Bryan Kolb,1 Robbin Gibb, and Terry Robinson
Canadian Centre for Behavioural Neuroscience,
University of Lethbridge, Lethbridge, Alberta, Canada (B.K., RG.), and
Department of Psychology, University of Michigan, Ann Arbor, Michigan (T.R.)
Abstract
Although the brain was once seen as a rather static organ, it is now clear that the organization of brain circuitry is constantly changing as a function of experience. These changes are referred to as brain plasticity, and they are associated with functional changes that include phenomena such as memory, addiction, and recovery of function. Recent research has shown that brain plasticity and behavior can be influenced by a myriad of factors, including both pre- and postnatal experience, drugs, hormones, maturation, aging, diet, disease, and stress. Understanding how these factors influence brain organization and function is important not only for understanding both normal and abnormal behavior, but also for designing treatments for behavioral and psychological disorders ranging from addiction to stroke.
addiction; recovery; experience;
brain plasticity
One of the most intriguing questions in behavioral
neuroscience concerns the manner in which the nervous system can modify its
organization and ultimately its function throughout an individual's lifetime, a
property that is often referred to as plasticity. The capacity to change
is a fundamental characteristic of nervous systems and can be seen in even the
simplest of organisms, such as the tiny worm C. elegans, whose nervous system has only 302
cells. When the nervous system changes, there is often a correlated change in
behavior or psychological function. This behavioral change is known by names
such as learning, memory, addiction, maturation, and recovery. Thus, for
example, when people learn new motor skills, such as in playing a musical
instrument, there are plastic changes in the structure of cells in the nervous
system that underlie the motor skills. If the plastic changes are somehow
prevented from occurring, the motor learning does not occur. Although
psychologists have assumed that the nervous system is especially sensitive to
experience during development, it is only recently that they have begun to
appreciate the potential for plastic changes in the adult brain. Understanding
brain plasticity is obviously of considerable interest both because it provides
a window to understanding the development of the brain and behavior and because
it allows insight into the causes of normal and abnormal behavior.
The
underlying assumption of studies of brain and behavioral plasticity is that if
behavior changes, there must be some change in organization or properties of the
neural circuitry that produces the behavior. Conversely, if neural networks are
changed by experience, there must be some corresponding change in the functions
mediated by those networks. For the investigator interested in understanding
the factors that can change brain circuits, and ultimately behavior, a major
challenge is to find and to quantify the changes. In principle, plastic changes
in neuronal circuits are likely to reflect either modifications of existing
circuits or the generation of new circuits. But how can researchers measure
changes in neural circuitry? Because
neural networks are composed of individual neurons, each of which connects with
a subset of other neurons to form interconnected networks, the logical place to
look for plastic changes is at the junctions between neurons, that is, at
synapses. However, it is a daunting task to determine if synapses have been
added or lost in a particular region, given that the human brain has something
like 100 billion neurons and each neuron makes on average several thousand
synapses. It is clearly impractical to scan the brain looking for altered
synapses, so a small subset must be identified and examined in detail. But
which synapses should be studied? Given that neuroscientists have a pretty good
idea of what regions of the brain are involved in particular behaviors, they
can narrow their search to the likely areas, but are still left with an
extraordinarily complex system to examine. There is, however, a procedure that
makes the job easier.
In
the late 1800s, Camillo Golgi invented a technique for staining a random subset
of neurons (1-5%) so that the cell bodies and the dendritic trees of individual
cells can be visualized (Fig. 1). The dendrites of a cell function as the
scaffolding for synapses, much as tree branches provide a location for leaves
to grow and be exposed to sunlight. The usefulness of Golgi's technique can be
understood by pursuing this arboreal metaphor. There are a number of ways one
could estimate how many leaves are on a tree without counting every leaf. Thus,
one could measure the total length of the tree’s branches as well as the
density of the leaves on a representative branch. Then, by simply multiplying
branch length by leaf density, one could estimate total leafage. A similar
procedure is used to estimate synapse number. About 95% of a cell’s synapses
are on its dendrites (the neuron’s branches). Furthermore, there is a roughly
linear relationship between the space available for synapses (dendritic
surface) and the number of synapses, so researchers can presume that increases
or decreases in dendritic surface reflect changes in synaptic organization.
