Evolution Proposes and Ontogeny Disposes

Brain and Language 73, 274–296 (2000) doi:10.1006/brln.2000.2307, available online at http://www.idealibrary.com on

Evolution Proposes and Ontogeny Disposes Victor H. Denenberg Biobehavioral Sciences Graduate Degree Program and Department of Psychology, University of Connecticut Genes, the basic building blocks of evolution, are highly conserved. For example, the mouse and human have approximately the same number of genes, and around 94% are identical in the two species. Since species differ on multiple dimensions (e.g., anatomy, physiology, and behavior), it follows that identical genes may subserve different functions in different species. Two reasons for this are gene–gene interaction and gene–environment interaction (and it is the presence of these interactions which prevents one from making deterministic statements about genetics, thus rendering obsolete the nature–nurture controversy). Behavioral examples of both types of interactions are presented, including studies showing that (1) the uterine environment enhances later cognitive competence, (2) early postnatal experiences affect learning and emotionality and can extend into future generations, (3) maternal behavior changes the offspring’s later behavior and physiology, and (4) knocking out one gene results in an animal less competent in one learning process but more competent in a complementary learning process.  2000 Academic Press

INTRODUCTION

The term ‘‘evolution’’ often conjures up images of higher-order species emerging, or evolving, from lower-order species. The evolutionary tree is such an image. However, before new species can emerge, it is first necessary that the current species survive. This is not a challenge for some simple organisms that live in stable conditions which do not change. However, as species get more complex (e.g., as nervous systems evolve) and the environments within which they live become more complicated, those which adapt to changes survive, while those that do not adapt disappear. Thus, a key feature of one’s evolutionary heritage is the ability to adapt to complex and changing environments. This, in a broad sense, is what is meant by the term ‘‘plasticity.’’ Organisms exhibit behavioral plasticity throughout their life span, but Address correspondence and reprint requests to Victor Denenberg, Biobehavioral Sciences Graduate Program, University of Connecticut, Storrs, CT 06269-4154. Fax: (860) 486-3827. E-mail: [email protected]. 274 0093-934X/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

275

adaptation to one’s early environment would be expected to have the greatest impact because it is necessary to survive into reproductive age and produce at least one round of progeny to contribute to the continuation of the species. The research field which specifically examines behavioral growth patterns, the effects of early experiences, and adaptations to environmental demands is called developmental psychobiology. Even though most research in this discipline is not guided by evolutionary theory, developmental studies within a species can provide us with insights into evolutionary processes. Indeed, it is argued here that there must be intimate links between adaptation during development and species survival. The purpose of this article is to present evidence supporting this thesis. For over 4 decades, the author has investigated developmental mechanisms which affect how immature organisms adapt to their immediate and later environments. The research findings obtained from these studies, in combination with research by others, has led to the derivation of several developmental principles which are sufficiently broad that they also contribute to an evolutionary perspective. PRINCIPLES DERIVED FROM EARLY EXPERIENCE RESEARCH

Early Experiences Have Long-Term Effects on Behavioral and Biological Systems On a probabilistic basis, an organism will continue to live in the environment within which it is born, whether that environment is arid or moist, hot or freezing, grasslands or deserts, and so on. Those animals which best adapt their behavior and biology to the multiple parameters of their early environment are most likely to survive in the long term. Experimental researchers investigating the effects of early environmental experiences upon later behavior have primarily used two procedures. To study adaptation between birth and weaning, animals have been exposed to handling experience. To study postweaning adaptation, the usual technique has been to place subjects into an enriched environment. Handling. The handling procedure starts at birth. On the first day of life the litter is removed from its nest, sexed, and culled to a constant number, typically eight pups. A litter is randomly assigned to the handling treatment or to be nonhandled (control). The controls are returned to their maternity cage and are not disturbed again until weaning at day 21. Each handled pup is placed separately into a can containing shavings, left there for a standard period of time (often 3 min) and then returned to the maternity cage. This procedure is repeated daily, usually until weaning (Denenberg, 1977). This seemingly modest procedure has been found to have major immediate impact. Handling reduces body temperature, causes plasma corticosterone to rise, and changes the dam’s maternal interaction with her pups when they are returned to the maternity cage (Denenberg, Brumaghim, Haltmeyer, &

