Brain Plasticity and Behavior in the Functions Mediated by Those Bryan Kolb,1 Robbin Gibb, and Terry E

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must be some corresponding change Brain Plasticity and Behavior in the functions mediated by those Bryan Kolb,1 Robbin Gibb, and Terry E. Robinson networks. For the investigator inter- ested in understanding the factors Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, that can change brain circuits, and Alberta, Canada (B.K., RG.), and Department of Psychology, University of Michigan, Ann Arbor, Michigan (T.E.R.) ultimately behavior, a major chal- lenge is to find and to quantify the changes. In principle, plastic changes in neuronal circuits are likely to re- ganisms, such as the tiny worm C. Abstract flect either modifications of exist- elegans, whose nervous system has Although the brain was once ing circuits or the generation of only 302 cells. When the nervous seen as a rather static organ, it is new circuits. But how can research- system changes, there is often a now clear that the organization ers measure changes in neural cir- correlated change in behavior or of brain circuitry is constantly cuitry? Because neural networks psychological function. This behav- changing as a function of expe- are composed of individual neu- ioral change is known by names rience. These changes are re- rons, each of which connects with a such as learning, memory, addiction, ferred to as brain plasticity, subset of other neurons to form in- maturation, and recovery. Thus, for and they are associated with terconnected networks, the logical example, when people learn new functional changes that include place to look for plastic changes is motor skills, such as in playing a phenomena such as memory, at the junctions between neurons, musical instrument, there are plas- addiction, and recovery of that is, at synapses. However, it is a tic changes in the structure of cells function. Recent research has daunting task to determine if syn- in the nervous system that underlie shown that brain plasticity and apses have been added or lost in a the motor skills. If the plastic behavior can be influenced by particular region, given that the changes are somehow prevented a myriad of factors, including human brain has something like from occurring, the motor learning both pre- and postnatal experi- 100 billion neurons and each neuron does not occur. Although psychol- ence, drugs, hormones, matu- makes on average several thousand ogists have assumed that the ner- ration, aging, diet, disease, and synapses. It is clearly impractical to vous system is especially sensitive stress. Understanding how scan the brain looking for altered to experience during develop- these factors influence brain synapses, so a small subset must be ment, it is only recently that they organization and function is identified and examined in detail. have begun to appreciate the po- important not only for under- But which synapses should be tential for plastic changes in the standing both normal and ab- studied? Given that neuroscientists adult brain. Understanding brain normal behavior, but also for have a pretty good idea of what re- plasticity is obviously of consider- designing treatments for be- gions of the brain are involved in able interest both because it pro- havioral and psychological dis- particular behaviors, they can nar- vides a window to understanding orders ranging from addiction row their search to the likely areas, the development of the brain and to stroke. but are still left with an extraordi- behavior and because it allows in- narily complex system to examine. sight into the causes of normal and Keywords There is, however, a procedure that abnormal behavior. addiction; recovery; experi- makes the job easier. ence; brain plasticity In the late 1800s, Camillo Golgi invented a technique for staining a random subset of neurons (1–5%) One of the most intriguing ques- THE NATURE OF BRAIN so that the cell bodies and the den- tions in behavioral neuroscience PLASTICITY dritic trees of individual cells can concerns the manner in which the be visualized (Fig. 1). The den- nervous system can modify its or- The underlying assumption of drites of a cell function as the scaf- ganization and ultimately its func- studies of brain and behavioral plas- folding for synapses, much as tree tion throughout an individual’s ticity is that if behavior changes, branches provide a location for lifetime, a property that is often re- there must be some change in orga- leaves to grow and be exposed to ferred to as plasticity. The capacity nization or properties of the neural sunlight. The usefulness of Golgi’s to change is a fundamental charac- circuitry that produces the behav- technique can be understood by teristic of nervous systems and can ior. Conversely, if neural networks pursuing this arboreal metaphor. be seen in even the simplest of or- are changed by experience, there There are a number of ways one

2 VOLUME 12, NUMBER 1, FEBRUARY 2003

ments 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 antici- pated. Factors that are now known to affect neuronal structure and behavior include the following:

• experience (both leading pre- and post-natal) • 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) Fig. 1. Photograph of a neuron. In the view on the left, the dendritic field with the • stress extensive dendritic network is visible. On the right are higher-power views of den- • brain injury and leading disease dritic 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. We discuss two examples to illustrate. could estimate how many leaves are Early Experience on a tree without counting every leaf. FACTORS AFFECTING BRAIN Thus, one could measure the total PLASTICITY It is generally assumed that ex- length of the tree’s branches as well periences early in life have differ- as the density of the leaves on a By using Golgi-staining proce- ent effects on behavior than similar representative branch. Then, by sim- dures, various investigators have experiences later in life. The reason ply multiplying branch length by shown that housing animals in for this difference is not under- leaf density, one could estimate to- complex versus simple environ- stood, however. To investigate this tal leafage. A similar procedure is ments produces widespread differ- question, we placed animals in used to estimate synapse number. ences in the number of synapses in complex environments either as ju- About 95% of a cell’s synapses are specific brain regions. In general, veniles, in adulthood, or in senes- on its dendrites (the neuron’s such experiments show that partic- cence (Kolb, Gibb, & Gorny, 2003). branches). Furthermore, there is a ular experiences embellish cir- It was our expectation that there roughly linear relationship be- cuitry, whereas the absence of would be quantitative differences in tween the space available for syn- those experiences fails to do so the effects of experience on synaptic apses (dendritic surface) and the (e.g., Greenough & Chang, 1989). organization, but to our surprise, we number of synapses, so researchers Until recently, the impact of these also found qualitative differences. can presume that increases or de- neuropsychological experiments Thus, like many investigators be- creases in dendritic surface reflect was surprisingly limited, in part fore us, we found that the length of changes in synaptic organization. because the environmental treat- dendrites and the density of syn-

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CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE 3 apses were increased in neurons in ments. We were not surprised to ganization. The parallels between the motor and sensory cortical re- find that postinjury experience, drug-induced sensitization and gions in adult and aged animals such as tactile stroking, could mod- memory led us to ask whether the housed in a complex environment ify both brain plasticity and behav- neurons of animals sensitized to (relative to a standard lab cage). In ior because we had come to believe drugs of abuse exhibit long-lasting contrast, animals placed in the that such experiences were power- changes similar to those associated same environment as juveniles ful modulators of brain develop- with memory (e.g., Robinson & showed an increase in dendritic ment (Kolb, Gibb, & Gorny, 2000). Kolb, 1999). A comparison of the ef- length but a decrease in spine den- What was surprising, however, fects of amphetamine and saline sity. In other words, the same envi- was that prenatal experience, such treatments on the structure of neu- ronmental manipulation had quali- as housing the pregnant mother in rons showed that neurons in am- tatively different effects on the a complex environment, could af- phetamine-treated brains had greater organization of neuronal circuitry fect how the brain responded to an dendritic material, as well as more in juveniles than in adults. injury that it would not receive un- densely organized spines. These To pursue this finding, we later til after birth. In other words, pre- plastic changes were not found gave infant animals 45 min of daily natal experience altered the brain’s throughout the brain, however, but tactile stimulation with a little response to injury later in life. This rather were localized to regions such paintbrush (15 min three times per type of study has profound impli- as the prefrontal cortex and nu- day) for the first 3 weeks of life. cations for preemptive treatments cleus accumbens, both of which are Our behavioral studies showed of children at risk for a variety of thought to play a role in the reward- that this seemingly benign early neurological disorders. ing properties of these drugs. Later experience enhanced motor and studies have shown that these drug- cognitive skills in adulthood. The induced changes are found not only anatomical studies showed, in ad- Psychoactive Drugs when animals are given injections by dition, that in these animals there an experimenter, but also when ani- was a decrease in spine density but Many people who take stimu- mals are trained to self-administer no change in dendritic length in lant drugs like nicotine, amphet- drugs, leading us to speculate that cortical neurons—yet another pat- amine, or cocaine do so for their similar changes in synaptic organi- tern of experience-dependent neu- potent psychoactive effects. The zation will be found in human drug ronal change. (Parallel studies have long-term behavioral consequences addicts. shown other changes, too, including of abusing such psychoactive neurochemical changes, but these drugs are now well documented, are beyond the current discussion.) but much less is known about how Other Factors Armed with these findings, we then repeated exposure to these drugs asked whether prenatal experience alters the nervous system. One ex- All of the factors we listed earlier might also change the structure of perimental demonstration of a very have effects that are conceptually the brain months later in adulthood. persistent form of drug experience- similar to the two examples that Indeed, it does. For example, the off- dependent plasticity is known as we just discussed. For instance, spring of a rat housed in a complex behavioral sensitization. For exam- brain injury disrupts the synaptic environment during the term of her ple, if a rat is given a small dose of organization of the brain, and pregnancy have increased synaptic amphetamine, it initially will show when there is functional improve- space on neurons in the cerebral cor- a small increase in motor activity ment after the injury, there is a cortex in adulthood. Although we do (e.g., locomotion, rearing). When related reorganization of neural not know how prenatal experiences the rat is given the same dose on circuits (e.g., Kolb, 1995). But not alter the brain, it seems likely that subsequent occasions, however, all factors act the same way across some chemical response by the the increase in motor activity in- the brain. For instance, estrogen mother, be it hormonal or otherwise, creases, or sensitizes, and the ani- stimulates synapse formation in can cross the placental barrier and al- mal may remain sensitized for some structures but reduces syn- ter the genetic signals in the develop- weeks, months, or even years, even apse number in other structures ing brain. if drug treatment is discontinued. (e.g., Kolb, Forgie, Gibb, Gorny, & Our studies showing that expe- Changes in behavior that occur as Rowntree, 1998), a pattern of rience can uniquely affect the de- a consequence of past experience, change that can also be seen with veloping brain led us to wonder if and can persist for months or years, some psychoactive drugs, such as the injured infant brain might be like memories, are thought to be due morphine. In sum, it now appears repaired by environmental treat- to changes in patterns of synaptic or- that virtually any manipulation

