How much more do we know about how the brain works than we knew before we conducted our enriched and impoverished studies? We have learned a great deal about the interaction of the external and internal environment with the structure of the brain. We have learned that different regions of the cortex increase in size as the duration of exposure to the stimulating conditions is extended. We have learned that every layer of cortical neurons in area 18, the area responsible for visual integration, responds to our experimental environment, with outer layers, II and III, showing the greatest changes. The neurons in the cerebral cortex exhibit an impressive amount of plasticity. We have learned that every part of the nerve cell from soma to synapse alters its dimensions in response to the environment.
The enlarged nerve cells with their more numerous glial support cells are apparently utilized by the rat to solve maze problems more effectively than rats without such modified cells. The mechanism by which the enlarged nerve cells improve learning ability is not yet known, but these findings clearly demonstrate brain enlargement as a result of brain use. One often wonders how we can hold a train of thought for hours or record a memory for an extended period of 90 years or more if the flexibility of the cortical structures is so great. Obviously, some molecular configurations must remain stable at the same time that others exhibit change.
Just as the cortical neurons become larger in a stimulating environment, they decrease in size when there is less input from the millions of sensory receptors reporting from the body surface and the internal organs. It is just as important to stress the fact that decreased stimulation will diminish a nerve cell's dendrites as it is to stress that increased stimulation will enlarge the dendrite tree. We have seen how readily the cortical thickness diminishes with an impoverished environment, and at times, the effects of impoverishment are greater than those brought about by a comparable period of enrichment. These cellular changes that we have measured in the brain provide us with a better understanding of how the environment interacting with an hereditary base possibly influenced the brains of higher organisms, including the human brain. Those members of species which happened-by genetic happenstance-to have free extremities, a tendency to explore, and/or bigger brains, were better able to survive and pass on those genes. The upright human, with free upper extremities, continuously sought new challenges, new enriched conditions, and in turn could alter the dimensions of his brain. It is the interaction of the environment with heredity which has changed the brain over millions of years.
Perhaps the single most valuable piece of information learned from all our studies is that structural differences can be detected in the cerebral cortices of animals exposed at any age to different levels of stimulation in the environment. First, we found that young animals placed in enriched environments just after weaning developed measurable changes in cortical morphology. Then, we worked backward in age to the animals not yet weaned and found such changes, and we even found measurable effects of pre natal enrichment. Later, we moved forward in age to learn that the enriched young adult demonstrated an increase in dendritic growth, not only above that found in his impoverished mates, but even above the level of the standard colony animal. In the very old animal, with the cortex following its normal decline with aging, we again found the enriched cortex significantly thicker than the nonenriched. In fact, at every age studied, we have shown anatomical effects due to enrichment or impoverishment. The results from enriched animals provide a degree of optimism about the potential of the brain in elderly human beings, just as the effects of impoverishment warn us of the deleterious consequences of inactivity. Our ultimate goal in studying the aging animal brain is to bring as much dignity as possible to the aging human being, to indicate the potential of aging cerebral cortical cells, and to challenge the myths regarding the aging brain by critically evaluating them.
For example, one of the most prevalent popular beliefs is that once we reach adulthood our brain cells are dying by the hundreds each day and therefore our mental capacities must be diminishing as well. The belief received support in 1958, when Benedict Burns calculated from Brody's data and Leboucq's data that during every day of our adult life more than 100,000 neurons die. These depressing data were derived in the following manner. Brody's estimation of neuron loss in the human cortex between 20 and 80 years of age was 30%, and Leboucq found a decrease in surface area of the brain between the ages of 20 and 76 years amounting to some 10%. Burns' estimated daily cell loss has been frequently quoted. More recently, however, Brody noted the prominence of this information in the lay literature and rejected it as scientifically inaccurate. The original studies included too few samples, and inadequate information was available about the living conditions of the brain donors prior to autopsy. Furthermore, Brody has since reported that some areas of the brain do not lose nerve cells at all with aging, a finding similar to our own. Apparently, the loss of cells varies from region to region. For example, the locus ceruleus in the hindbrain and the nucleus of Meynert in the forebrain do lose nerve cells with aging; whereas, several of the cranial nerve nuclei and a nucleus in the hindbrain called the inferior olivary nucleus do not lose nerve cells throughout the lifetime of the individual.
