Memory and neurogenesis
There
is growing evidence that new neurons are generated in the brain of adult
animals, both mammals and birds throughout life (Gage 2002; Kempermann 2002;
Nottebohm 2002; Ming & Song 2005). In particular, intensive neurogenesis and
neuron replacements have been observed in the hippocampus, an area of the brain
thought to be responsible for spatial memory processing (Barnea & Nottebohm
1994; Gould et al. 1999, 2000; Banta Lavenex et al. 2001; Gage 2002; Gould &
Gross 2002; Prickaert et al. 2004; Kempermann et al. 2006). It has been
hypothesized that adult neurogenesis plays an important role in memory function
and neurogenesis regulation and its relationship with memory has received much
attention (e.g. Kempermann 2002; Nottebohm 2002; Winocur et al. 2006). Memory is
an important component of mental health and thus it is crucial to understand its
neural mechanisms and their regulation.
Animals in natural conditions live in diverse physical and social
environments and such environments appear to have a strong effect on both memory
and the brain (e.g. van Praag et al. 2000). Most laboratory studies, on the
other hand, are conducted in relatively impoverished laboratory conditions and
thus it is crucial to establish which features of the environment are absolutely
essential for maintaining healthy memory and the brain.
To understand the
relationship between environment and the brain, we need to study different model
systems as different species may have evolved different adaptations to their
social and physical environment. For example, most of the studies demonstrating
negative effects of chronic stress on cognitive abilities and the brain have
been done on laboratory rats and/or mice in conditions that are not natural to
these animals. Memory with its underlying neural mechanisms has evolved in
response to different environmental pressures and it would be advantageous to
study natural memory-based behaviors in naturalistic animal models, which could
be easily manipulated in a laboratory and in natural conditions. Food-caching
birds appear to represent such an ideal animal model which might offer many
advantages over traditional rodent model in studies of memory and hippocampal
neurogenesis.
Whereas it appears that
demands for better spatial memory indeed resulted in animals evolving better
spatial memory with an enlarged hippocampus, it is critical to understand the
relationship between memory, memory-based experiences, hippocampal development
and hippocampal maintenance. The development of the hippocampus in food-caching
birds appears to depend on natural memory-based caching and retrieval experience
(Clayton and Krebs 1994, Clayton 1995, 1996).
Clayton (1995) proposed a “use it or lose it” hypothesis which
postulates that animals need memory-based experiences to develop and maintain
their hippocampal structure. The evidence for this hypothesis, however, comes
only from developmental studies. Clayton and Krebs (1994) showed that caching
and retrieving experience in young developing marsh tits (Parus palustris)
stimulates an increase in hippocampal volume and neuron number over a period of
just three weeks. Patel et al. (1997) demonstrated that memory-based
cache-retrieval experience in young marsh tits induces neuron proliferation
rates in the ventricular zone. Considering
that programmed cell death in the hippocampus was not different between
experienced and naïve birds, Patel et al. (1997) concluded that
experience-dependent hippocampal growth in young birds occurs as a result of
more new neurons. Later, Clayton (2001) performed a similar experiment with
mountain chickadees and demonstrated that memory-based cache retrieval is
necessary for normal development of the hippocampus. Clayton (2001) also showed
that birds needed at least three food caching and retrieval events to stimulate
an increase in hippocampal volume. Clayton
(2001) demonstrated that young birds, which experienced several cache-retrieval
events but were then deprived of caching and retrieval experiences for one month
had hippocampal volumes that were reduced to the level of inexperienced birds.
This finding supported the “use it or lose it” hypothesis because
memory-based experiences seemed to be important for both hippocampal development
and maintenance. The most important
point here is that all these studies were performed with young, still
developing birds which were only one month old at the beginning of the
experiments. In addition, all birds in Clayton & Krebs (1994) and in Clayton
(2001) had very limited cache-retrieval experience (just a few trials) compared
to wild birds, which cache quite intensively (thousands of caches) during the
first autumn (Pravosudov 1985). Thus, a very important question remains largely
unanswered: does maintenance of the hippocampal structure indeed specifically
depend on memory-based experiences in fully developed animals and does lack of
such experiences lead to hippocampal atrophy with reduced hippocampal volume,
fewer neurons and reduced neurogenesis in fully-grown adults?
This question of the role of memory-based experiences in hippocampal
maintenance is innately related to the important question of the relationship
between environmental enrichment and the hippocampus in the mammalian literature
(van Praag et al. 2000). Analogously to the bird studies, Kempermann et al.
(1997) demonstrated that young mice placed in enriched environments had a larger
hippocampus with more neurons and higher neurogenesis rates than those living in
standard “poor” laboratory conditions. At the same time, Kempermann et al.