276

VICTOR H. DENENBERG

Zarrow, 1967; Levine, 1975; Liu, Diorio, Tannebaum, Daldji, Francis, Freedman, Sharma, Pearson, Plotsky, & Meaney, 1997; Schaefer, Weingarten, & Towne, 1962). On a long-term basis, when compared to nonhandled animals, adult handled rats weigh more, have a lesser adrenocortical response to a novel stimulus but are more responsive to a distinctly noxious stimulus, are more exploratory, are less emotionally reactive, and are better avoidance learners (Denenberg, 1967, 1969b). Handling causes an increase in the number of glucocorticoid receptors in the hippocampus and frontal cortex, and it has been suggested that these changes might be the mediators of the behavioral effects of handling (Meaney, Aitkin, Bodnoff, Iny, Tatarewicz, & Sapolsky, 1985; Meaney, Aitkin, Viau, Sharma, & Sarrieau, 1989). Environmental enrichment. Enrichment experience is generally introduced at weaning. The enriched environment is a box substantially larger than a maternity or standard laboratory cage that contains a variety of playthings such as ramps, wooden blocks, cans, and ladders as well as food and water. Some researchers change the ‘‘toys’’ daily. There may be as many as a dozen or so rats placed into one of these units. In some studies the rats remain in the environments even while being tested in adulthood. In other studies, they remain in the environments for a stipulated period of time, are then placed into standard laboratory cages, and are tested at a later date. The latter procedure is used to determine the long-term effects of the prior enrichment experience. Animals given enrichment are typically found to do far better on perceptual and problem-solving tasks, to differ in weight and brain chemistry, and to have a thicker cortex and greater dendritic growth (Bennett, 1976; Comery, Shah, & Greenough, 1995; Greenough, 1976; Hebb, 1949; Juraska, Henderson, & Miller, 1984; Krech, Rosenzweig, & Bennett, 1962; Rosenzweig, 1971, Rosenzweig, Bennett, & Diamond, 1972; Volkmar & Greenough, 1972; Wallace, Kilman, Withers, & Greenough, 1992). Some or all of the biological consequences noted above are likely to be the mediators of the behavioral changes induced by environmental enrichment. Comment. Broadly speaking, handling between birth and weaning reduces an animal’s later emotionality. This acts to facilitate exploration of a novel environment and lessens the likelihood of freezing or fleeing when a novel or fearful stimulus is first encountered. A critical consequence of reduced emotionality is that other behavioral mechanisms (e.g., learning, perception, and attention) can be brought into play to aid the animal in responding to a new challenge. Postweaning enrichment enhances cognitive competence, thereby improving the animal’s ability to learn to adjust to new and complex environments. Thus these experiences broaden the animal’s repertoire of behavioral reactions and that in turn helps it adapt to changes in its environments. One would expect these changes to increase the likelihood of survival and hence have evolutionary significance.