There is some evidence that the decrease in brain weight and the degree of cortical atrophy in healthy old subjects who have no brain pathology is relatively slight. The brains of such individuals are within normal weight ranges for young adults and have cerebral hemispheres exhibiting no apparent cortical atrophy. Evidence does indicate that the number of the spines on cerebral cortical nerve cells are reduced in old individuals. But even spines can still be present in active old nerve cells; at least , they are clearly present in animals two-thirds of the way through a lifespan. In studying the brains of old human beings it is important to be aware of the lifestyle prior to death, something scientists have been taking more seriously in recent studies. With such considerations, some medical texts now state that in many respects the healthy old brain is similar to the healthy young brain. The experimental environment is a major factor in maintaining the healthy old brain. A few of the myths about the deterioration of functioning during aging are slowly being replaced as scientific knowledge is beginning to offer some contrary evidence.
Such information stimulates us to adopt new attitudes toward aging and encourages us to plan for an active life in old age. Of course, many bright, energetic individuals have always done this; the knowledge of the potential of the brain was not a necessary inducement. Many people have looked to their grandparents who lived a long full life and concluded that they too could follow a similar path. There is no doubt that one's genetic background is important, but our studies suggest that the use of our nerve cells is critical to their continued health. Interviews with some active elderly supported this view. For example, the 89-year-old California wine taster still had his acute taste buds as well as a keen olfactory sense for sniffing good wines. The perspective developed in this book suggests that his continuous attention to his senses of taste and smell enabled them to remain acute during aging. The university chemist active at 98, was still publishing and reading without his glasses. His alert 92-year-old wife continued to read out loud to him. We all know older people like these whose lives illustrate what we have learned about the potential of the cortical nerve cells to respond to the information coming in from the environment.
But what about the millions of human beings who are discouraged and do not continue to stimulate their brains? Many people attend school for a dozen or so years and then find a job only to provide an income until retirement. Their living pattern usually moves toward slowing down until they finally fade away, The generally accepted knowledge about the brain is that it starts "going downhill" fairly early in life (which is true) and that after that, there is little one can do about changing this pattern ( which is not true). As mentioned in Chapter 2, recent studies on the developing human brain have shown that the size of the cerebral cortex is already decreasing after the age of ten. In fact, the patterns of an increasing and subsequently decreasing curve were very similar for rats and humans during the early postnatal period. If we take advantage of our more recent knowledge regarding plasticity of a lower mammalian cortex at any age, then we can offer encouragement to counteract the downhill slope in human beings. A different outlook emerges toward lifestyle, as a whole, and toward learning, in particular.
Opportunities for learning should be encouraged from shortly after conception and continued until death. The data from a Japanese laboratory and from ours showed the beneficial effects of stimulating environments during intrauterine life: improved maze behavior and increases in cortical structure in the animals after birth. Though the western world is only recently becoming aware of such a practice, for centuries Asian people have encouraged the pregnant mother to enrich her developing fetus by having pleasant thoughts and avoiding angry, disturbing behavior. At the same time, one is made aware of other beneficial factors in aiding the development of the fetus such as good diets and plenty of exercise after which the dendritic trees in cortical nerve cells are richly developed. On the other hand, mothers need to be alerted to the negative effects of fetal development of such substances as alcohol. Alcohol administered to pregnant rats (5% alcohol in a protein-rich diet throughout gestation from day 2) has been reported to cause a decrease in the body size of cortical pyramidal cells and in their number of dendrites in the brains of the offspring. Other results have shown that the nerve cells adjacent to the ventricles in the brain are also defective in rats exposed to alcohol before birth. Thus, the prenatal brain has been shown to be sensitive to negative influences like alcohol and malnutrition as well as to the positive influence of enrichment.
