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The Journal of Neuroscience, February 1, 2002, 22(3):635-638
MINI REVIEW
Why New Neurons? Possible Functions for Adult Hippocampal
Neurogenesis
Gerd
Kempermann1, 2
1 Research Group VolkswagenStiftung at the Department
of Experimental Neurology, Charité University Hospital, Humboldt
University Berlin, 10117 Berlin, Germany, and 2 Max
Delbrück Center for Molecular Medicine, Berlin-Buch, 13125 Berlin, Germany
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ARTICLE |
The dentate gyrus of the adult
hippocampal formation generates neurons throughout life. To date, it
remains unclear why. What are the new neurons used for? How can an
existing functional neural network integrate and even actively recruit
new neurons? The prevailing theories of cognition are based on the
assumption that the adult brain is a stable network with regard to the
number of neurons. In the current view, structural neural plasticity
occurs only at the level of synapses, dendrites, and neurites. The
clear demonstration of adult hippocampal neurogenesis, the generation
of new granule cell neurons from resident neuronal stem or progenitor
cells and their integration in the trisynaptic circuit of the
hippocampus, has called this assumption into question. In the light of
data on the activity-dependent regulation of adult hippocampal
neurogenesis, some conclusions can be drawn, why and how new neurons
might contribute to hippocampal function. Our hypothesis is that new
neurons do not add memory, but insert strategically "new
gatekeepers" at the "gateway to memory".
In hindsight, there is a clear line from the groundbreaking work by
Nottebohm (1981) , Goldman and Nottebohm (1983), and Barnea and
Nottebohm (1996) on functionally regulated neurogenesis in the
vocal nucleus and the hippocampus of songbirds to the analogous findings in mammals. However, for the researchers studying neurogenesis in the adult mammalian hippocampus, structural questions came before
functional considerations. Only after several studies had confirmed the
early reports by Altman and Das (1965) and Kaplan and Hinds (1977) that
adult hippocampal neurogenesis indeed occurs, and after improved
methods had been introduced to quantitatively identify new neurons with
relative ease (Kuhn et al., 1996), did questions of function become
imminent. The first studies, particularly the work by Bruce McEwen's
group, focused on the negative regulators of adult hippocampal
neurogenesis (Gould et al., 1992, 1994), especially severe stress
(Gould et al., 1997). In contrast, our own findings that living in an
enriched environment led to a robust increase in adult hippocampal
neurogenesis indicated that adult hippocampal neurogenesis might indeed
be regulated in relation to normal behavior (Kempermann et al., 1997,
1998a). Since then a number of studies have extended these findings
(Gould et al., 1999b; Nilsson et al., 1999; Van Praag et al., 1999b),
and it became evident that the mammalian hippocampus does indeed show an activity-dependent regulation of adult neurogenesis similar to that
seen in birds. Despite all similarities, however, there are important
differences between birds and mammals, and although the considerations
regarding the influence of seasons, food storage behavior, and song
learning led the way, they cannot be applied directly to mammals. In
contrast to some bird species (Barnea and Nottebohm, 1994), adult
neurogenesis in mammals, for example, seems to show very limited
dependency on seasons (Lavenex et al., 2000). An equivalent to
neurogenesis in song learning has not been identified. In addition, the
neuroanatomical structures that exhibit neurogenesis in the songbird
and adult mammals have not been demonstrated to be strictly analogous.
Almost all data on adult mammalian neurogenesis have been derived from
laboratory animals, kept under rather artificial conditions not
directly related to their natural habitat. Even the enriched
environments of our experiments arguably represent much deprived
conditions compared with wildlife conditions. The studies in birds, in
contrast, have largely been performed in free-ranging birds or birds
held in large aviaries. It is possible, if not likely, that in more closely analogous studies between species common mechanisms and general
functional components will be discovered.
The question about the function of new neurons in the adult hippocampus
is tightly linked to the more fundamental question of the function of
the hippocampus in general, and despite the hippocampus being arguably
the best studied functional system of the brain, no detailed consensus
has been reached. The hippocampus is classically characterized as
"the gateway to memory" (Fig. 1a), but it is clear that the
hippocampus is not the "hard drive" of the brain. Although it has
some capacity for memory storage, this storage is transient, and the
function of the hippocampus therefore appears to be to prepare contents
for long-term storage in the cortical areas. The term "gateway"
implies just this: a structure, through which all information must
pass, before it can be memorized. Despite many profound and elaborate
theories, no clear mechanism has been revealed regarding what exactly
happens to information, when it passes through the hippocampus. It is obvious, however, that the hippocampus represents a bottleneck in
processing the information. In a simplified schematic input, pathways
from the entorhinal cortex and other regions project to only 250,000 granule cells of the dentate gyrus (in a mouse). Output from the
dentate gyrus through the mossy fiber tracts reaches even fewer
pyramidal cells in area CA3. From axons of the CA3, output progresses
via CA1 and then once again to the cortical regions. Adult hippocampal
neurogenesis occurs at exactly the narrowest spot within the
three-synaptic circuit. New granule cells are generated, and mossy
fibers are the axons of granule cells (Fig. 1a). There is no
evidence that memory storage occurs at this level of the circuit.