4 VOLUME 12, NUMBER 1, FEBRUARY 2003 that produces an enduring change swer. We provide a single exam- that remodeling neural circuitry is in behavior leaves an anatomical ple to illustrate. a good thing, it is reasonable to footprint in the brain. Neurotrophic factors are a class wonder if plastic changes might of chemicals that are known to af- also be the basis of pathological be- fect synaptic organization. An ex- havior. Less is known about this ample is fibroblast growth factor-2 possibility, but it does seem likely. CONCLUSIONS AND ISSUES (FGF-2). The production of FGF-2 is For example, drug addicts often increased by various experiences, show cognitive deficits, and it There are several conclusions to such as complex housing and tactile seems reasonable to propose that at draw from our studies. First, expe- stroking, as well as by drugs such as least some of these deficits could rience alters the brain, and it does amphetamine. Thus, it is possible arise from abnormal circuitry, es- so in an age-related manner. Second, that experience stimulates the pro- pecially in the frontal lobe. both pre- and postnatal experience duction of FGF-2 and this, in turn, In sum, the structure of the brain have such effects, and these effects increases synapse production. But is constantly changing in response are long-lasting and can influence again, the question is how. One to an unexpectedly wide range of not only brain structure but also hypothesis is that FGF-2 somehow experiential factors. Understanding adult behavior. Third, seemingly alters the way different genes are how the brain changes and the rules similar experiences can alter neu- expressed by specific neurons and governing these changes is impor- ronal circuits in different ways, al- this, in turn, affects the way synapses tant not only for understanding though each of the alterations is are generated or lost. In other words, both normal and abnormal behav- manifest in behavioral change. factors that alter behavior, including ior, but also for designing treat- Fourth, a variety of behavioral con- experience, can do so by altering gene ments for behavioral and psycho- ditions, ranging from addiction to expression, a result that renders the logical disorders ranging from neurological and psychiatric disor- traditional gene-versus-environment addiction to stroke. ders, are correlated with localized discussions meaningless. changes in neural circuits. Finally, Other issues revolve around the Recommended Reading therapies that are intended to alter limits and permanence of plastic behavior, such as treatment for ad- changes. After all, people encounter Kolb, B., & Whishaw, I.Q. (1998). Brain diction, stroke, or schizophrenia, and learn new information daily. Is plasticity and behavior. Annual Re- view of Psychology, 49, 43–64. are likely to be most effective if there some limit to how much cells Robinson, T.E., & Berridge, K.C. (in they are able to further reorganize can change? It seems unlikely that press). Addiction. Annual Review relevant brain circuitry. Further- cells could continue to enlarge and of Psychology. more, studies of neuronal structure add synapses indefinitely, but what Shaw, C.A., & McEachern, J.C. provide a simple method of screen- controls this? We saw in our studies (2001). Toward a theory of neuro- plasticity. New York: Taylor and ing for treatments that are likely to of experience-dependent changes in Francis. be effective in treating disorders infants, juveniles, and adults that ex- such as dementia. Indeed, our perience both adds and prunes syn- studies show that the new genera- apses, but what are the rules govern- Acknowledgments—This research was supported by a Natural Sciences and tion of antiarthritic drugs (known ing when one or the other might Engineering Research Council grant to as COX-2 inhibitors), which act to re- occur? This question leads to another, B.K. and a National Institute on Drug duce inflammation, can reverse age- which is whether plastic changes in Abuse grant to T.E.R. related synaptic loss and thus ought response to different experiences to be considered as useful treatments might interact. For example, does ex- for age-related cognitive loss. posure to a drug like nicotine affect Although much is now known how the brain changes in learning a Note about brain plasticity and behav- motor skill like playing the piano? 1. Address correspondence to Bryan ior, many theoretical issues re- Consider, too, the issue of the perma- Kolb, CCBN, University of Lethbridge, main. Knowing that a wide vari- nence of plastic changes. If a person Lethbridge, AB, Canada T1K 3M4. ety of experiences and agents can stops smoking, how long do the nico- alter synaptic organization and tine-induced plastic changes persist, behavior is important, but leads to and do they affect later changes? a new question: How does this One additional issue surrounds References happen? This is not an easy ques- the role of plastic changes in disor- Greenough, W.T., & Chang, F.F. (1989). Plasticity tion to answer, and it is certain dered behavior. Thus, although of synapse structure and pattern in the cerebral that there is more than one an- most studies of plasticity imply cortex. In A. Peters & E.G. Jones (Eds.), Cere-