277

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

Brain Laterality Can Be Induced by Early Experiences A number of animal species below the level of primates have been found to have lateralized brains, with the left hemisphere specialized for information processing and the right for affective behavior (Denenberg, 1981; Rogers, 2000; Rogers & Anson, 1978, 1979). These findings establish that brain laterality has an evolutionary history and is not a phenomenon unique to humans. Research from two different laboratories have shown that laterality can be induced by stimulation during early development. Brain laterality in the rat. Rats were handled in infancy or were left undisturbed. When adult, four males from a litter were randomly assigned to (1) left-hemisphere neocortical ablation (i.e., right-hemisphere-intact group), (2) right-hemisphere neocortical ablation (left-hemisphere-intact group), (3) sham surgery, or (4) no surgery. Since in all experiments there was no difference between the sham and nonsurgery groups, their data were combined. In a series of studies we investigated open-field activity, right–left directional preference, taste aversion, and mouse killing (for experimental details and references to the original papers, see Denenberg, 1981). Table 1 summarizes the findings for the handling variable. In order to demonstrate a brain laterality effect, it is necessary that the group with an intact right hemisphere differ from the group with an intact left hemisphere. If that occurs, a comparison of each of the two lesion groups with the intact controls allows one to draw a reasonable inference concerning the nature of the brain dynamics (Denenberg, 1980, 1981). As an example, consider the open-field data. The open field consists of a black 115-cm square box with the floor marked off into 25 squares (23 cm on a side). The rat was placed in a corner and the number of squares entered in 3 min was used as an index of exploratory behavior. They were tested TABLE 1 Effects of Handling in Infancy upon Brain Laterality (from Denenberg, 1981)

Dependent variable Open-field (activity) Open-field (R-L directionality) Taste aversion (milliliters of milk consumed) Muricide (% kill)

Handling Experience

Intact Controls

RightBrainIntact

LeftBrainIntact

NH H NH H NH H NH H

8.90a 12.51a 0.0305a ⫺0.3862a* 23.9a 28.7a 96.0a 78.0a

27.64b 17.91a ⫺1.0268b* ⫺0.7389b* 23.7a 21.7b 75.0b 94.6b

22.33b 36.27b 0.5082c* 0.3300c* 23.8a 25.6c 68.8b 67.6a

Note. Within a row, groups with the same letter do not differ, while those with different letters are significantly different. Significance via analysis of variance with p ⬍ .05. * Significantly different from zero.

278

VICTOR H. DENENBERG

on 4 successive days. Table 1 shows no evidence of brain laterality for the nonhandled rats since the activity scores of the two lesion groups do not differ, even though both are more active than the intact control. However, within the handled animals those with an intact left hemisphere had higher activity than those with an intact right hemisphere. Since the intact control animals had an activity score similar to the right-brain-intact group, we infer that in the intact brains of handled rats, the right hemisphere is inhibiting the activity of the left. Thus, when the right is lesioned, this inhibition is removed, and the animal’s activity is increased (Denenberg, 1980, 1981). A different brain control pattern is seen for right-left directional preference. Rats were tested for 4 days in the open field, and their direction of movement to the left or right when they left the starting square was noted daily. A directionality index was obtained by the formula (R ⫺ L)/ (R ⫹ L)1/2, where R ⫽ number of right choices and L ⫽ number of left choices. Though the intact nonhandled group shows no evidence of laterality (the score of .0305 is not significantly different from zero), directional bias is seen in the two lesion groups. As expected, each group moves in a direction ipsilateral to the lesion (negative scores in Table 3 mean a leftward bias and positive scores a rightward bias). However, the right-hemisphere-intact group has a greater absolute bias than the left-intact group, leading to the inference that in the intact animal the left hemisphere is inhibiting the right sufficiently to yield an unbiased animal. In contrast, the intact handled group is left-biased (⫺.3862 is significantly different from zero). In a sense, the handling procedure has ‘‘uncovered’’ the laterality latent within the nonhandled group. Taste aversion was studied by presenting the animals with sweetened milk, a novel and preferred substance, for 30 min a day for 2 days. After the second day, they were injected with lithium chloride to induce a marked visceral disturbance. Twenty-five days later brain surgery was done, and 4 weeks after that they were tested for retention of taste aversion by presenting the bottle daily (30 min) for 13 days. Table 1 shows the average amount of milk ingested daily. There was no evidence of brain laterality for nonhandled rats, while handled rats with an intact right hemisphere had greatest retention of the lithium poisoning conditioning as reflected by their low drinking score. The same configuration of findings was obtained when muricide was measured. This was done by placing a mouse into a cage with an isolated rat and leaving it there for 5 days. Table 1 shows the percentage of mice killed by each brain group. Thus, handled rats with an intact right hemisphere had greatest retention of the lithium poisoning conditioning and also had a higher killing incidence. Brain laterality in the chick. Newly hatched chicks have asymmetrical hemispheres, with the left lateralized for visual discrimination learning and the right for affective responses, including copulation (Andrew, 1988; Mench & Andrew, 1986; Rogers, Zappia, & Bullock, 1985; Zappia & Rog-