By using
Golgi-staining procedures, various investigators have shown that housing animals
in complex versus simple environments produces widespread differences in the
number of synapses in specific brain regions. In general, such experiments show
that particular experiences embellish circuitry, whereas the absence of those
experiences fails to do so (e.g., Greenough & Chang, 1989). Until recently,
the impact of these neuropsychological experiments was surprisingly limited, in
part because the environmental treatments were perceived as extreme and thus
not characteristic of events experienced by the normal brain. It has become
clear, however, not only that synaptic organization is changed by experience,
but also that the scope of factors that can do this is much more extensive than
anyone had anticipated. Factors that are now known to affect neuronal structure
and behavior include the following:
§
experience (both pre- and
postnatal)
§
psychoactive drugs (e.g.,
amphetamine, morphine)
§
gonadal hormones (e.g.,
estrogen, testosterone)
§
anti-inflammatory agents
(e.g., COX-2 inhibitors)
§
growth factors (e.g., nerve
growth factor)
§
dietary factors (e.g.,
vitamin and mineral supplements)
§
genetic factors (e.g., strain
differences, genetically modified mice)
§
disease (e.g., Parkinson’s
disease, schizophrenia, epilepsy, stroke)
We discuss two examples to
illustrate.
It
is generally assumed that experiences early in life have different effects on
behavior than similar experiences later in life. The reason for this difference
is not understood, however. To investigate this question, we placed animals in
complex environments either as juveniles, in adulthood, or in senescence (Kolb,
Gibb, & Gorny, 2003). It was our expectation that there would be
quantitative differences in the effects of experience on synaptic organization,
but to our surprise, we also found qualitative differences. Thus, like
many investigators before us, we found that the length of dendrites and the
density of synapses were increased in neurons in the motor and sensory cortical
regions in adult and aged animals housed in a complex environment (relative to
a standard lab cage). In contrast, animals placed in the same environment as
juveniles showed an increase in dendritic length but a decrease in spine
density. In other words, the same environmental manipulation had qualitatively
different effects on the organization of neuronal circuitry in juveniles than
in adults.
To pursue
this finding, we later gave infant animals 45 min of daily tactile stimulation
with a little paintbrush (15 min three times per day) for the first 3 weeks of
life. Our behavioral studies showed that this seemingly benign early experience
enhanced motor and cognitive skills in adulthood. The anatomical studies
showed, in addition, that in these animals there was a decrease in spine
density but no change in dendritic length in cortical neurons; yet another
pattern of experience-dependent neuronal change. (Parallel studies have shown
other changes, too, including neurochemical changes, but these are beyond the
current discussion.) Armed with these findings, we then asked whether prenatal
experience might also change the structure of the brain months later in
adulthood. Indeed, it does. For example, the offspring of a rat housed in a
complex environment during the term of her pregnancy have increased synaptic
space on neurons in the cerebral cortex in adulthood. Although we do not know
how prenatal experiences alter the brain, it seems likely that some chemical
response by the mother, be it hormonal or otherwise, can cross the placental
barrier and alter the genetic signals in the developing brain.
Our
studies showing that experience can uniquely affect the developing brain led us
to wonder if the injured infant brain might be repaired by environmental
treatments. We were not surprised to find that postinjury experience, such as
tactile stroking, could modify both brain plasticity and behavior because we
had come to believe that such experiences were powerful modulators of brain
development (Kolb, Gibb, & Gorny, 2000). What was surprising, however, was
that prenatal experience, such as housing the pregnant mother in a complex
environment, could affect how the brain responded to an injury that it would
not receive until after birth. In other words, prenatal experience altered the
brain’s response to injury later in life. This type of study has profound
implications for preemptive treatments of children at risk for a variety of
neurological disorders.
Many
people who take stimulant drugs like nicotine, amphetamine, or cocaine do so
for their potent psychoactive effects. The long-term behavioral consequences of
abusing such psychoactive drugs are now well documented, but much less is known
about how repeated exposure to these drugs alters the nervous system. One
experimental demonstration of a very persistent form of drug
experience-dependent plasticity is known as behavioral sensitization. For
example, if a rat is given a small dose of amphetamine, it initially will show
a small increase in motor activity (e.g., locomotion, rearing). When the rat is
given the same dose on subsequent occasions, however, the increase in motor
activity increases, or sensitizes, and the animal may remain sensitized for
weeks, months, or even years, even if drug treatment is discontinued.
Changes
in behavior that occur as a consequence of past experience, and can persist for
months or years, like memories, are thought to be due to changes in patterns of
synaptic organization. The parallels between drug-induced sensitization and
memory led us to ask whether the neurons of animals sensitized to drugs of
abuse exhibit long-lasting changes similar to those associated with memory
(e.g., Robinson & Kolb, 1999). A comparison of the effects of amphetamine
and saline treatments on the structure of neurons in a brain region known as
the nucleus accumbens, which mediates the psychomotor activating effects of
amphetamine, showed that neurons in the amphetamine-treated brains had greater
dendritic material, as well as more densely organized spines . These plastic
changes were not found throughout the brain, however, but rather were localized
to regions such as the prefrontal cortex and nucleus accumbens, both of which
are thought to play a role in the rewarding properties of these drugs. Later
studies have shown that these drug-induced changes are found not only when
animals are given injections by an experimenter, but also when animals are
trained to self-administer drugs, leading us to speculate that similar changes
in synaptic organization be found in human drug addicts.
