Neuroscience & Biobehavioral Reviews, Vol. 22, No. 2, pp.

143–159, 1998
䉷 1998 Elsevier Science Ltd
Pergamon Printed in Great Britain. All rights reserved
0149-7634/98/$32.00 + .00

PII: S0149-7634(97)00008-0

Age, Experience and the Changing Brain

BRYAN KOLB*, MARGARET FORGIE, ROBBIN GIBB, GRAZYNA GORNY AND SHARON ROWNTREE

Department of Psychology, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada

KOLB, B., M. FORGIE, R. GIBB, G. GORNY, S. ROWNTREE. Age, experience and the changing brain. NEUROSCI BIOBEHAV
REV 22(2) 143–159, 1998.—In this review, various aspects of how environmental experience affects the structure of the cortex at
different times in the age of the animal are summarized. The interactions of brain injury and sex on the age-dependent plastic changes in
the cortex are also considered. Finally, we have attempted to reach some general conclusions that describe the effects of age, experience,
sex, and injury on the cortex. 䉷 1998 Elsevier Science Ltd. All rights reserved.

Cortex Enriched experience Sex differences Gonadal hormones Cortical development Aging Spines Dendrites

1. INTRODUCTION experiences has provided a rich broth of information that is

IN PRINCIPLE, there are two ways that experience could
alter the brain: either by modifying existing circuitry or by
creating novel circuitry (63). It is reasonable to suppose that
the brain makes use of both strategies, although the details
of the particular strategy will likely vary with the age of the
animal. Indeed, during development of the brain all circuitry
is, by definition, novel. One way to examine the experience-
dependent changes in the brain is to look at the effects of
different experiences on neuronal structure and function.
For psychologists, this rationale usually means adopting one
of two approaches: either animals are placed in differential
environments such as so-called ‘‘enriched environments’’
versus ‘‘impoverished environments’’; or animals are
trained in specific types of tasks, such as mazes. In either
paradigm, the experience is correlated with some measure
of structure such as brain weight or dendritic extent (e.g.
(17)). These experiments generally show that particular
experiences embellish circuitry relative to the absence of
experience, which fails to do so. Although this type of
experimental psychological approach would appear to have
considerable appeal in understanding experience-dependent
changes in the brain, the impact of this type of research has
been surprisingly limited. Indeed, Purves (63) noted that for
reasons that are as much sociological as scientific, the
experimental neuropsychological perspective has not been
embraced generally by most neurobiologists and that these
psychological experiments are rarely referred to in the
mainstream literature. Oddly, again for reasons that are
both sociological as much as scientific, the importance of
studies of enriched experience also have had limited impact
in mainstream psychology where there has been a long-
standing bias against structural interpretations of psycho-
logical phenomena. Nevertheless, the study of experience-
dependent changes in experiments that manipulate external
relevant both to basic neurobiological theories of brain
function as well as to general theories of behavioral
organization. The goal of the current review is to illustrate
some of principles that have emerged. The review will begin
with a summary of some of experience-dependent changes
in the intact brain followed by a consideration of the effects
of manipulating factors such as gonadal hormones or
neurotrophins and the effects of cortical injury.
2. ASSUMPTIONS
As we begin, we must first admit to several biases. Firstly,
we assume that the structural properties of the brain are
important in understanding its function. Although such an
assumption is self-evident to most neuroscientists, it is not
as ubiquitously assumed by psychologists who do not study
the brain (e.g. (69,83)). An important corollary of this
assumption is that changes in the structural properties of
the brain reflect changes in the function of neural circuits.
Secondly, we assume both that the mechanisms of corti-
cal plasticity are most likely to be found at the synapse and
that synaptic changes can be measured by analysis of either
pre- or post-synaptic structure. Traditionally, the emphasis
in the literature on synaptic plasticity has been upon the
presynaptic, or axonal terminal side. For example, in the
studies of the effects of unilateral entorhinal cortex in rats,
various investigators have shown a major reorganization of
the remaining hippocampal afferents (e.g. (85)). Similar
inferences have been made in other models, such as in
studies of cholinergic outgrowth after cortical injury (e.g.
(6)), collateral sprouting after peripheral nerve crush (7),
and terminal sprouting after various types of central injuries
(e.g. (12)). One difficulty with studying presynaptic changes
is that they are very difficult to locate unless one knows a

*Corresponding author. Tel.: 403-329-2405; Fax: 403-329-2555; E-mail Kolb@HG.ULETH.CA.

143
144
priori where to look. In addition, once found, they are
difficult to quantify. The ability to quantify specific mor-
phological features is critical if one is to correlate structural
change with behavior.
An alternative way to look at synaptic change is to study
the postsynaptic or dendritic side. This requires that the
complete cell body and dendritic tree be stained, such as
in a Golgi-type stain. Since the dendritic surface receives
more than 95% of the synapses on a neuron it is, therefore,
possible to infer changes in synapse number from measure-
ments of dendritic extent and spine density. One clear
advantage of this measure is that one need not know a priori
where to look since it is possible to stain, and to examine,
the structure of cells throughout the entire brain. In addition,
analysis requires only a light microscope (and a lot of
time!). Golgi analysis of the postsynaptic side has proven
useful in several types of studies of cortical plasticity. For
example, various groups have shown that housing animals
in ‘‘enriched’’ environments leads to increased dendritic
outgrowth (e.g. (17)). Similarly, training animals in specific
tasks leads to dendritic changes in specific populations of
neurons (e.g. (21)). One inescapable conclusion of post-
synaptic studies is just how plastic dendritic (and presum-
ably synaptic) structure is. One example is especially
intriguing. Purves and Hadley (64) were able to label cells
in vivo in the dorsal root ganglion of mice. The dendritic
field was then mapped. The same cell was relabelled at
different times ranging from a few days to weeks and it was
possible to see obvious qualitative changes in dendritic
extent, which can be taken as at least suggestive evidence
of synaptic plasticity (Fig. 1). Perhaps the most surprising
aspect of the Purves and Hadley study was that the dendritic
FIG. 1. Camera lucida reconstructions of portions of the dendritic arbors of five mouse superior cervical ganglion cells visualized at an interval of 3 months.
Changes involving both the extension and retraction of particular branches are evident. Open arrowheads show examples of branches that appear to have
retracted; asterisks mark examples of branches that have formed de novo in the interval. The black arrows indicate the appearance after the specified number
of days. (After Purves and Voyvodic (68).)
KOLB ET AL.
morphology was so changeable in absence of any particular
training. One could reasonably expect even greater change
in an animal that was given special somatosensory-related
training or that had peripheral nerve injury.
Thirdly, although the emphasis in most studies of
structure–function relationships falls upon the analysis of
neurons, there are solid grounds for looking at changes in
the structure and number of glial cells. Glial cells play an
important role in synaptic modification, and thus, can be a
clue to the location and nature of experience-dependent
changes in neurons and their synapses.
Fourthly, it is implicit in the foregoing discussion that
changes in the postsynaptic structure will be visible in the
light microscope. Although the final verification of the nat-
ure of structural modification must be at the ultrastructural,
and thus, electron microscopic (EM) level, EM studies are
impractical on a large scale as they are time (and money)
consuming, even if one knows where to look. Practically,
therefore, our studies are carried out in tissue that is stained
with a Golgi-type stain (for neurons) or with other
specialized histochemical procedures that identify specific
proteins, such as glial fibrillary acidic protein (GFAP), in
glial cells.
Fifthly, the emphasis of our work and this review will be
on the cerebral cortex. As psychologists, our primary
interest is in cognitive function and it is our assumption
that the changes in the cerebral cortex form the principal
mechanism for cognitive change. This assumption comes
from several lines of evidence. For instance, it is generally
agreed that the relative increase in cortical volume across
mammalian evolution is associated with increased cognitive
capacity. It follows that changes in cognitive functions in a
AGE, EXPERIENCE AND THE CHANGING BRAIN 145

particular mammal likely will involve changes in cortical
structure or organization. Furthermore, studies of decorti-
cated rats show that although they are capable of a remark-
able behavioral repertoire (e.g. (94)), there is limited
functional flexibility under conditions that would normally
lead to marked functional and/or structural change in intact
animals (e.g. (56,96)). Finally, there are marked interspecies
differences in the details of cortical organization, such as in
and his colleagues who have utilized environments that are
richer in visual complexity, and thus, these researchers have
focused upon analyses of structural changes in the visual
system (e.g. (17–19,90–93)). These two approaches are,
thus, complementary and will be considered in this way.
3. HISTORICAL CONTEXT