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

279

ers, 1987). This behavioral asymmetry is a consequence of stimulation received during embryonic development. The embryo is situated in the egg so that the right eye receives light input through the shell, while the left eye does not. Rogers (1990) reversed the light distribution during the latter phase of development in the egg by occluding the right eye and arranging for the left to receive light stimulation. This caused a reversal in behavioral laterality, with the left hemisphere controlling copulation and the right controlling visual discrimination learning. A final experiment found that chicks which had not received light stimulation did not exhibit behavioral asymmetry on either measure. Comment. Behavioral asymmetry has now been found in a wide range of vertebrate species (Denenberg, 1981; Rogers, 2000; Vallortigara, 2000), thereby establishing its long evolutionary history. One normally thinks of evolutionary processes as being mediated solely by genetic mechanisms. However, the rat and chick research establishes that the genetic substrate involved in laterality must be acted upon by an appropriate set of environmental stimuli, occurring at a restricted time in development, for the organism to have a lateralized brain. There is a methodological matter to note as well. Failure to find evidence of behavioral asymmetry (as seen in the nonhandled rat and the chick not receiving light stimulation) does not allow one to conclude that the brain is not lateralized. Some other set of environmental circumstances (light during embryonic development of the chick, extra stimulation during the preweaning period for the rat) may interact with the genetic substrate to induce brain asymmetry. In addition, other behavioral testing paradigms might uncover evidence of brain laterality in nonhandled rodents or in chicks that have not had embryonic exposure to light. Early Experiences Affect Future Generations The procedures of handling and enrichment in early life produce profound long-term behavioral and biological effects. Since these changes have adaptive significance, they may have an effect upon the next generation. For example, a change in the female’s physiology as a consequence of early experiences could have an impact upon her developing fetus. Changes in her behavior pattern could influence her postnatal maternal care for her pups. Below are described studies which establish that the experiences a female receives in her infancy can affect her offspring and her grandoffspring. Early experience effects upon the next generation. Adult female rats that had been handled or not disturbed in infancy were randomly mated to a homogeneous group of males. At birth, some litters remained with their natural mothers (nonfostered groups) while other litters were fostered (1) to mothers that had received the same early experience as the natural mother or (2) to mothers that had received the opposite early experience from that

280

VICTOR H. DENENBERG

TABLE 2 Weaning Weights, Open-Field Behavior, and Number of Rats (in Parentheses) as a Function of the Early Handling Experiences of Their Natural Mother and Their Rearing Foster Mother (from Denenberg & Whimbey, 1963) Natural Mothers Handling Experience

Foster Mothers Handling Experience

NH

NH

NH

H

H

NH

H

H

Offspring Weight (grams)

Offspring Activity (squares)

Offspring Boluses (number)

36.9b (62) 41.3a (62) 38.2b (101) 38.9a (56)

114.9b (32) 188.3a (32) 139.6b (32) 121.6b (28)

10.7b (32) 17.9a (32) 12.2b (32) 22.7a (28)

Note. Within a column, groups with the same letter do not differ, while those with different letters are significantly different; NH, nonhandled; H, handled. Significance via analysis of variance with p ⬍ .05.