Consequently, we think that the function of adult hippocampal
neurogenesis has nothing to do with long-term memory per se. There is
no evidence that adult hippocampal neurogenesis equals "putting in
more memory, while the computer is running," much less "installing
a new hard drive" (Fig. 1b).
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Figure 1.
A, The hippocampus presumably
serves as the "gateway to memory." New neurons are added at the
bottleneck of the neuronal circuitry in response to functional
stimulation. The theory presented here is that adult neurogenesis is
not involved in increasing memory per se, but in a long-term adjustment
of the processing unit "hippocampus" to increased functional needs.
B, In contrast, a simplifying computer analogy considers
new neurons in the dentate gyrus as a means of increasing working
memory ("RAM" in computer terminology). There is no indication that
hippocampal neurogenesis is involved in increasing storage memory
("hard disk" in computer terminology). C, A small
number of new neurons can only make a big difference if they are
strategically used to adapt the existing network. Here, the new neurons
are marked in red.
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If one considers the hippocampus a processing unit, adding neurons here
might be more equivalent to an increase in working memory. Even then,
however, the small number of new neurons argues against any meaningful
"RAM upgrade." In general, there is no evidence that storage of
information occurs in single individual neurons. Rather, memory seems
to be distributed over the synaptic weights of a network of neurons.
Single new neurons, if strategically introduced to a network, might
significantly increase in the complexity that can be processed by the
network (Fig. 1c).
We have found that the upregulating effects of environmental enrichment
on adult hippocampal neurogenesis was paralleled by an improvement on a
hippocampal learning task (Kempermann et al., 1997). This is a strong
suggestion of a correlation, but no proof of causality. Furthermore,
the link between adult hippocampal neurogenesis and learning seems to
be bidirectional. Thus, neurogenesis is correlated with experience, and
experience effects neurogenesis. It appears that new cells are
recruited for function without it being clear to us what this function
is. A more isolated learning stimulus alone has been shown to exert
such a survival-promoting effect and thus enhance neurogenesis (Gould
et al., 1999b), although this result has not been found in other
studies with different experimental set-up (Van Praag et al., 1999b).
For a discussion of this discrepancy, see Greenough et al. (1999).
Still, intuition favors an interpretation that learning can influence neurogenesis.
The question, what the individual new neurons are used for, is
difficult to address experimentally. Van Praag et al. (1999a) have
shown that long-term potentiation at the level of field
potentials, the best known electrophysiological measure of learning, is
enhanced in the same mice, in which hippocampal neurogenesis was
induced by physical activity. Shors et al. (2001) have treated rats
with cytostatic agent methylazoxymethanol acetate (MMA) to reduce
hippocampal neurogenesis. They described that the treated animals
performed worse than controls on a hippocampus-dependent conditioning
task, whereas a hippocampus-independent task was spared. Despite adding another piece of suggestive information, this finding can neither prove
that new neurons are necessary for hippocampal function nor precisely
elucidate the function of the new cells. Although eye-blink
conditioning is well known to be a hippocampus-dependent task, one
could not say that the function of the hippocampus is mediating
eye-blink conditioning. Drugs inhibiting protein synthesis, such as the
cytostatic drug MMA, block memory formation, but this effect is
presumably independent of effects on cell genesis. In addition,
cytostatic drugs tend to have a wide spectrum of effects and side
effects, and it is not possible to easily distinguish direct from
indirect effects. Intuitively, however, the result of Shors et al.
(2001) fit the prevailing theories and are in accordance with earlier
results. Thus, the question of what the new neurons actually contribute
to hippocampal function remains open.
This functional benefit from adult hippocampal neurogenesis cannot be
acute, because it takes several days to generate a functionally integrated new neuron. The new cells extend neurites within a couple of
days after division (Hastings and Gould, 1999; Markakis and Gage,
1999), but it is obvious that the new connection cannot benefit the
particular functional event, which triggered neurogenesis, because this
will long be over when the new neurons are in place. Hippocampal
neurogenesis will rather represent a long-term adjustment of the
hippocampal circuitry to an experienced level of higher complexity. It
would allow the hippocampus to modify the gatekeeper at the gateway to
memory and allow a strategic increase in network complexity. This would
explain why old animals learn quite well, although they have a reduced
level of adult hippocampal neurogenesis (Kempermann et al., 1998a). If
the new neurons were to expand storage capacity precisely for the one
task at hand, this would not make sense. Old animals in a new situation
would be in similar need for new neurons as younger ones. If the new
neurons, however, represent a refinement of a "processing unit,"
then it is plausible, why with increasing age, adult hippocampal
neurogenesis can decrease without negative functional effects. The
overall benefit would not be linked to the one particular stimulus, but
would be cumulative. This may be the heart of the question of what we
think the use of adult neurogenesis is.