Old world and New world monkeys, and it has been
assumed that these differences reflect the clear differences
in perceptual and cognitive abilities (36).
Finally, since most work on cortical plasticity and
behavior is done using rats, we have assumed that changes
in cortical structures are likely to be largest, and thus, easiest
to study in those structures that play a central role in somato-
sensory and motor function. Rats are nocturnal animals that
rely heavily on tactile sensitivity, especially in the represen-
tation of the face and snout, and they have well developed
forelimb manipulatory abilities. In fact, rats are skilled
climbers and jumpers, and are able to use their forelimbs
in ways that are strikingly similar to those seen in primates
(95). Thus, our enriched environments are organized to
allow considerable motor activity and feature many tunnels,
the opportunity to climb, and to manipulate objects with
both the forelimbs and mouth (Fig. 2). This contrasts
somewhat with the extensive experiments of Greenough
Although the idea that experience can modify brain struc-
ture can probably be traced back at least to Ramon y Cajal
(70), it was Hebb who made this a central feature of his
neuropsychological theory (25). Hebb did the first experi-
ments on the consequences of enriched rearing on the
behavior of the rat (24), but it was not until the group at
Berkeley began to demonstrate changes in brain weight,
cortical thickness, acetylcholine levels, and dendritic struc-
ture that there was any structural correlate of the behavioral
changes related to experience (8,9,10,15,74,75). Later,
beginning in the 1970s and continuing still, Greenough
and his colleagues initiated a multidisciplinary investigation
of the effects of rearing animals in visually or motorically
enriched environments (Table 1). These experiments
demonstrated that not only were there changes in the
dendritic structure but that these changes reflected an
increase in the number of synapses that could be identified
using EM techniques. Evidence that changes in dendritic
structure reflect changes in connectivity is important for it
implies that it is possible to make inferences about con-
nectivity from dendritic structure. More recently, Purves
and his colleagues have demonstrated that there is a direct
relationship between dendritic geometry and synaptic input
(63–67,73). These authors have shown that the number of
inputs to a sympathetic or parasympathetic ganglion in an
adult animal is directly related to the number of dendritic
branches (Fig. 3). Importantly, however, these experiments
have also shown that this relationship is not found in
newborn animals. Rather, the number of inputs to a given
neuron in young animals is about the same regardless of the

TABLE 1
PRINCIPAL CELLULAR DIFFERENCES IN THE OCCIPITAL
CORTEX BETWEEN RATS RAISED IN ENRICHED CONDITION (EC)
AND IMPOVERISHED CONDITION (IC)

Cellular variable Environment Reference

Neuron size EC ⬎ IC (9)

Neuron density IC ⬎ EC (91)
Dendritic branching EC ⬎ IC (92)
Dendritic spine density EC ⬎ IC (15)
Number of unmyelinated axons EC ⬎ IC (35)
in splenium of corpus callosum
Size of unmyelinated axons in EC ⬎ IC (35)
splenium of corpus callosum
Number of synapses per neuron EC ⬎ IC (91)
Size of synaptic contact EC ⬎ IC (93)
Synaptic plate perforations EC ⬎ IC (19)

Percentage of total tissue volume

Capillary vessels EC ⬎ IC (2)
Astrocytic nuclei EC ⬎ IC (80)
Oligodendrocytic nuclei EC ⬎ IC (80)
Mitochondria EC ⬎ IC (80)
FIG. 2. Schematic illustration of the rat condominiums used in studies of
the effects of enriched experience. After Juraska (32).
146 KOLB ET AL.

distributed. The disadvantage historically has been that the

FIG. 3. Correlation between input number and postsynaptic geometry
among rabbit ciliary ganglion cells, using the number of primary dendrites
as an index of the complexity. Each point represents the mean of measure-
ments on a number of neurons ( ⫾ SE). The straight line was fitted to the
data by a least squares linear regression program and has a slope of about 1.
(After Purves and Hume (65).)
size of the dendritic field. It is reasonable to presume that
experience plays an important role in shaping the adult
structure but the details of how this might happen are not yet
known. The Purves experiments can be generalized to other
parts of the brain, such as the cortex, where such experi-
ments are impractical because of the very large number of
inputs, which may range up towards 100 000 per neuron.
The accumulating evidence showing that experience
could modify cortical structure even in adult animals led
many investigators to turn to environmental manipulations
as a method for influencing recovery from brain injury (e.g.
(82,97)). After all, if experience could modify cortical
structure and allow enhanced performance in a variety of
cognitive tasks, then one would expect that specific envir-
onmental experiences could also enhance the reorganization
of the brain after cerebral injury. Although some studies
have shown clear beneficial effects of such treatments,
others have failed to find enhanced functional recovery.
Furthermore, it has become apparent that the direct effects
of brain injury interact not only with the experience but also
with various factors such as age and sex (see below).
staining is capricious and sometimes obscured with
precipitate. In recent years, there have been several modi-
fications to the procedures that have made the staining more
consistent. One assumption of Golgi studies is that the stain-
ing of neurons is random and does not reflect some specific
feature of particular neurons. That is, since only about 1% of
cells stain, it is important that those cells that are stained are
not unique in some consistent manner. Several studies have
now demonstrated the aselectivity of the Golgi procedures
(60). We have modified the Golgi-Cox procedure to allow
us to stain consistently and with a high signal-to-noise ratio
(14). In addition, our procedure allows us to visualize spines
clearly and consistently (Fig. 4).
The second type of staining procedure is to inject indi-
vidual cells with dyes that diffuse throughout the cell,
including the dendrites and axons (e.g. (61)). The advantage
of this procedure is that specific cell populations can be
labelled and the issue of stain selectivity is removed,
although there is obvious experimenter selectivity. The
disadvantages are that it is very time consuming and that
it is only practical if one knows a priori where one wishes to
look at cells. However, very often in our experiments we
wish to look in many regions of the brain, making this
procedure impractical.
Once the cells are stained, the dendritic length can be
measured in several ways. Cells first are drawn using a
microscope, which is typically set at 250–400 ⫻ magni-
fication. The drawing can be done using some type of com-
puterized imaging system or it can be done by using a
camera-lucida procedure (Fig. 5) in which cells are drawn
with pen and ink. The advantage of the computerized
systems is that the precise length of all dendritic segments