We still do not know whether an enriched condition during pregnancy can prevent some of the massive nerve cell loss, as much as 50% to 65% of the total population of cells, which occurs during the development of the fetus. It is apparent that overproduction of neurons occurs in the fetus because most neurons do not reproduce themselves after being formed: an excess number is needed as a safety factor. Therefore, those that are not involved in the early neuronal processing are "weeded out." At the present time it is believed that the limits of cell number are set by the same genetic constitution. As mentioned in Chapter 1, investigators found the same number of cells in a single column of cortical cells, in rats, cats, dogs, monkeys and human beings. The genetic regulation of these cells appears to transcend species. Understanding the causes of this constancy in number is a complex process, for even fluctuations in body temperature can influence brain cell number. The body temperature of the pregnant female has a marked influence on the number of neurons that survive in the fetus. If the temperature is increased in the female guinea pig by 3 to 4 degrees C for I hour in the latter part of gestation, the fetal brain weight is reduced by 10 percent. This reduction in brain weight is due to a loss of brain cells. Hyperthermia has not yet been established as a cause of human fetal brain damage and mental retardation, but we should be alerted to this possibility whether studying animals or man.
Though enriched experimental environments have not been shown to alter the number of nerve cells, our results have indicated that variation in the experimental environment can readily alter the size of the preexisting nerve cells in the cerebral cortex, whether in the cell body or in its rich membrane extensions, the dendrites, or in synapses. The importance of stimulation for the well-being of the nerve cells has been demonstrated in many species. But of equally weighty significance is the possible detrimental effect of too much stimulation. The eternal question arises, When is enough enough or too much too much? The reputed pediatrician, T. Berry Brazelton, points out that infants exposed to too much stimulation respond either by crying, by extending their periods of sleep, or by developing colic or withdrawing from any new approaches. In providing increased stimulation for the young, the adult, or the old, one always has to keep in mind the need for adequate time at each phase of information processing: input, assimilation, and output. The integration of the input is essential before we can anticipate a meaningful output. As adults, we frequently say, "Let me think things over." It is essential to give the infant the same opportunity.
We have learned from our results that the nervous system possesses not just a "morning" of plasticity, but an "afternoon" and an "evening" as well. It is essential not to force a continuous stream of information into the developing brain but to allow for periods of consolidation and assimilation in between. I often tell the overworked student to go out and just be on the lawn and watch the clouds drift slowly by. We do not yet know the true capacity or potential of the brain. Our data at present suggest that nerve cells benefit from "moderate" sources of stimulation, allowing for new connections to be formed, and thus providing the substrate for more options. We have yet to try too much stimulation. Will the stimulated brain continue to increase or will its reticular formation sift out the excess stimulation?
To date we do not know whether there is a "ceiling" effect on brain growth beyond which no further expansion will occur. In our rats in the preweaning stage, one area (area 39) differed as much as 16% between the brains from the enriched rats and those from the nonenriched. A Swiss group, using superenriched conditions, including additional space and toys, were also able to produce 16% differences in rats past the age of weaning. Does this mean that 16% cortical thickness differences represent the maximum change we can induce with environmental enrichment? I hesitate to accept such a premise at this time. Undoubtedly, with more imaginative experimental designs, utilizing additional creativity, we will find greater responses in the future. Of course, quantity of brain tissue is not our only goal. Quality is the ultimate objective. So far it has been shown that the thicker cortex is positively correlated with a better maze performance. Only further studies will provide information on the actual potential of the cerebral cortex to alter its structure with increased stimulation.
I recently uncovered a small book published in 1901 by the Macmillan Company called The Education of the Nervous System, by Reuben Halleck. In essence, its message was that the best education we can provide the developing nervous system is one of stimulating all the five known senses. Halleck wrote that a person who has only one or even two senses properly trained is at best a pitiful fraction of a human being. He points out that recalled images of sensations we receive from the world around us are powerful and necessary aids in further modifying and developing the sensory cells; not images of sight alone, but of every sense. What does lilac smell like? How do tastes of cinnamon and nutmeg differ? It is possible for us to conscientiously train our senses, all of them, at any time in our lives. If we fine-tune the primary sensory areas early, the association cortices might then respond to more subtle differences in a greater variety of ways. Creative ideas could arise from a broader experiential base. The finding of more widespread changes in the brains of enriched rats than in those of rats trained to learn a specific task supports the claims of numerous educators, from Dewey on, that providing a wide variety of experiences to the growing child enhances intellectual development.