In the context of adult hippocampal neurogenesis, hippocampal function
has normally been assessed by testing spatial learning in the water
maze task (Morris, 1984), but the water maze task might not be optimal
to assess this causality (cf. Eichenbaum, 1996; Eichenbaum et al.,
1999; Suzuki and Clayton, 2000). The question is, how far the functions
of the rodent hippocampus go beyond spatial memory. A broader
functional perspective might, for example, help to explain, why
different groups obtained conflicting results when the direct effect of
water maze performance on the regulation of adult hippocampal
neurogenesis was investigated (Gould et al., 1999a; Van Praag et al.,
1999a). "Experience," which is learning in a very broad sense, can
stimulate adult hippocampal neurogenesis (Kempermann et al., 1997,
1998a,b; Kempermann and Gage, 1999), but spatial learning might benefit
from increased neurogenesis (as seen in our experiment with 129/SvJ;
Kempermann et al., 1998b) without being the most relevant factor to
stimulate neurogenesis. This idea is supported by the otherwise
surprising finding that physical activity causes a dramatic increase in
adult neurogenesis and leads to improved performance in the water maze task (Van Praag et al., 1999a,b). Consequently, it will not be sufficient to show that new neurons contribute to learning. It will
also be necessary to demonstrate a quantitative correlation between
neurogenesis and a functionally (and ethologically) meaningful test of
hippocampal function.
From our data we have derived the theory that the function of adult
hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty. This would fit well with the gateway concept of the hippocampus. The interpretation of adult hippocampal neurogenesis as a mechanism for preparing the hippocampus for processing greater levels of complexity might also explain why the
regulation of neurogenesis is linked to physical activity. Physical
activity does not per se represent a functional challenge to the
hippocampus. Therefore, an upregulation of neurogenesis in this context
would not result in any benefit attributable to the stimulus. In
contrast to stimulation by environmental enrichment, which led to a
survival-promoting effect on the progeny of the proliferating cells in
the dentate gyrus, physical activity induced cell proliferation in the
subgranular zone. One possible interpretation is that physical activity
leads to an increased potential for neurogenesis by inducing stem or
progenitor cell proliferation. Learning stimuli could then act on this
increased potential by survival and differentiation of the new neurons
into functional circuits. It is very difficult to design an experiment
that allows sharp distinction between these two forms of stimulation.
Neither pure physical activity nor pure learning without any component of physical activity are easily obtainable. Preweaning enrichment is an
experimental set-up that exposes very young animals to sensory stimuli
during the first 3 weeks of life. This manipulation is known to result
in long-lasting effects on cognitive function. However, it did not lead
to increased adult hippocampal neurogenesis later in life (Kohl et al.,
2002). In contrast, withdrawal from a post-weaning enrichment
paradigm had lasting effects at least on the level of cell
proliferation (Kempermann and Gage, 1999). One possible interpretation
is that the lack of an effect in preweaning enrichment is based on the
fact that preweaning enrichment does not involve physical activity or
active exploratory pursuit. In this sense, activity might be necessary
to elicit the initiation, completion, or maintenance of the neurogenic response.
Taken together, we do not yet know why there are new neurons in the
adult brain, but research on regulation of adult neurogenesis, as well
as an increasing number of studies directly aimed at elucidating the
function of the new cells, have lead us to two conclusions. First,
hippocampal neurogenesis is effected by behavior, and in particular
behaviors related to hippocampal function. Therefore, difficulties in
defining the function of new neurons in the hippocampus also reflects
our incomplete understanding of hippocampal function. Second, changes
in rate or extent of neurogenesis can have an effect on subsequent
behavior. Thus, although behavior can change the structure of the
hippocampus, changes in structure can subsequently change or at least
effect subsequent behaviors. In a less concrete sense we speculate that
the link between activity and adult neurogenesis suggests that new
neurons are involved in a general aspect of hippocampal function, most
likely sustaining the ability of the dentate gyrus to accommodate the
continued modulation of cortical input replete with novel complexities.
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FOOTNOTES |
I thank Fred H. Gage for intensive discussion of the viewpoint
expressed in this review and for helpful comments on this manuscript. I
also thank Laurenz Wiskott and Ulrich Anders for their contributions that helped to shape the theory presented in this text.
Correspondence should be addressed to Dr. Gerd Kempermann, Max
Delbrück Center for Molecular Medicine, Berlin-Buch,
Robert-Rössle-Strasse 10, 13125 Berlin, Germany. E-mail:
gerd.kempermann{at}mdc-berlin.de.
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Copyright © 2002 Society for Neuroscience 0270-6474/02/223635-04$05.00/0
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