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CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE 5

bral cortex: Vol. 7 (pp. 391–440). New York: Ple- Kolb, B., Gibb, R., & Gorny, G. (2000). Cortical and sex. Neurobiology of Learning and Memory, num Press. plasticity and the development of behavior af- 79, 1–10. ter early frontal cortical injury. Developmental Kolb, B. (1995). Brain plasticity and behavior. Mah- Robinson, T.E., & Kolb, B. (1999). Alterations in Neuropsychology, 18, 423–444. wah, NJ: Erlbaum. the morphology of dendrites and dendritic Kolb, B., Forgie, M., Gibb, R., Gorny, G., & Rown- spines in the nucleus accumbens and prefron- tree, S. (1998). Age, experience, and the chang- Kolb, B., Gibb, R., & Gorny, G. (2003). Experi- tal cortex following repeated treatment with ing brain. Neuroscience and Biobehavioral Reviews, ence-dependent changes in dendritic arbor amphetamine or cocaine. European Journal of 22, 143–159. and spine density in neocortex vary with age Neuroscience, 11, 1598–1604.

tiles may continue to have a special The Malicious Serpent: Snakes as a psychological significance even for Prototypical Stimulus for an Evolved humans, and considerable evidence suggests this is indeed true. Module of Fear Furthermore, the pattern of find- Arne Öhman1 and Susan Mineka ings appears consistent with the evolutionary premise. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden (A.Ö.), and Department of Psychology, Northwestern University, Evanston, Illinois (S.M.)

THE PREVALENCE OF SNAKE Abstract Keywords FEARS IN PRIMATES As reptiles, snakes may evolution; snake fear; fear have signified deadly threats module Snakes are obviously fearsome in the environment of early creatures to many humans. Agras, mammals. We review findings Sylvester, and Oliveau (1969) inter- suggesting that snakes remain Snakes are commonly regarded viewed a sample of New England- special stimuli for humans. In- as slimy, slithering creatures worthy ers about fears, and found snakes tense snake fear is prevalent in of fear and disgust. If one were to be- to be clearly the most prevalent ob- both humans and other pri- lieve the Book of Genesis, humans’ ject of intense fear, reported by mates. Humans and monkeys dislike for snakes resulted from a 38% of females and 12% of males. learn snake fear more easily divine intervention: To avenge the Fear of snakes is also common than fear of most other stimuli snake’s luring of Eve to taste the fruit among other primates. According through direct or vicarious of knowledge, God instituted eternal to an exhaustive review of field conditioning. Neither the elici- enmity between their descendants. data (King, 1997), 11 genera of pri- tation nor the conditioning of Alternatively, the human dislike of mates showed fear-related responses snake fear in humans requires snakes and the common appear- (alarm calls, avoidance, mobbing) in that snakes be consciously per- ances of reptiles as the embodiment virtually all instances in which they ceived; rather, both processes of evil in myths and art might reflect were observed confronting large can occur with masked stimuli. an evolutionary heritage. Indeed, snakes. For studies of captive pri- Humans tend to perceive illu- Sagan (1977) speculated that human mates, King did not find consistent sory correlations between fear of snakes and other reptiles evidence of snake fear. However, snakes and aversive stimuli, may be a distant effect of the condi- in direct comparisons, rhesus (and and their attention is automati- tions under which early mammals squirrel) monkeys reared in the cally captured by snakes in evolved. In the world they inhabited, wild were far more likely than lab- complex visual displays. To- the animal kingdom was dominated reared monkeys to show strong gether, these and other findings by awesome reptiles, the dinosaurs, phobiclike fear responses to snakes delineate an evolved fear mod- and so a prerequisite for early mam- (e.g., Mineka, Keir, & Price, 1980). ule in the brain. This module is mals to deliver genes to future gen- That this fear is adaptive in the selectively and automatically erations was to avoid getting caught wild is further supported by inde- activated by once-threatening in the fangs of Tyrannosaurus rex pendent field reports of large stimuli, is relatively encapsu- and its relatives. Thus, fear and re- snakes attacking primates (M. lated from cognition, and de- spect for reptiles is a likely core Cook & Mineka, 1991). rives from specialized neural mammalian heritage. From this This high prevalence of snake circuitry. perspective, snakes and other rep- fear in humans as well as in our