While all sensory input facilitates learning, the visual association cortex was the first to be responsive to enrichment in our experiments. This may be related to the fact that cortical association areas are the last areas to develop embryologically and the most recent phylogenetically. Thus, it is reasonable for the visual association area to show morphological changes in response to stimulation in a learning circuit. As far back as 1901, Fleschig proposed that learning took place by impulses first entering a primary sensory cortical area, then going to the secondary or association cortex, and then into the limbic system. For visual input in Fleschig's model, the primary sensory cortex would be area 17 and the secondary or association cortex would be area 18, and then continuing to the limbic system. Within this pathway we might anticipate area 18 to be the region most likely to show change. And we find that it does respond in the shortest period of time to our experimental conditions. With a longer duration of exposure to the environmental conditions, area 17, the primary visual cortex, also demonstrates cellular changes. On the other hand, one part of the limbic system we have measured, the male hippocampus, has not demonstrated the same degree of plasticity as has the occipital cortex. However, some investigators have shown small amounts of hippocampal increases with enriched environments using female rats. Our findings offer support to our hypothesis that neural activity within the visual cortex is important for the initial information processing that facilitates learning. Our results indicate that it is the posterior part of the cortex rather than the frontal cortex which possesses the most plasticity. Future studies on the biochemistry of learning and memory in the mammalian cortex might therefore be most appropriately focused on this posterior region.
Though we have demonstrated the plasticity of the cerebral cortex, we are very much aware that the brain does not work by itself. Healthy support systems, i.e., the cardiovascular, respiratory, urinary, and digestive systems, are essential to the maintenance of the healthy brain. The heart and its accompanying blood vessels need to be maintained through balanced diet and exercise. With exercise, the connective tissue surrounding the skeletal muscles and blood vessels can remain strong and aid with efficient circulation of the blood. The lungs should be free of disease, such as emphysema which can be caused by smoking or breathing air contaminated with pollutants. The body needs to take in adequate fluids to keep the kidneys working efficiently, these, in turn, keep the blood free of concentrated waste products. The digestive system needs to benefit from strong teeth that can break down food for efficient digestion, and from a fibrous diet to maintain the well-being of the large intestine. All of this is nothing new. It was Plato who said, back in 400 B.C., that a healthy body promotes a healthy brain and a healthy brain, a healthy body.
Not only is the brain dependent upon other systems, but each part of the brain interacts with another. The cortex, with its more refined intellectual functions, attempts to coordinate with the limbic system, with its more emotional functions. One without the other is only half an experience. In Nathaniel Hawthorne's story Ethan Brand , his main character is searching for the unpardonable sin. He concentrates to such an extent on his intellectual pursuit that he becomes emotionally starved. He eventually becomes dismayed and throws himself into his fiery kiln. When others discover the remains, all that is left is his charred rib cage enclosing a cold marble heart. He had discovered the unpardonable sin by neglecting to integrate the warm, emotional heart, in a metaphorical sense, with his intellectual pursuit.
Satisfying emotional needs is essential at any age. As we learned from our studies on aging rats, by giving our old rats a little tender loving care, we were able to increase their life span; those rats that received additional attention lived longer that those that did not. These results imply that the two regions of the brain, the limbic system and the cortex, need to work together efficiently for the well-being of the whole individual. Thus it is important to stimulate the portion of the brain that initiates emotional expression, which encompasses the connections between the cerebral cortex and the limbic system, including the hippocampus, amygdala and hypothalamus. In our studies it was the cortex which responded more readily to the environmental conditions and not those parts o f the limbic system which we measured, such as the hippocampus and amygdala. The fact that these structures are less adaptable to a varied environment implies that they are more basic to the survival of the individual, suggesting that emotional well-being may be more essential for survival than intellectual. Other kinds of stimulation besides mental challenges, e.g., considerable personal attention and other forms of emotional involvement, may be essential to create changes in limbic structures. If this is so, how much more effort should we be making toward giving attention and care to each other? And how important it is for the intellectual components of the brain to be taught ways to guide the emotional ones. Several of our measurements have indicated that even the deprived brain can adapt by changing in structure as a result of enriched living conditions. Such changes were discovered in both prenatally and postnatally deprived animals. If mother rats were protein-deprived during pregnancy and lactation and their newborn pups were given both protein-rich diets and enriched living conditions after birth, the pups' brains grew more than those of standard colony rats that were only nutritionally rehabilitated. In the experiment dealing with postnatal deprivation, the cerebral cortices were lesioned or damaged during infancy, and then the animals were placed in enriched living conditions. Upon measuring the length of these animals' cortices after enrichment, the investigators found that the length had increased to compensate for the previous damage. Thus, we must not give up an people who begin life under unfavorable conditions. Environmental enrichment has the potential to enhance their brain development too, depending upon the degree of severity of the insult.