4. ANALYSIS OF DENDRITIC MATERIAL

We indicated earlier that there is a high correlation

between the extent of dendritic arborization and the number
of synapses. Although synapses can only be studied (and
counted) directly with EM procedures, an estimate of
synapse number can be made by calculating the total den-
dritic length. Cells can be stained using one of two different
procedures. The oldest procedure was devised by Golgi in
the late 19th century and it involves depositing a heavy
metal, such as gold or silver, on cell bodies. A more recent
recipe, known as Golgi-Cox, uses mercury. The Golgi stains FIG. 4. Photograph of a layer-V pyramidal neuron from the parietal cortex.
have the advantage that they stain about 1% of the cells in The cell is stained with a variant of the Golgi-Cox procedure. Dendritic
the tissue and these cells are thought to be randomly spines are clearly visible.
AGE, EXPERIENCE AND THE CHANGING BRAIN
FIG. 5. Illustration of the camera lucida method for tracing neurons. Mirrors
in the drawing tube allow the drawer to visualize both the cell through the
microscope as well as the tracing page. Cells, therefore, can be traced.
can be calculated and various statistical measurements
can be made (e.g. (4)). The disadvantage is that these
semi-automated procedures are very slow and, somewhat
paradoxically, are labor-intensive. Although only 1% of the
neurons are stained in Golgi-type stains, the cells are still
close together and dendritic branches from different cells
overlap. The human eye can easily distinguish which
branches belong to which cells, but computers cannot yet
FIG. 6. An illustration of the two main methods of quantifying dendrites. The concentric rings on the left form the grid for the Sholl analysis. The number of
ring crossings of each branch gives an estimate of length of dendrite. The numbers on the branches on the right indicate the branch order, which offers a
different estimate of dendrite length.
147
do so. This means that an operator must guide all of the
computer drawing. If cells are drawn using pen and ink, then
the analysis is normally done by using a procedure that
estimates dendritic length. One way is to count the total
number of dendritic branches, whereas another way is to
place some sort of grid over the drawing and to count the
number of intersections of the dendrites with the grid lines
(Fig. 6). Although the two procedures give very different
statistical views of dendritic arborization, both measures
lead to the same conclusions. For example, in a study of the
effects of ovariectomy on dendritic growth in the cortex of
rats, Stewart and Kolb (87) measured dendritic growth using
both methods (Fig. 7) and found essentially the same result:
removal of the ovaries in adult female rats led to an increase
in dendritic arborization relative to intact female controls. It
can be seen in the branching analysis that the increased
arborization was seen at the higher order branches, meaning
that it reflected growth at the end of the existing branches. It
can be seen in the Sholl analysis that the branches crossed
more of the circles, meaning that the branches were longer
in the ovariectomized animals.
A second measure of synaptic density is to look at the
distribution of dendritic spines on the dendrites (Fig. 8).
About 90% of excitatory synapses are made on dendritic
spines so a count of the number of spines allows an estimate
of the number of synapses (22). Spine density varies on
different parts of the neuron (Fig. 8), so it is typical to
measure spine density at several places on the neuron.
Measurement of spine density requires a higher magnifica-
tion than dendritic arbor, with most investigators using a
148
FIG. 7. A comparison of data summaries from Sholl and branch order
analyses of the same neurons. Adult female rats were ovariectomized
(OVX) and layer-III parietal pyramidal neurons were drawn several months
later. The branch order analysis shows that all branch orders after the first
were increased in the OVX rats. The Sholl analysis shows that the increased
branching was near the cell body, falling at about 30–60 m along the
branches. (After Stewart and Kolb (86).)
magnification of at least 1000 ⫻ . Dendritic segments are
drawn using camera lucida procedures, the segments
are measured, and the number of spines per unit length
are calculated. One of the difficulties in measuring spine
density with standard light microscopy is that spines that lie
either on the backside of the dendrite or spines that are
pointed directly up at the viewer cannot be seen. Thus,
measurements of spine density with the light microscope
will necessarily underestimate the total number of spines.
The newly developed confocal microscopes overcome this
difficulty, and thus, yield higher estimates of spine
density.
One of the decisions that must be made in measuring
dendrites is which cells to measure. In any slice of brain
there will be multiple cell types (e.g. pyramidal versus
granule cells). In addition, there is the issue of which
brain regions to draw. In our experiments, we have chosen
to draw excitatory neurons, which are spiny and are best
KOLB ET AL.
exemplified by pyramidal cells in the cortex. In our initial
studies, we looked at cells in cortical layers II, III, and V but
since we have found cells in layer II to be less affected by
experience or other factors, we have focused on layers III
and V in our more recent studies. Although other investi-
gators have focused upon cells in the occipital areas, we
have focused more on cells in the somatosensory, motor
and prefrontal cortices. Our selection of the somatosensory
cortex has been guided by our recognition that rats are very
tactile animals, by the ease in identifying the primary
somatosensory cortex in animals with cortical injuries,
and by the fact that most of our lesion studies have investi-
gated the effects of prefrontal or motor cortex injuries (e.g.
(37,38)). Somatosensory cortex changes in response to these
injuries and we have been able to investigate the interaction
of these changes with various factors such as experience and
sex.
5. ANALYSIS OF GLIA
There are three main types of glia in the cortex: astro-
cytes, microglia, and oligodendroctyes. The oligodendro-
ctyes form the myelin and have not been studied with
respect to experience. The astrocytes are large glia that
are found both in the white matter as well as the grey matter
of the cortex. Many astrocytes have processes that resemble
dendrites and these processes expand in response to various
events, including experience. Microglia are normally visible
only when the brain is injured and they function as macro-
phages. Both astrocytes and microglia can be visualized by
using immunohistochemical procedures. Histological
sections are exposed to antibodies to different proteins
expressed by the cells. For example, astrocytes express pro-
teins such as glial fibrillary protein (GFAP) or vimentin and
with appropriate reactions the cells can be visualized (Fig.
9). Similarly, microglia can be located with an antibody
known as OX-42. Once visualized, the glia can be quantified
in two different ways. Astrocytes are best identified by using
procedures analogous to the grid crossing systems used for
dendrites. In this case, the cells are not drawn but rather a
video camera is attached to a microscope, and under rela-
tively high power magnification (200–400 ⫻ ), the cells are
visualized on a monitor that has a grid superimposed. The
number of astrocytic branch crossings over the grids are
counted. When astrocytes are measured in this manner,