of the natural mother. Body weights were obtained at weaning and on day 53. At 50–53 days the rats were tested in the open field and recordings were made of activity (number of squares entered) and used as an index of exploratory behavior, and number of boluses dropped was used as an index of emotionality (Denenberg, 1969a). Significant findings from the four foster groups are presented in Table 2. See Denenberg and Whimbey (1963) for further details. Young reared by foster mothers that had been handled in infancy weighed more at weaning. However, this effect had disappeared by adulthood. With respect to open-field activity, young born of mothers not handled in infancy and fostered to handled mothers had greater activity than the other three groups, which did not differ from each other. Analysis of boluses in the open field found that young raised by mothers handled in infancy defecated more than young raised by mothers that had not been handled. Intergenerational effects of mothers and grandmothers. Having established a maternal generational effect, we next asked whether an effect could be traced back to the grandmother (Denenberg & Rosenberg, 1967). Females were handled or not disturbed in infancy. These were the grandmothers of the experimental subjects. They were mated and, when pregnant, were placed into either maternity cages or enriched environments. At weaning, the female offspring were placed into standard laboratory cages or enriched environments until 50 days old. These females became the mothers of the experimental subjects. When pregnant, they were placed into standard maternity cages where they gave birth. At weaning the pups (who were the grandchildren of the original handled and nonhandled females in the experiment) were given 1 day of open-field testing and then were weighed.

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

281

TABLE 3 Offspring Performance as a Function of Grandmother Handling ⫻ Mother Postweaning Housing Interactions (from Denenberg & Rosenberg, 1967) Grandmothers Handling Experience NH NH H H

Mothers Housing 21–50 Days

Offspring Weight (grams)

Offspring Activity (squares)

N

LC EE LC EE

49.7a 46.2b 46.4b 46.9b

54.4b 71.4a 79.5a 64.3b

205 218 174 172

Note. Within a column, groups with the same letter do not differ, while those with different letters are significantly different; NH, nonhandled; H, handled; LC, laboratory cage; EE, enriched environment. Significance via analysis of variance with p ⬍ .05.

Statistical analysis of the weaning weight and activity data found complex interactions. An example of two such interactions is shown in Table 3 for Grandmother Handling ⫻ Mother Postweaning Housing. Pups whose grandmothers were nonhandled and whose mothers lived in standard laboratory cages weighed more than the other three groups. The activity data are quite different. Grandpups of nonhandled grandmothers were more active if their mothers had been placed into enriched environments after weaning, whereas grandpups of handled grandmothers were more active if their mothers had been kept in standard laboratory cages after weaning. Comment. The specific nature of the findings are not as important as the documentation of the phenomenon that one’s experiences during early development can feed forward to influence the behavior and biology of future generations. These effects are presumably mediated via changes (1) in the female’s physiology which may affect the uterine environment and (2) in her behavior, which can affect her maternal care of the pups. Evidence concerning the effects of uterine physiology upon later behavior is presented below. With respect to postnatal maternal behavior, studies have shown that the amount of contact between the mother and her pups is a critical determiner of later behavior and that handling experience interacts with maternal contact. Thus, Liu et al. (1997) found that mothers lick and groom handled pups more than nonhandled pups. Licking and grooming have long-term consequences because the more maternal contact in early life, the less is the offspring’s adrenocortical response in later life (Liu et al., 1997; Rosenberg, Denenberg, & Zarrow, 1970; these findings are discussed below). Further, adult female rats, handled as pups, engaged in more licking and grooming of their offspring than did nonhandled controls, though this effect was restricted to females whose own mothers had low licking and grooming scores (Francis, Diorio, Liu, & Meaney, 1999). Thus, imposing an experimental intervention (handling) causes a change