All
of the factors outlined in Table 1 have effects that are conceptually similar
to the two examples that we just discussed. For instance, brain injury disrupts
the synaptic organization of the brain, and when there is functional
improvement after the injury, there is a correlated reorganization of neural
circuits (e.g., Kolb, 1995). But not all factors act the same way across the
brain. For instance, estrogen stimulates synapse formation in some structures
but reduces synapse number in other structures (e.g., Kolb, Forgie, Gibb,
Gorny, & Rowntree, 1998), a pattern of change that can also be seen with
some psychoactive drugs, such as morphine. In sum, it now appears that
virtually any manipulation that produces an enduring change in behavior leaves
an anatomical footprint in the brain.
There are
several conclusions to draw from our studies. First, experience alters the
brain, and it does so in an age-related manner. Second, both pre- and postnatal
experience have such effects, and these effects are long-lasting and can
influence not only brain structure but also adult behavior. Third, seemingly
similar experiences can alter neuronal circuits in different ways, although
each of the alterations is manifest in behavioral change. Fourth, a variety of
behavioral conditions, ranging from addiction to neurological and psychiatric
disorders, are correlated with localized changes in neural circuits. Finally,
therapies that are intended to alter behavior, such as treatment for addiction,
stroke, or schizophrenia, are likely to be most effective if they are able to
further reorganize relevant brain circuitry. Furthermore, studies of neuronal
structure provide a simple method of screening for treatments that are likely
to be effective in treating disorders such as dementia. Indeed, our studies
show that the new generation of antiarthritic drugs (known as COX-2
inhibitors), which act to reduce inflammation, can reverse age-related synaptic
loss and thus ought to be considered as useful treatments for age-related
cognitive loss.
Although
much is now known about brain plasticity and behavior, many theoretical issues
remain. Knowing that a wide variety of experiences and agents can alter
synaptic organization and behavior is important, but leads to a new question:
How does this happen? This is not an easy question to answer, and it is certain
that there is more than one answer. We provide a single example to illustrate.
Neurotrophic
factors are a class of chemicals that are known to affect synaptic
organization. An example is fibroblast growth factor-2 (FGF-2). The production
of FGF-2 is increased by various experiences, such as complex housing and
tactile stroking, as well as by drugs such as amphetamine. Thus, it is possible
that experience stimulates the production of FGF-2 and this, in turn, increases
synapse production. But again, the question is how. One hypothesis is that
FGF-2 somehow alters the way different genes are expressed by specific neurons
and this, in turn, affects the way synapses are generated or lost. In other
words, factors that alter behavior, including experience, can do so by altering
gene expression, a result that renders the traditional gene-versus-environment
discussions meaningless.
Other
issues revolve around the limits and permanence of plastic changes. After all,
people encounter and learn new information daily. Is there some limit to how
much cells can change? It seems unlikely that cells could continue to enlarge
and add synapses indefinitely, but what controls this? We saw in our studies of
experience-dependent changes in infants, juveniles, and adults that experience
both adds and prunes synapses, but what are the rules governing when one or the
other might occur? This question leads to another, which is whether plastic
changes in response to different experiences might interact. For example, does
exposure to a drug like nicotine affect how the brain changes in learning a
motor skill like playing the piano? Consider, too, the issue of the permanence
of plastic changes. If a person stops smoking, how long do the nicotine-induced
plastic changes persist, and do they affect later changes?
One
additional issue surrounds the role of plastic changes in disordered behavior.
Thus, although most studies of plasticity imply that remodeling neural
circuitry is a good thing, it is reasonable to wonder if plastic changes might
also be the basis of pathological behavior. Less is known about this possibility,
but it does seem likely. For example, drug addicts often show cognitive
deficits, and it seems reasonable to propose that at least some of these
deficits could arise from abnormal circuitry, especially in the frontal lobe.
In
sum, the structure of the brain is constantly changing in response to an
unexpectedly wide range of experiential factors. Understanding how the brain
changes and the rules governing these changes is important not only for
understanding both normal and abnormal behavior, but also for designing
treatments for behavioral and psychological disorders ranging from addiction to
stroke.
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(2001). Toward a theory of neuroplasticity. New York: Taylor and
Francis.
Acknowledgments--
This research was supported by a Natural Sciences and Engineering Research
Council grant to B.K. and a National Institute on Drug Abuse grant to T.R..
1. Address correspondence to Bryan
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Fig. 1. Photograph of a neuron. In
the view on the left, the dendritic field with the extensive dendritic network
is visible. On the right are higher-power views of dendritic branches showing
the spines, where most synapses are located. If there is an increase in
dendritic length, spine density, or both, there are presumed to be more
synapses in the neuron.