(1998) failed to find an effect of environmental enrichment on hippocampal
volume and neuron numbers in adult mice. Most other mammalian studies did not
detect an effect of environmental enrichment specifically on hippocampal volume
and neuron numbers in adult animals while detecting a significant effect on
neurogenesis only (see van Praag et al. 2000 for review). Environmental
enrichment does not always involve memory-based tasks, thus it is critical to
separate the effects of memory-based experiences on the hippocampus from all
other experiences occurring in the enriched environment. For example, it has
been shown that increased physical activity (e.g. running) experienced by
animals in artificially enriched environments is enough to increase hippocampal
cell proliferation and neurogenesis in adult mice while learning experiences per
se did not produce any additional effects (van Praag et al. 1999a,b). Gould et
al. (1999), on the other hand, reported that hippocampus-dependent learning
experience specifically affects adult neurogenesis. Clearly, the issue still
remains unresolved because of difficulty separating different behaviors in
complex environment and of showing that neural consequences of the enriched
environment are specifically related to learning rather than to increased
activity levels using the rodent model (van Praag et al. 2000). Ehninger &
Kempermann (2006) even suggested that the Morris water maze, which is a
traditional apparatus to study memory in rodents, cannot provide pure learning
experiences to investigate the effects of learning experiences on hippocampal
neurogenesis. The only bird study by
Barnea & Nottebohm (1994) also has serious shortcomings, which should
preclude the conclusion that memory-based experiences have an effect on neuron
recruitment rates. Barnea &
Nottebohm (1994) demonstrated that free-ranging black-capped chickadees have
neuronal recruitment rates twice as high compared to birds housed in an aviary
and they concluded that these differences were most likely due to differences in
memory acquisition. However, the data presented in this study only shows that
free-living animals had higher hippocampal neuron recruitment rates and there
are no data on differences in memory-based behaviors between wild and captive
birds. Thus, higher intensity of physical exercise in the wild could have
resulted in increased neurogenesis, as demonstrated in mammalian studies (van
Praag et al. 2000). More experiments are necessary to test whether specifically
memory-based experiences may affect hippocampal structure and plasticity in
fully-grown animals.
Thus, two important questions remain that require future experimental
evidence: (1) whether maintenance of the hippocampal structure (volume and total
number of neurons) requires hippocampal-dependent memory-based experiences in
fully developed animals and (2) whether specifically hippocampal-dependent
memory-based experiences have a direct effect on hippocampal neurogenesis,
including both cell proliferation and neuron survival.
Food-caching birds present an excellent model to test these hypotheses
and offer an advantage over traditional rodent models because food caching and
retrieval is a natural memory-based behavior that is freely expressed by
food-caching birds in controlled laboratory settings. In addition, there have
been reports that hippocampal volume and neuron numbers can significantly
fluctuate in adult food-caching birds (Smulders et al. 1995, 2000). Another
advantage of using wild birds is that it gives us a true control to which the
experimental birds could then be compared in order to see how experimental
treatments affected hippocampal anatomy and plasticity. While it remains
debatable whether mammalian studies actually observed increased neurogenesis in
enriched environment or whether experimental enrichment is simply a reversal of
impoverished conditions commonly experiences by laboratory animals (van Praag et
al. 2000), these studies lack a proper control which would provide normal
environmental conditions in which these animals have evolved (Banta Lavenex et
al. 2001). Until such control data are available, it remains impossible to
determine whether neurogenesis might be enhanced by memory-based experiences
above the normal naturally occurring levels or whether all available evidence
only suggests that impoverished environments result in reduced neurogenesis
(Banta Lavenex et al. 2001). The reason that mammalian studies failed to detect
an effect of environmental enrichment on hippocampal volume and neuron numbers
in adult animals could simply be due to the possibility that the differences
between standard “poor” and “enriched” laboratory conditions are not
large enough to have an effect on hippocampal structure. It is likely that
differences between the natural and laboratory “enriched” environment are
much greater than the differences between standard and enriched laboratory
conditions created in most experiments. Thus, it would be critical to
investigate whether bringing animals to the level of natural environment
complexity would result in increased hippocampal volume with more neurons in
addition to increased neurogenesis or conversely, whether placing animals in
unnaturally impoverished conditions (compared to natural conditions) actually
results in reduced hippocampal volume with fewer neurons.
Food-caching birds allow for the comparison of animals living under
natural conditions with animals undergoing different experimental treatments.
Previously,
Cristol (1996) failed to find an effect of caching experience on hippocampal
volume in adult marsh tits, but that study had a few serious drawbacks: (a) the
treatment was very short (28 days), (b) the birds were very old
(4-years or older), (c) the birds were maintained in captive impoverished
environment for more than 3 years (d) these birds were not compared to control
birds living in a natural environment, and (e) neurogenesis was not
investigated. Thus, it is possible
that these birds already had reduced hippocampal volume with fewer neurons as a
result of exposure to a long-term impoverished environment before the experiment
began. The study I propose will compare fully developed but not old birds (6-7
months old), it will last for 90 days which should be enough to detect potential
changes, and it will compare all experimental birds to controls (free-living
chickadees). Mountain chickadees start caching intensively by the end of August
when they are about 2 months old (pers. observ.).
At 6-7 months of age these birds would have extensive experience in food
caching and retrieval.