Greenough and his colleagues have found that there is a
consistent increase in astrocytic branching in the brains of
animals housed in enriched environments (23,81). The
simplest way to measure microglia is to use an imaging
system to measure the density of staining in different
cortical regions. Microglia are small and it is impractical
to count individual cells. Rather, it is more common simply
to measure the density of staining, and to infer that there are
larger numbers of microglia present. Microglia are not
usually present in large numbers unless the brain is injured
or if cells are dying for some other reason, such as in early
development or in dementia. Thus, they have not been
systematically studied in studies of experience-dependent
changes. There are studies, however, showing that the
density of microglia can be affected by experience. For
example, we have found that environmental stimulation in
infancy will reduce the density of microglia observed both
during infancy and in adulthood (47).
AGE, EXPERIENCE AND THE CHANGING BRAIN
FIG. 8. Illustrations of representative layer-III parietal pyramidal neurons from a rat placed in an enriched environment at weaning versus a littermate that
was housed in standard laboratory housing. The dendritic branches down the midline are expanded views of terminal (T), oblique (O), and basilar (B)
portions, illustrating the dendritic spines. Note that the spine density varies with location on the dendritic tree. Enriched housing produced an increase in
branching but a decrease in spine density.
FIG. 9. Photomicrographs illustrating staining of by antibodies specific for
basic fibroblast growth factor (bFCF) and glial fibrillary acidic protein
(GFAP).
149
6. EXPERIENCE-DEPENDENT CHANGE IN THE INTACT BRAIN
As we began our studies of experience-dependent
changes in the brain, we used the logic of those before us
who had compared animals in laboratory cages to others in
‘‘enriched environments’’ (e.g. (25,18,74)). Thus, we
placed animals in same-sex groups of 4–6 in rat condomi-
niums, which are 1 m ⫻ 0.6 m ⫻ 1.8 m high enclosures
(Fig. 2). The condominiums feature sawdust floors to allow
digging and three hardware cloth walls to allow climbing.
The enclosures contain numerous objects, tree branches,
and pieces of PVC pipe, and the objects are moved about
weekly. The animals are allowed to live in this environment
for about 90 days, at which time their brains and behavior
are compared to littermate controls that were group-housed
in standard hanging cages. In adulthood, the animals housed
in the condominiums typically have a decrease in body
weight, presumably because they are more active, and an
increase in brain weight of about 6%. Although this
increased brain weight likely reflects changes throughout
the brain, there are large effects upon cortical thickness,
with a typical increase in thickness the order of 7%.
6.1. Age, experience and dendritic changes
It has long been assumed in the psychological literature
that experiences in early childhood have greater effects
upon later behavior than do similar experiences in adult-
hood. Our analysis of dendritic changes following exposure
to enriched environments suggests that there is a structural
basis to this differential effect of early experience on
behavior. We placed rats in enriched environments for 3
months beginning either at weaning (21 days of age), at
young adulthood (4 months of age), or in senescence (2
years or older). The principal finding was that the age at
which animals were placed in the enriched environments
150
has qualitatively different effects upon dendritic structure.
Rats placed into the condominiums in young adulthood
showed effects similar to those reported by others: there
was a large increase in dendritic length relative to cage-
housed control animals (Fig. 10). In addition, there was an
increase in spine density (e.g. (45)). Parallel results were
seen in senescent animals, as they showed increases in
dendritic length and spine density relative to age-matched
control rats (45). In contrast, when we analyzed the changes
in animals who were placed in the condominiums as
juveniles, we saw an increase in dendritic branching but a
consistent decrease in spine density. That is, the young
animals showed a qualitatively different change in the
distribution of synapses on pyramidal neurons compared
to older animals.
The differential effect of enrichment in the young versus
older animals led us to look at the effects of environmental
manipulation even earlier in the animals’ lives. It has been
shown that tactile stimulation of premature human babies
with a brush leads to faster growth and earlier hospital dis-
charge (11,79,84). In addition, studies in infant rats have
shown that similar treatment alters the structure of olfactory
FIG. 10. Summary of the effects of housing in condominiums beginning at
weaning (young), young adulthood (adult) or in old age (old). Enriched
housing led to an increase in dendritic branching in all groups. In contrast,
spine density was decreased in the young group and increased in the adult
and old groups. (After Kolb and Gibb (45).)
KOLB ET AL.
bulb neurons and has effects on later behavior (e.g.
(6,57,88,98)). We therefore stroked infant rats with a
camel hair paintbrush three times daily from day 7 to day
21 of life. Animals were subsequently raised in standard lab
cages and were sacrificed in adulthood. Golgi analysis
revealed that the early experience had no effect upon
dendritic length in adulthood but there was a significant
drop in spine density (45). These results surprised us and led
us to consider other changes in cortical morphology in the
tactile-stroking paradigm. For example, in one experiment
infant rats were given tactile stimulation and then were
sacrificed at different ages. At sacrifice we measured: (1) the
density of acetylcholinesterase staining, which allowed an
indirect measure of acetylcholine innervation in the cortex;
and 2) the density of immunohistochemical staining for
OX-42, which is a marker of microglia; and 3) the density of
staining for GFAP, which is a marker for astrocytes. The
results showed that acetylcholinesterase levels were signifi-
cantly increased after only 7 days of stimulation and that
this increase was still present 6 weeks after the stimulation
was ended. Similarly, the number of microglia was signifi-
cantly decreased after only 7 days of stimulation and
remained lower than in controls 6 weeks later. Surprisingly,
GFAP-positive astrocytes were virtually unchanged by the
experience.
These results lead us to several conclusions. First,
‘‘enriched’’ experience can have very different effects
upon the brain at different ages. Second, experience not
only leads to ‘‘more’’ but can also lead to ‘‘less’’. That is,
although there is a temptation to presume that experiences
lead to increased numbers of synapses and probably to
increases in glia, it appears that there may be either
increases or decreases, the details varying with age at
experience. Third, changes in dendritic length and dendritic
spine density are clearly dissociable. It is not immediately
clear what the differences mean in terms of neuronal
function but it is clear that experience can alter these two
measures independently and in different ways at different
ages.
6.2. Task-dependent changes in dendritic arbor
Greenough and his colleagues probably were the first to
look at the effects of training in specific tasks on the struc-
ture of cortical neurons. In their first studies, they trained
rats in visual mazes and then analyzed the structure of
neurons in the visual cortex (e.g. (17–20,91,92)). Their
