiological Society

ABROUS, KOEHL, AND LE MOAL

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NEUROGENESIS IN THE ADULT BRAIN

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ABROUS, KOEHL, AND LE MOAL

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NEUROGENESIS IN THE ADULT BRAIN

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ABROUS, KOEHL, AND LE MOAL

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Physiol Rev VOL

NEUROGENESIS IN THE ADULT BRAIN

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ABROUS, KOEHL, AND LE MOAL

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NEUROGENESIS IN THE ADULT BRAIN

m n mproE n m then n 0 m (4h) 0 m Neurosteroids m m n Neurotransmitters

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DHEA PregS Allopreg

254 349 349

m n m m m n 0 m m m 0 m 0 m 0 m m m m m m m m m n m m m n 0 m 0 n m m n m 0 0 n 0 0 0 n m m Growth or trophic factors 0 0 m m 0 m m Morphogenic factors m n m n m n m Vitamins and retinoids

0 n m 0 n m m (ovx) m 0 n 0 or m (hpx) m 0 0 0 292 335 587

bFGF EGF HB-EGF TGF- IGF-I BDNF CNTF VEGF

Shh BMP Noggin

295 311 311

Vitamin E Deciency Supplementation (tocopherol) Retinoic acid (chronic treatment)

86, 87 83, 102 99

Physiol Rev VOL

ABROUS, KOEHL, AND LE MOAL

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NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012

ABROUS, KOEHL, AND LE MOAL

Downloaded from physrev.physiology.org on May 26, 2012

NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012

ABROUS, KOEHL, AND LE MOAL

Downloaded from physrev.physiology.org on May 26, 2012

NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012

ABROUS, KOEHL, AND LE MOAL

Downloaded from physrev.physiology.org on May 26, 2012

NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012

ABROUS, KOEHL, AND LE MOAL

Downloaded from physrev.physiology.org on May 26, 2012

NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012

Physiol Rev VOL

ABROUS, KOEHL, AND LE MOAL

Downloaded from physrev.physiology.org on May 26, 2012

Physiol Rev VOL

NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012

ABROUS, KOEHL, AND LE MOAL

Downloaded from physrev.physiology.org on May 26, 2012

NEUROGENESIS IN THE ADULT BRAIN

Downloaded from physrev.physiology.org on May 26, 2012