In this limitless field of possibilities for future study, a few specific research avenues beckon most immediately. We wish to gain a better understanding about what elements are responsible for the growth of the cerebral cortex. In Chapter 1 the normal cortical growth pattern was presented, but we do not know what causes the rapidly growing cortex to reverse its direction shortly after birth. At present we are studying the role of opioid blockers, substances which block the endogamous or natural opiates (opioids) in the brain, because some investigators have demonstrated that various regions of the brain increase in size and cellular content when opioid receptors are blocked. Our initial results support these findings. In addition we wish to learn more about nerve growth factor and its role in cortical development. For years, nerve growth factor was thought to be confined to specific regions such as the sympathetic ganglia, but more recently it has been found in the hippocampus and cerebral cortex. We are particularly interested in its role and when it is active in the cerebral cortex. In light of the large number of people who are taking drugs for therapeutic reasons for long periods of time, it is important to learn more about how the cerebral cortex responds under such medication. Thus, one specific question I would like to pursue now is whether the enriched condition favorably alters the brains of animals on antiepileptic drugs. For example, it is possible to obtain a type of rodent, a gerbil, which has spontaneous seizures. If this animal is given a seizure-reducing drug, will the enriched environment still increase the cortical dimension?
In addition, we wish to pursue a study to determine what agents play a role in creating the enlarged cortex in the offspring, the Fl and F2 generations, from the enriched parents. The high level of progesterone during pregnancy was suggested as one possible responsible factor. This suggestion has to be tested as well as others.
The ultimate goal of all of our studies has been to gain a better understanding of human behavior by examining its source, the brain. The simple enriched environmental paradigm allowing rats to interact with toys in their cages produced anatomical changes in the cerebral cortex. Now how do we apply this knowledge for the benefit of people? Since no two human brains are exactly alike, no enriched environment will completely satisfy any two individuals for an extended period of time. The range of enriched environments for human beings is endless. For some, interacting with objects is gratifying; for others, obtaining information is rewarding; and for still others, working with creative ideas is most enjoyable. But no matter what form enrichment takes, it is the challenge to the nerve calls which is important. In one experiment where the rats could watch other rats "play" with their toys but could not play themselves, the brains of the observer rats did not show measurable changes. These data indicate that passive observation is not enough; one must interact with the environment. One way to be certain of continued enrichment is to maintain curiosity throughout a lifetime. Always asking questions of yourself or others and in turn seeking out the answers provides continual challenge to nerve cells.
Finally, now that we have begun to appreciate the plasticity of our cerebral cortex, the seat of the intellectual functioning that distinguishes us as human beings, we must learn to use this knowledge. It must stimulate and guide our efforts to work toward enriching heredity through enriching the environment ... for everyone ... at any age.
Dr. Diamond is professor of Anatomy at the University of California, Berkeley, and is a former Director of the Lawrence Hall of Science. She has also taught at Harvard, Cornell, and at universities in China, Australia, and Africa. She received the Outsta nding Teaching Award and Distinguished Teacher's Award from the University of California, and is a member of the American Association of University Women Hall of Fame. In 1989-90, she received the CASE Award, California Professor of the Year, and National Gold Medalist, and she was made a member of the San Francisco Chronicle Hall of Fame.
This article were taken from Enriching Heredity, by Marian Cleeves Diamond. Copyright (c) 1988 by Marian Cleeves Diamond. Reprinted by permission of The Free Press/Simon and Schuster. Please do not repost or recirculate without obtaining express permission in writing from the author and The Free Press/Simon and Schuster.
The Brain Lab