Learning and adult neurogenesis: Survival with or without proliferation?

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Abstract

Recent high quality papers have renewed interest in the phenomenon of neurogenesis within the adult mammalian brain. Many studies now show that neurogenesis can be modulated by environmental factors including physical activity, stress, and learning. These findings have considerable implications for neuroscience in general, including the study of learning and memory, neural network plasticity, aging, neurodegeneration, and the recovery from brain injury. Although new light has been shed on this field, many contradictory findings have been reported. Here we propose two principle issues which underlie these inconsistencies, with particular focus on the interaction between learning and neurogenesis. The first issue relates to the basic methodology of measuring the generation of new brain cells, i.e., proliferation, as compared to survival of the newly made cells. Mostly, measures of neurogenesis reported are a combination of proliferation and survival, making it impossible to distinguish between these separate processes. The second aspect is in regards to the role of environmental factors which can affect both proliferation and survival independently. Especially the interaction between stress and learning is of importance since these might counteract each other in some circumstances. Reviewing the literature while taking these issues into account indicates that, in contrast to some findings, cell proliferation in the dentate gyrus of the hippocampus as a result of learning cannot be ruled out yet. On the other hand, increased survival of granule cells in the dentate gyrus as a result of hippocampal-dependent learning has been clearly demonstrated. Moreover, this learning-induced survival of granule cells, which were born before the actual learning experience, might provide a molecular mechanism for the ‘use it or lose it’ principle.

Introduction

The generation of new neurons within the postnatal rat brain was first described in 1901 (Hamilton, 1901), a report which includes hand drawn plates of what we now call the subventricular zone. This was later discovered to occur also within the adult brain by Altman and Das (1965) who called this neurogenesis. However, only recently has neurogenesis become accepted as a general phenomenon in the brains of birds (e.g., Barnea & Nottebohm, 1994), rodents (e.g., Gould, Beylin, Tanapat, Reeves, & Shors, 1999a; Kempermann, Kuhn, & Gage, 1997b; Van Praag, Christie, Sejnowski, & Gage, 1999a; Van Praag, Kempermann, & Gage, 1999b), monkeys (e.g., Gould, Tanapat, McEwen, Flugge, & Fuchs, 1998), and humans (Eriksson et al., 1998). Two principal regions within the adult brain have been identified where progenitor cells are able to give rise to new neurons in adulthood namely; the subgranular zone of the dentate gyrus within the hippocampal formation and the subventricular zone lining the walls of the lateral ventricles within the forebrain.

Under ‘normal’ environmental conditions it is estimated that at least 50% of the newly generated cells within the hippocampus or subventricular zone die within 1–2 months after birth (Cameron, Woolley, McEwen, & Gould, 1993; Gould et al., 1999a; Kempermann & Gage, 2002; Kempermann, Gast, Kronenberg, Yamaguchi, & Gage, 2003; Van Praag et al., 1999b; Winner, Cooper-Kuhn, Aigner, Winkler, & Kuhn, 2002). In the young adult rats it has been shown that approximately 9000 new cells are generated in the dentate gyrus each day and that within 5–12 days 50% of these cells can be double-labeled with neuron-specific markers (Cameron & McKay, 2001). Assuming that most of the new granule neurons were to survive for 4 weeks, the number of new neurons generated in the hippocampus could be as large as an impressive 6% of the total granule cell population.

Various environmental factors have been found to modulate the rate of proliferation of new cells in the dentate gyrus of rodents. For example, physical activity (e.g., Van Praag et al., 1999b) and enriched environment (e.g., Kempermann, Brandon, & Gage, 1998a) were found to increase hippocampal proliferation. Also, it has recently been found that hippocampal-dependent learning can enhance proliferation of hippocampal cells (Lemaire, Koehl, Le Moal, & Abrous, 2000). Two other studies did not, however, observe an effect of hippocampal-dependent learning on hippocampal proliferation (Gould et al., 1999a; Van Praag et al., 1999b). A factor that negatively affects proliferation is stress (Czeh et al., 2002; Gould & Tanapat, 1999; Tanapat, Galea, & Gould, 1998; Tanapat, Hastings, Rydel, Galea, & Gould, 2001).

Similar to proliferation, the survival of cells is also partly dependent on environmental conditions. For example, in rodents it has been shown that exposure to an enriched environment (Kempermann et al., 1998a, Kempermann et al., 1997b; Kempermann, Kuhn, & Gage, 1998b; Van Praag et al., 1999b), physical activity (Van Praag et al., 1999a, Van Praag et al., 1999b) or hippocampal-dependent learning (Gould et al., 1999a) can increase or prolong the survival of newly proliferated cells. On the other hand, in contrast to the latter study no effect on the survival of new neurons was found by a different group using the same hippocampal-dependent learning task (Van Praag et al., 1999b). Stress has been shown to decrease the survival rate in the hippocampus of rodents (Czeh et al., 2002).

The principle of neurogenesis (i.e., proliferation and survival) has major implications for different areas of central nervous system research in which until recently adult brain plasticity was assumed to be related to changes in neuronal connections (neurobiology of learning and memory, neuronal network models) and compensation for neuronal loss (aging, neurodegeneration). These new insights have already led to the suggestion that physical and mental activities may reduce both the incidence and severity of neurodegenerative disorders in man (Mattson, 2000). We suggest that this may also provide a mechanism for the already proposed principle of ‘use it or lose it’ during aging and neurodegeneration (Swaab, 1991). According to the ‘use it or lose it’ hypothesis, activation of neuronal activity within the physiological range could preferentially stimulate the action of protective mechanisms during aging and in Alzheimer’s disease. Enriched environment was identified as one possible activating stimulus. However, DNA repair was assumed to be the possible protective mechanism instead of new neurons. We assume that during non-pathological conditions the ‘use it or lose it’ principle might also be applicable since it might determine which new cells or neurons survive (used) or die (not used).