principal finding was that both pyramidal and stellate
neurons had significantly increased dendritic arbor in the
brains of trained relative to untrained control rats. In fact, in
one experiment the investigators took advantage of the fact
that the visual projections from the eyes to the visual cortex
of the rat are nearly completely crossed. Thus, input from
one eye goes largely to the contralateral hemisphere. The
authors therefore exposed one hemisphere to a visual task
by occluding the ipsilateral eye, and subsequently only one
hemisphere had the visual experience (5). As might be
expected, there was an effect of training on the visually
trained hemisphere but not on the untrained hemisphere.
Greenough and colleagues (21) subsequently trained
animals to reach for food with a single forelimb and
showed growth in pyramidal neurons in layer III and V,
but not II, in the motor cortex. More recently, we trained rats
AGE, EXPERIENCE AND THE CHANGING BRAIN
either to reach with a single forelimb to obtain food or to
pull up strings with both forelimbs to retrieve food attached
to the end (54). We found that there was a significant
increase in dendritic branching in layer V pyramidal
neurons in the hemisphere controlling the reaching forelimb
versus the nonreaching forelimb in the unimanual task. In
contrast, neurons in both hemispheres showed increased
growth in the bimanual task. These changes were specific to
the forelimb region of the motor cortex and were not
observed in motor cortex neurons located more laterally.
We also measured spine density in these animals and found
no changes in any of the treatment groups. Thus, once again
it appears that dendritic branch length and spine density are
independent processes.
6.3. Experience and the aging brain
There have been few systematic studies of experience-
dependent changes in the aging brain. One difficulty in put-
ting senescent rats that have lived their lives in laboratory
cages into enriched environments is that the animals do not
interact with the environment in the same manner as
younger animals. For example, in our rat condominiums
we have observed that whereas young or middle-aged rats
explore the entire complex, and spend much time climbing
to the upper levels, old rats do not appear to have the
motoric abilities (or inclination?) to explore the upper levels
and stay on the ground level. In one experiment we were
able to identify ‘‘climbers’’ and ‘‘nonclimbers’’ and
showed that climbers had significantly larger brains (45).
This observation is important as it demonstrates that mere
passive exposure to experiences is not sufficient to ensure
neuronal change: there must be active interaction with the
environment. This study also underscores the importance of
observing the behavior of animals in specific environments
for it may account for some of the individual variation in
experience-induced brain changes.
One interesting result in our study was seen in the com-
parison of the old adult animals and young adult animals
with the same lab-cage housing. The old animals had much
simpler cells than did the younger animals. Curiously, a
comparison of the enriched old rats and the young adults
showed that the enriched housing returned the cells of the
old animals to the level of younger impoverished animals. It
would be interesting to determine if a longer period of hous-
ing might have stimulated growth similar to that seen in the
younger enriched rats. Furthermore, it would be interesting
to determine if a period of enriched housing during young
adulthood or even middle age might prevent the atrophy of
the neurons in the aged lab-reared rat.
7. EXPERIENCE AND PLASTICITY IN THE INJURED ADULT BRAIN
7.1. Plasticity in the injured adult brain
When the cortex is damaged there are changes in the
remaining cortex that are correlated with functional out-
come. For example, when we removed the frontal cortex
in adult rats, we found an initial drop in dendritic arboriza-
tion in proximal cortical regions such as parietal cortex.
This atrophy slowly resolved and 4 months later there was
a significant increase in dendritic morphology, which was
correlated with partial restitution of function (e.g.
151
(39,40,77)). This morphological plasticity may be related
to lesion size or locus, however, as we have also found that
large unilateral devascularizing lesions including portions
of motor, parietal and anterior visual cortex lead to a
permanent atrophy of remaining cortical neurons (41).
These animals showed little restitution of function, which
would be consistent with the neuronal atrophy. Two addi-
tional factors may be important in understanding neuronal
changes after cortical injury in adulthood. First, in an
innovative series of experiments, Jones and Schallert
(28,29) demonstrated that rats with unilateral lesions of
the forelimb region showed compensatory changes in
behavior (they favored the limb ipsilateral to the lesion)
and that these behavioral changes were correlated with
dendritic growth in the normal hemisphere. When we
replicated these experiments we failed to find the same
changes in the normal hemisphere (13,61) but one funda-
mental difference was in the nature of the brain damage. In
our experiments, we surgically removed tissue whereas in
the Jones and Schallert experiments, tissue was damaged in
such a manner as to lead to slow neuronal death. It now
appears that slow death of neurons leads to changes in
mRNA in neurons in the intact hemisphere that are different
from what is observed after rapid death of neurons (59).
Thus, a second factor affecting injury-induced neuronal
plasticity is the etiology of the disease process.
We have already noted the possibility that changes in glia
may correlate with changes in neuron morphology. One
consistent effect of cortical injury is a marked proliferation
of astrocytes in both the grey and white matter proximal to
the injury. For example, when we made lesions to motor
cortex, we observed a marked increase in the number of
reactive astrocytes in the adjacent motor cortex, as well as
more distal ipsilateral cortical regions, but there was no
detectable change in contralateral, uninjured hemisphere
(11,77). Astrocytes also express other proteins that are
only observed after brain injury. For example, in post-
mortem immunohistochemical studies astrocytes show
virtually no reaction to antibodies specific for basic fibro-
blast growth factor (bFGF) until the brain is injured. Then
there is a dramatic expression of bFGF, which peaks 7 days
after the injury and declines to basal levels about 2 weeks
later. We return to this reaction below. The key point here is
that like neurons, astrocytes change after cerebral injury.
7.2. Experience and the injured adult brain
7.2.1. Changes in neurons
In view of the plastic nature of the injured brain, it is
reasonable to suppose that environmental manipulation
might influence both morphological change and functional
outcome. Although there have been many studies of the
effects of experience on functional outcome after cerebral
injury, the results have been inconsistent (for reviews, see
(82,97)). One difficulty with these studies is that few have
actually measured neuronal morphology but many have
focused upon functional outcome with different environ-
mental manipulations. One exception is an experiment in
which we made large frontal lesions in rats and then either
placed them in our rat condominiums or returned them to
their standard laboratory cages (44). After 2 months of
recovery and experience, the animals were tested on various
152 KOLB ET AL.

behavioral tasks. Our functional results were disappointing injury to the hippocampus mimics, to some extent, the
as we found only a limited benefit from the special housing immature state. This result is intriguing and leads us to
in the brain-injured animals. This result made sense, how- wonder if lesions to other regions implicated in cortical
ever, when we analyzed the neuronal morphology of the plasticity, such as the striatum, might produce parallel
animals. We found that the enriched experience interacted effects.
with the endogenous lesion-induced changes in neuronal
morphology. Thus, the frontal lesions stimulated an increase 7.2.2. Changes in astrocytes and neurotrophins
in dendritic arborization in parietal cortex but did not affect We noted earlier that astrocytes change with experience
visual cortex. Enrichment had no additional effect on the and with cortical injury. In order to determine if lesion and
parietal neurons but stimulated growth in the occipital experience interact, we have measured astrocytic mor-
neurons. It, therefore, appears that neuronal changes phology in animals housed in our rat condominiums for a
induced by the lesion may place limits upon the environ- month prior to sustaining unilateral motor cortex lesions
ment’s capacity for further neuronal, and subsequently (76). As would be anticipated, the animals with enriched
functional, change. Specifically, once having been altered rearing showed an increased expression of GFAP but,
in response to a frontal injury, adjacent parietal neurons may unexpectedly, there was an interaction between injury,
be unable to change further in response to experience. enrichment and astrocyte reactivity. Cortically injured
However, it may be that although the total change in animals with condominium experience had an enhanced
dendritic space is similar in the enriched and lab-housed
brain-injured animals, there is a qualitative difference in the
nature of the changes. Indeed, in view of our observations
on the changes in spine density with similar experience at
different ages, one might predict differences in this measure
to vary with experience after injury. This prediction is
particularly germane because we did find a small functional
benefit from the enriched experience. Unfortunately, we did
not measure spine density in this experiment. (We shall see
in Section 7.2.2 that changes in spine density are indeed
correlated with functional outcome after enriched
experience in animals with lesions in infancy.)
There is now a long history of experiments in which
damage to the hippocampal formation is associated with
deficits in various forms of learning and memory (e.g.
(55)). It is, thus, a logical question to ask how injury to
the hippocampus might affect experience-dependent
changes in the cortex. In principle, it should be easy to
answer this question. One need simply make hippocampal
lesions and place animals in enriched environments and see
what happens. Unfortunately, there is a problem with such a
study. Hippocampal lesions produce a variety of behavioral
changes so it would be difficult to determine if any reduc-
tion in the effects of enrichment on the cortex was due to a
direct effect of the hippocampal injury preventing
experience-dependent change in the cortex or, alternatively,
it was due to a change in the behavior of the animals such
that they did not interact with the environment in the same
manner as unoperated animals. In order to solve this
problem, we made unilateral hippocampal lesions in rats
and placed them in enriched environments or standard lab
cages (89). It was our expectation that, by using this
paradigm, we would control behavioral changes since one
would anticipate that both hemispheres in the same animal
would have the same experience. Thus, any difference in the
effects of experience on the two hemispheres would be a
result of the hippocampal lesion on cortical plasticity. Our
findings were quite unexpected. First, the intact hemisphere
changed as it did in intact rats. That is, there was a growth of
dendrites and an increase in spine density. In contrast, FIG. 11. Summary of the effect of 14 days of enriched housing on the
however, the hemisphere without a hippocampus showed number of GFAP-reactive astrocytes (top) or bFGF-reactive astrocytes
an increase in dendritic length but a decrease in spine (bottom). Rats either received a sham lesion (Control) or a unilateral
density. That is, this hemisphere behaved like an immature motor cortex ablation in the forelimb region. The lesion animals were killed
7 or 21 days after the lesion. The lesions and the enrichment both increased
cerebrum. In retrospect, this effect is perfectly sensible: the the reactivity to both GFAP and bFGF antibodies. Note, however, that
developing brain has an immature hippocampus which is control animals showed no reactivity to antibodies for bFGF. (After
presumably functioning only at a rudimentary level. Hence, Rowntree (76).)
AGE, EXPERIENCE AND THE CHANGING BRAIN
FIG. 12. Schematic illustration of the effects of infusion of nerve growth factor (NGF) into the lateral ventricle of adult rats. Both the dendritic branching and
the spine density were increased in neurons throughout the cerebral cortex. (After Kolb et al. (50).)
expression of GFAP, but even more importantly, these
animals also had an enhanced bFGF (basic fibroblast
growth factor) reaction even though enriched animals with-
out brain damage did not show this bFGF reaction (Fig. 11).
These results suggest that prior experience may affect the
nature of the astrocytic response to injury. We can speculate
that this is likely to enhance the neuronal plasticity and
functional outcome but this has not yet been demonstrated.
One of the functions of bFGF appears to be to encourage
the brain to produce other proteins, one of which is nerve
growth factor (NGF). NGF is known to facilitate recovery
from certain types of brain injury. For example, Kolb et al.
(41) treated rats, that had sustained large unilateral vascular
injuries to the cerebral cortex, with intraventricular infu-
sions of NGF. These animals showed enhanced recovery on
motor and cognitive tasks and this recovery was associated
with a reversal of atrophy in cortical neurons. Furthermore,
and unexpectedly, animals with NGF treatment and no brain
injury showed a dramatic growth in dendritic length and
spine density in cortical neurons (Fig. 12). This result is
intriguing because the animals were trained on various tasks
after the NGF infusion. Thus, it is possible that the NGF
effects reflected an increased sensitivity of the brain to
various experiences. It would be instructive to determine
the effects of NGF on condominium experience.
8. EXPERIENCE AND PLASTICITY IN THE INJURED DEVELOPING BRAIN
8.1. Plasticity in injured developing brain
One of our consistent findings over the past decade has
been that the anatomical sequelae of cortical injury vary
with precise developmental stage. In brief, when the brain
of rats is damaged in the first few days of life, which corre-
sponds to a time just after neural proliferation is complete
but neural migration and differentiation are still ongoing,
there is a marked generalized atrophy of dendritic
153
arborization and a decrease in spine density in neurons
throughout the cortical mantle (43,49). This result is
correlated with a miserable functional outcome and is
reminiscent of the marked abnormalities in the brains of
retarded children (62) (see Fig. 13). In contrast, when the
cortical mantle of rats is damaged in the second week of life,
which corresponds to the period of rapid dendritic growth
and synaptic formation, there is a generalized enhancement
of dendritic arborization and/or spine density throughout the
remaining cortex (49,51). This enhanced dendritic response
is correlated with dramatic functional recovery. Thus, we
see that if the injury in the developing brain leads to
increased dendritic space there is a good functional out-
come, whereas if the injury leads to a retarded development
of dendritic material, there is a poor functional outcome. It
was our expectation, therefore, that if we could potentiate
dendritic growth in the animals normally showing poor
recovery of function, we would enhance functional
recovery.
FIG. 13. Representative examples of dendritic branches from cortical neu-
rons of children (A) and rats (B). A. The left branch is from a child of
normal intelligence, whereas the right branch is from a child with mental
retardation. B. The left branch is from an adult rat that sustained a frontal
lesion at 10 days of age, whereas the right branch is from an adult rat that
sustained a frontal lesion at 1 day of age. The latter rat performed miserably
on all behavioral tests administered. Thus, the animals with severely com-
promised cognitive skills had dendritic branches with few spines. (After
Purpura (62) and Kolb (39), respectively)
154
8.2. Experience and the injured infant brain
We saw earlier that the young brain responds to
experience differently at different ages, and that it also
responds to injury differently at different ages. It is, thus,
reasonable to presume that there will be complex inter-
actions between the type of experience, the time of
experience and the time of injury. We shall consider these
interactions by considering the effects of the earliest injuries
(days 1–5) before considering the effects of injuries at days
7–10.
Because the animal with a cortical lesion in the first days
of life is functionally devastated in adulthood, and because
it shows atrophy of cortical neurons, we anticipated that
such animals would benefit the most from early experience.
Animals were given frontal or posterior parietal lesions at 4
days of age, followed by tactile stimulation (stroking) until
weaning. They were group-housed in laboratory cages and
then tested on various tasks sensitive to frontal or parietal
injury (47). The rats with tactile stimulation showed an
unexpectedly large attenuation of the behavioral deficits of
cerebral injury as a result of this rather brief environmental
‘‘therapy’’. Analysis of the brains showed a reversal of the
atrophy of cortical neurons normally associated with such
early lesions, and more interestingly, a reversal of the