Although the studies available at present have increased our understanding of the factors which mediate neurogenesis, discrepant findings between similar studies, especially in relation to whether hippocampal-dependent learning and neurogenesis are directly related to each other, indicate that the precise nature of this phenomenon still has to be resolved. Table 1 summarizes the findings on the effects of hippocampal-dependent learning on neurogenesis.

It is well known that the behavior and biology of rodents can vary considerably between strains. Further, given that the effect of a treatment is to a great extent strain dependent it is not surprising that recent studies have shown that neurogenesis also depends on the mouse strain that is studied (cf. Kempermann et al., 1998a, Kempermann et al., 1997a; Kempermann & Gage, 2002; Van Praag et al., 1999b). Other factors including species (cf. Gould et al., 1999a; Lemaire et al., 2000; Van Praag et al., 1999b), age (Kempermann, Gast, & Gage, 2002; Kempermann et al., 1998b; Kuhn, Dickinson-Anson, & Gage, 1996), and sex (Tanapat, Hastings, Reeves, & Gould, 1999) also seem to influence the level of both proliferation and survival. In particular the stage of estrus, i.e., fluctuating estrogen levels, appears to directly affect the number of new cells found. Examples can be cited where factors like sex and species may underlie discrepant findings in the literature. For instance, the effect of hippocampal-dependent learning on survival was found using male rats (Gould et al., 1999a) and not with female mice (Van Praag et al., 1999b). The same applies to two conflicting studies with respect to learning and proliferation in which different species were used (i.e., female mice (Van Praag et al., 1999b) vs. female rats (Lemaire et al., 2000)). A valid comparison between studies can be made only if these factors are accounted for.

Here we propose that, in addition to the factors strain, species, age, and sex, the differences in the detection methods used and confounding interactions between the environmental factors hippocampal-dependent learning, stress, and physical activity, can explain the variable effects on cell proliferation and survival of new neurons found in response to stimuli. Moreover, because of these potential pitfalls the conclusions as formulated in the literature with respect to learning and neurogenesis may not be warranted. With differences in methods or confounded methods we will comment on the most widely used technique, BrdU labeling.

Section snippets

General

BrdU protocols, as reported in most studies, do not solely reflect the true level of newly proliferating cells. A confounding factor might be that BrdU can also detect DNA repair, although there are strong arguments against DNA repair as the major source of BrdU labeling in the intact adult brain (Cooper-Kuhn & Kuhn, 2002). Also, changes in the integrity of the blood–brain barrier as a result of an environmental condition might influence the number of cells labeled, e.g., an increased number of

Learning and stress

Proliferation and survival data are influenced by the interaction of factors including genetics, learning, stress, and physical activity. The separate contribution of each factor and their interactions determine the net rate of proliferation and survival. Thus, the lack of a positive effect on proliferation or survival can be nullified by a counteracting factor (e.g., stress). This may explain why no effect of learning in the spatial Morris water escape task was found on proliferation in some

Does only hippocampal-dependent learning affect neurogenesis?

As mentioned above, the increased survival of dentate gyrus granule cells has been found within a hippocampal-dependent learning paradigm, i.e., Morris water escape task and trace paired eye-blink conditioned response (Gould et al., 1999a). Conversely, non-hippocampal-dependent learning in variants of these tasks had no effect on the survival of hippocampal neurons (Gould et al., 1999a). Further, the increased proliferation of dentate gyrus cells has also been found in the spatial Morris water

Conclusions

Besides that appropriate protocols should be used for measuring proliferation and survival independently, both processes should be measured within the same experiment since they are directly related to each other. For instance, changes in survival of cells supposed to be caused by an environmental factor may just be due to changes in the rate of initial proliferation caused by the same environmental factor. The complex nature of the interaction between proliferation and survival, and the

References (46)

  • M.P. Mattson

    Neuroprotective signaling and the aging brain: Take away my food and let me run

    Brain Research

    (2000)
  • S.-M. Ra et al.

    Treadmill running and swimming increase cell proliferation in the hippocampal dentate gyrus of rats

    Neuroscience Letters

    (2002)
  • D.A. Rusakov et al.

    Ultrastructural synaptic correlates of spatial learning in rat hippocampus

    Neuroscience

    (1997)
  • D.F. Swaab

    Brain aging and Alzheimer’s disease: ‘Wear and tear’ vs. ‘use it or lose it’

    Neurobiology of Aging

    (1991)
  • P. Tanapat et al.

    Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus

    International Journal of Developmental Neuroscience

    (1998)
  • J. Altman et al.

    Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

    Journal of Comparative Neurology

    (1965)
  • A. Barnea et al.

    Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees

    Proceedings of the National Academy of Sciences USA

    (1994)
  • M. Boswald et al.

    Tracer dose and availability time of thymidine and bromodeoxyuridine: Application of bromodeoxyuridine in cell kinetic studies

    Cell and Tissue Kinetics

    (1990)
  • H.A. Cameron et al.

    Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus

    Journal of Comparative Neurology

    (2001)
  • P.S. Eriksson et al.

    Neurogenesis in the adult human hippocampus

    Nature Medicine

    (1998)
  • E. Gould et al.

    Learning enhances adult neurogenesis in the hippocampal formation

    Nature Neuroscience

    (1999)
  • E. Gould et al.

    Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress

    Proceedings of the National Academy of Sciences USA

    (1998)
  • W.T. Greenough et al.

    New neurons in old brains: Learning to survive?

    Nature Neuroscience

    (1999)
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