decrease in spine density that is normally associated with
the tactile stimulation (Table 2). In other words stroking
leads to a decrease in spine density in normal animals but to
an increase in spine density in the lesion animals. Thus, it is
clear that environmental events can have different effects on
the normal and the injured brain. We are left, of course, with
the question, ‘‘why?’’ One possibility is that the lesion
differentially affects the production of something, such as
astrocytes and/or growth factors, and these, in turn, influ-
ence the effect of experience on the remaining brain.
Another possibility is that behavior has been changed, and
the change in behavior alters the experience-dependent
effects. Although this latter explanation has some appeal
in the older animal, it seems unlikely in the neonate that has
so little behavior other than feeding and sleeping.
In another series of experiments, we placed animals, who
had lesions on postnatal day 4, in our rat condominiums for
3 months, beginning at the time of weaning (42,47). Once
again, there was a reversal of the behavioral impairments
and this was, again, correlated with a reversal of the
dendritic atrophy. As with the tactile stimulation, there
was also a reversal of the decreased spine density in the
normal animal that was associated with the recovery. We
have not yet examined the effects of condominium housing
in the adult animal with a perinatal cortical injury, but our
TABLE 2
SUMMARY OF THE EFFECTS OF TACTILE STIMULATION ON
BASILAR SPINE DENSITY
Group Non-stroked Stroked
Control 7.8 ⫾ .1 7.3 ⫾ .1*
Frontal 7.8 ⫾ .1 7.4 ⫾ .1*
After Kolb et al. (48).
Numbers represent mean spines per 10 m ( ⫾ SE) for layer-III pyramidal
cells in parietal cortex.
*Differs significantly from nonstroked group.
KOLB ET AL.
prediction is that we would still get improved functional
outcome. In this case, however, we would predict enhanced
dendritic growth and increased spine density, which would
be parallel to effects of enrichment in the control animals.
Testing this prediction is important for it would show that
behavioral therapy consistently improves behavioral out-
come by using a consistent anatomical change, namely
growth of synaptic space, even though in the normal
brain, the response to experience appears to vary with age.
Although we have lumped together the effects of lesions
over the first few days, there is a large behavioral difference:
lesions on day 1 are far more debilitating than comparable
lesions on day 5. Similarly, we have found that the effect of
experience varies depending on whether the lesion was on
day 1 or 5: animals with injuries on day 1 show a much
greater behavioral response to the experience than do
animals with lesions on day 5. Furthermore, although we
did not measure dendritic changes, we did find that there
was an increase in cortical thickness in the younger operates
that was more than twice as large as in the older operates,
which is consistent with the behavioral result (42). It, thus,
appears that the youngest animal with the largest behavioral
impairment is most influenced by the experience. Presum-
ably the experience at least partially reverses the dendritic
atrophy that lead to the dismal behavioral outcome; the
greater the atrophy, the greater the potential recovery. This
result speaks directly to the importance of initiating
behavioral therapies in children with cerebral injuries late
in gestation or at birth for these are the children with the
worst functional outcomes after cerebral injury.
Now let us consider the brain of the animal with good
functional recovery after injury in the second week of life.
Our first experiments looked at animals with frontal lesions
that were placed in condominiums at weaning (47). These
animals showed a much reduced enhancement of behavioral
recovery, presumably, in part, because they were not as
impaired to begin with. Indeed, on some behavioral tasks
there was really no improvement at all with the behavioral
treatment. When we analyzed the brains, we found an
unexpected result. Recall that normal animals show an
increase in branching and a decrease in spine density
when they are placed in the condominiums at weaning.
Furthermore, animals with day-7 frontal lesions show no
change in branching but an increase in spine density, which is
associated with a good behavioral outcome. Enrichment in
day-7 animals produced an increase in dendritic branching
TABLE 3
SUMMARY OF THE EFFECTS OF ENRICHMENT BEGINNING AT
WEANING
Group Isolated Enriched
A. Apical branches
Control 28.8 ⫾ .8 32.1 ⫾ .7*
Frontal 27.0 ⫾ .8 30.4 ⫾ .8*
B. Apical spines
Control 5.5 ⫾ .1 5.2 ⫾ .1*
Frontal 5.8 ⫾ .1 5.2 ⫾ .1*
After Kolb et al. (47).
Numbers represent mean branches per cell or spines per 10 m ( ⫾ SE) for
layer-III pyramidal cells in parietal cortex.
*Differs significantly from isolated group.
AGE, EXPERIENCE AND THE CHANGING BRAIN
but a decrease in spine density relative to cage-reared
animals (Table 3). In other words, an increase in spine
density is associated with recovery after day-7 lesions but
this effect is reversed with enrichment! It appears that the
brain’s response to the injury is altered fundamentally by the
enrichment, even though the behavioral compensation is
only minimally affected. It is unclear what this may mean to
the animal but one prediction is that, unlike the adult brain-
injured rat who could not easily change its brain with
experience (see above), the infant brain-injured rat may
still be capable of considerable change. For example, we
would predict that there would be greater changes in
response to specific experiences (e.g. training to reach or
pull strings) in the infant versus adult injured animal.
To sum up, the effects of experience on the injured brain
are complex and vary with precise age at injury as well as
the time of onset of experience. Perhaps the most important
message is that the infant with the most miserable functional
outcome is especially helped by behavioral therapy. This is
an important lesson for treatment of children with perinatal
brain injuries.
9. SEX AND EXPERIENCE-DEPENDENT CHANGES IN THE BRAIN
There is accumulating evidence that the male and female
brain differ in their structure, respond differently to
environmental events, and respond differently to injury.
We consider each aspect in turn.
9.1. Structural differences in the male and female brain
The first place to look for structural differences in the
brains of males and females is in those structures controlling
behaviors such as sexual behavior or maternal behavior in
mammals or singing in birds. Sexual behavior is known to
be highly dependent upon the hypothalamus and there is
now considerable evidence that the preoptic area of rodents
and primates is sexually dimorphic (3,16). Similarly, there
is substantial literature documenting sex-related differences
in structures related to singing in the song bird. Thus, there
is now little doubt that sexually dimorphic behaviors are
related to sexually dimorphic structure in the brain regions
of mammals and birds that are related in some way to
reproductive behavior. What is more interesting, however,
is the more recent evidence that there are sex-related
differences in cortical structures that are not known to be
related to the control of behaviors related to mating. For
example, morphometric analyses of the male and female
brain have shown differences in neuron numbers in different
cortical regions (e.g. (71,72)), as well as in dendritic
structure (32). Recently, Seymoure and Juraska (78)
reported that there may be sex differences in visual perceptual
abilities of male and female rats. In particular, although they
found no differences in visual acuity, they did find that males
had more acute vernier acuity than females, a result that has,
at least, circumstantial correlation with the morphological
difference in the visual cortex of male and female rats.
In our own work, we have found differences in prefrontal
and parietal regions as well (e.g. (53,86,87)). The sex
differences in the prefrontal regions are intriguing because
we find greater dendritic arborizations in the midline pre-
frontal regions in males and, in contrast, greater dendritic
155
arborizations in the orbital prefrontal regions in females
(52). Thus, these sex differences are not evidence of more
synapses in one sex than the other, but rather they suggest a
fundamental difference in the organization of the prefrontal
regions in males and females. Furthermore, we have found
sex differences in the effects of lesions to these regions, a
result that would be consistent with the anatomical results
(e.g. (40)). One explanation for the sex-related differences
in the prefrontal areas is that the presence of gonadal
hormones during development fundamentally alters the
structure of the cells. We have tested this hypothesis directly
by looking at the effects of neonatal gonadectomy or
treatment with testosterone on cortical morphology and
have found that hormone manipulations do indeed alter
the neuronal structure in the different cortical regions (e.g.
(86,87)).
Recently, Jacobs et al. (27) have described a sex differ-
ence in their quantitative dendritic analysis of Wernicke’s
area, which is a language-related area, in humans. Their
finding was that females have more extensive dendritic
arbors than males. This result is consistent with the reliable
finding that females are superior in certain verbal skills than
males (for a review see (55)). Furthermore, in a subsequent
study, Jacobs and Scheibel (26) found that this sex differ-
ence was present as early as age 9, suggesting that such sex
differences emerge within the first decade. These sex
differences in cortical architecture in humans are parallel
to those reported in other studies showing sex differences in
cerebral blood flow and glucose metabolism with females
having about at 15% higher level than males (e.g. (1,73)).
The importance of hormones to cortical structure is not
restricted to development. When Stewart and Kolb (87)
ovariectomized or gonadectomized adult rats they found a
significant change in cortical structure, especially in the
females. Thus, the brains of the ovariectomized rats not only
grew heavier but the cortical neurons showed an 25%
increase in dendritic arbor and an 10% increase in spine
density (Table 4). Males showed only an increase in spine
density. This result is surprising as it implies that cortical
morphology is hormone-dependent throughout the life of a
mammal. The finding of hormone-dependent changes in
cortical structure in the adult animal is corroborated by more
recent studies of astrocytes.
To summarize, there are sex-dependent differences in
neuronal architecture in the cortex. These differences are
due, in part, to the effects of gonadal hormones during
development but, especially in females, there is evidence
that circulating hormones alter cortical architecture in
TABLE 4
SUMMARY OF THE EFFECTS OF OVARIECTOMY OR
CASTRATION IN ADULTHOOD
Group Branches Terminal spines Secondary spines
Male 30.3 5.3 ⫾ .2 8.6 ⫾ .2
Castrated 28.0 6.0 ⫾ 3 9.4 ⫾ .1
Female 24.8 5.7 ⫾ .1 9.1 ⫾ .2
Ovariectomy 31.6 5.9 ⫾ .1 9.9 ⫾ .2
After Stewart and Kolb (87).
Numbers represent mean branches per cell or spines per 10 m ( ⫾ SE) for
apical field of layer-III pyramidal cells in parietal cortex.
156
adulthood as well. Finally, although it has not been studied
in detail, it also seems likely that there are sex-related
differences in astrocytic numbers and morphology in the
cortex as well.
9.2. Sex, experience, and cortical structure
Juraska (e.g. (30–35)) was the first to report that neurons
in the occipital cortex of the male rat show significant
dendritic growth with 30 days of enriched experience,
whereas neurons in the occipital cortex of the female rat
do not. In contrast, she found that hippocampal neurons
show a greater response to the enriched rearing in the female
brain than in the male brain. Although we found these
experiments intriguing, they were also puzzling since it
seemed reasonable to suppose that experience was altering
the cortex of both males and females. We hypothesized that
perhaps Juraska’s sex differences were at least partly due to
differences in the sensitivity of the cortex to experience. In
other words, we wondered what would happen if animals
were given more prolonged exposure to the enriched
environments. We therefore placed adult male and female
rats in condominiums for 5 months. Analysis of the
pyramidal cells in layer III of both parietal and occipital
cortex revealed an unexpected result: Although the dendritic
arborization of both males and females increased with 5
months of living in the condos, the increases were greater in
females. Thus, in contrast to Juraska’s studies of visual cortex
after 30 days of enrichment, we found a larger increase in
dendritic arborization in the cells in female cortex than in
male cortex (Table 5). Somewhat surprisingly, however, when
we examined the spine density, we found a larger increase in
spine density in males than in females (46,58). These results
lead us to two conclusions. First, both males and females show
experience dependent changes in the pyramidal neurons of the
cortex. It may be, however, that males are more sensitive than
females and show morphological changes sooner than
females. If so, this may account for the apparent difference
between the results of Juraska and the results of our experi-
ments. Second, there is a sex difference in the details of the
structural changes in cortical neurons: males show a greater
increase in spine density, whereas females show a greater
increase in dendritic length.
The next question we considered was whether age at
enrichment would interact with sex. We had shown
previously that age at the onset of enriched rearing differ-
entially affected spine density (see Section 6.1) but we had
TABLE 5
SUMMARY OF THE EFFECTS OF 5 MONTHS EXPERIENCE IN THE
CONDOMINIUMS
Group Isolated Enriched
Apical Basilar Apical Basilar
Male 29.5 40.6 30.7 51.4*
Female 26.3 38.9 33.5* 53.3*
After Kolb et al. (46).
Numbers represent mean branches per cell for layer-III pyramidal cells in
parietal cortex.
*Significantly different from same-sex isolated group.
KOLB ET AL.
not considered the role of sex. We therefore reanalyzed our
studies in which juvenile rats were placed in the condo-
miniums or infant rats were given tactile stimulation (46).
The results showed that the sex-dependent differences in the
effects of enrichment varied with age. Firstly, we found that
females showed a greater response to tactile stimulation
than males. Hence, females showed a greater decrease in
spine density than males. Secondly, we found that both
sexes showed an increase in dendritic arborization and a
decrease in spine density when they were placed in the
condominiums at weaning.
Thus, it appears that sex differences in the effect of
experience are not only influenced by the length of the
enrichment experience but that the details of the
environment-responsive changes vary with age.
10. CONCLUSIONS
One of the most intriguing questions in behavioral
neuroscience concerns the manner in which the brain, and
especially the neocortex, can modify its structure and
ultimately its function throughout one’s lifetime. As the
review has suggested, the cortex can be changed dramati-
cally by experience and this change is modulated by various
factors. Several basic conclusions can be extracted regard-
ing the nature of the relationship between experience, brain
plasticity, and behavior.
1. Experience alters the synaptic organization of the cortex.
It is possible to visualize with a light microscope the morpho-
logical changes in the cortex that reflect synaptic modification.
These structural changes include modification of both neurons
and glia. The neuronal changes can be quantified as increases
or decreases in the amount of dendritic arborization as well as
in the density of dendritic spines. The glial changes can be
measured by calculating the number and the size of astrocytes
and the density of microglia.
2. Experience can alter different parts of neurons differ-
ently. For instance, alterations in dendritic length can occur
independently of changes in dendritic spine density.
Environmental stimulation during the juvenile and adoles-
cent period produces increased growth of dendritic length,
while at the same time producing a decrease in spine
density. The increase in dendritic length would act to
increase the number of synapses, whereas the decrease in
spine density would act to decrease the total number of
synapses. Furthermore, different parts of the neuron can
change independently of other parts. Thus, there may be
changes in distal parts of the dendritic arbor that are
independent of changes in proximal parts.
3. Changes in synaptic organization are correlated with
changes in behavior. Animals with extensive dendritic
growth relative to untreated animals show facilitated per-
formance on many types of behavioral measures, especially
measures of cognitive activity. Such changes are visible not
only in laboratory animals but also in humans. For example,
Jacobs and Scheibel (26) and Jacobs et al. (27) found a
relationship between the extent of dendritic arborization in a
cortical language area (Wernicke’s area) and the amount of
education. The cortical neurons from the brains of deceased
people with a university education had more dendritic arbor
than those from people with a high-school education who, in
turn, had more dendritic material than those with less than
high-school education.
AGE, EXPERIENCE AND THE CHANGING BRAIN
4. The effects of experience vary both qualitatively and
quantitatively with age. For example, ‘‘enriched’’ experi-
ences during the immediate postnatal period have no
measurable effect on dendritic length and lead to a decrease
in spine density. Enriched experiences during the juvenile
and adolescent period produce increases in dendritic length
but decreases in spine density. Similar experiences later in
life produce increases in both dendritic length and spine
density. All of these experiences have behavioral sequelae
in adulthood. The age-dependent plastic changes in the
cortex are likely very important and reflect the differential
sensitivity of the child’s brain to experience during develop-
ment. What is not yet known is how different experiences at
different times in life might interact and to what extent the
absence of a particular experience might be compensated
for later in life.
5. There are compensatory plastic changes in the brain
following brain injury that are similar in kind to those
observed when animals learn from experience. These
injury-induced changes are also age-dependent and are
thought to reflect the age-related recovery observed after
brain injury at different times throughout the lifetime. For
example, animals with cortical injuries in the first week of
life show decreased dendritic arborization that is associated
with a poor functional outcome. In contrast, animals with
cortical injuries in the second week of life show increased
dendritic arborization and a good functional outcome.
The similarity between the plastic changes in the brain in
response to injury or experience suggests that there may be
basic mechanisms of synaptic change in the mammalian
cortex that are used in many forms of synaptic plasticity.
This is an encouraging possibility, for it allows hope that we
will be able to improve recovery from cerebral injury by
taking advantage of the innate mechanisms that the brain
uses for other forms of plasticity. Furthermore, to offer a
more speculative hypothesis, it may also be possible to
reverse the effects of impoverished experience by using
pharmacological treatments that are effective in improving
recovery from brain injury.
6. Injury-induced changes in cortical structure are
modified by experience. Furthermore, brains that show the
least change in response to a cortical injury appear to be the
most responsive to experience. For instance, animals with
neonatal brain injuries show a poor functional outcome and
an atrophy of cortical neurons but these animals show
dramatic functional recovery and marked synaptic growth
in response to environmental manipulations. This is
encouraging for it suggests that behavioral therapies should
be especially helpful in reversing some of the devastating
consequences of brain damage in the latter periods of
prenatal development in human infants.
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