282

VICTOR H. DENENBERG

in maternal behavior (increased licking and grooming), which may be expressed in the next generation by an increase in maternal contact; these handling/maternal experiences are found to change the offspring’s physiology (corticosterone response). Note that we started with a controlled experimental manipulation applied randomly to animals and ended with correlation coefficients, a measure of individual differences, suggesting that one major function of early experiences is to create individual differences. That issue is addressed next. Differential Developmental Experiences Are a Source of Stable Individual Differences For species survival, there must be systematic phenotypic variability, also called individual differences. This variability increases the likelihood that some members of the species will survive if a catastrophe occurs. The study of individual differences has found a number of dimensions which can be reliably measured and are stable over time. It is often assumed that these individual difference dimensions are genetic in origin. This is evident in selection studies with animals. Thus, rats and mice have been selectively bred for maze brightness or dullness, high or low emotionality, good or poor avoidance learning, and unilateral versus ambidextrous paw usage. The behavioral results of such selective breeding provides substantial evidence that genetic factors play a major role in the formation and maintenance of many behavioral traits. In the experimental studies described above, differential experiences during early development caused significant changes in affective behavior, cognition, morphology, physiology, and CNS indices. This is the stuff that individual differences are made of, the source for psychometric studies of human behavior. Yet these experiments were designed explicitly to eliminate genetic variance by randomly assigning rats from our partially inbred colony to the experimental treatments. These findings imply that individual differences, of the kind commonly thought of as being genetically based, can be created through the systematic manipulation of early experiences in situations where genetic variance is minimized and randomized. Because individual differences is one major mechanism to insure species survival, if it could be shown that such stable differences could be generated via experience, this would be another example of how developmental processes can have evolutionary implications. The experimental design used to test the hypothesis that early experiences can create stable individual differences is shown in Table 4 (Denenberg, 1970a; Whimbey & Denenberg, 1967). Handled and nonhandled females were mated and placed in standard maternity cages or in enriched environments until their pups were weaned. When their pups were born, they were handled or were not disturbed. When weaned, they were placed into standard

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

283

TABLE 4 Experimental Design for Programming Life Histories and Creating Individual Differences (from Denenberg, 1970a) Mothers Handling Experience NH NH NH NH NH NH NH NH H H H H H H H H

Mothers & Pups Preweaning Housing

Pups Handling Experience

Pup Postweaning Housing

MC MC EE EE MC MC EE EE MC MC EE EE MC MC EE EE

NH NH NH NH H H H H NH NH NH NH H H H H

LC EE LC EE LC EE LC EE LC EE LC EE LC EE LC EE

Abbreviations: NH, nonhandled; H, handled; MC, maternity cage; EE, enriched environment; LC, laboratory cage.

laboratory cages or into enriched environments until 42 days of age, when they were all placed into standard laboratory cages. Starting on day 220, the animals were given a variety of behavioral tests, selected to measure the constructs of emotional reactivity and/or exploratory behavior. The 16 groups in Table 4 each contained six animals (three males and three females) and represent a 2 ⫻ 2 ⫻ 2 ⫻ 2 factorial design. The usual statistical evaluation would be via analysis of variance procedures. However, there is another way of viewing Table 4, namely through the eyes of a psychometrician. The 16 groups can be thought of as 16 individuals who are genetically the same because the subjects were randomly assigned to the different treatment conditions. Therefore, any measures of ‘‘individual differences’’ among the 16 would have to be brought about by their differential rearing histories, not by their biological heritage. To determine whether individual differences could be found, we intercorrelated the various behavioral measures and then subjected the correlation matrix to factor analysis (Whimbey & Denenberg, 1967). The factor analysis extracted three meaningful factors. The first factor was Emotional Reactivity; the second, Exploratory Behavior; the third, Consumption–Elimination. These are listed in Table 5. The term ‘‘homogeneous rats’’ means that there was no systematic genetic variance which could account for the correlations and subsequent factor structure. Table 5 also lists

284

VICTOR H. DENENBERG

TABLE 5 Factors Found in Psychometric Studies of Homogeneous Rats and Heterogeneous Mice Homogeneous rats (Whimbey & Denenberg, 1967)

Heterogeneous mice (Willingham, 1956)

Emotional Reactivity Exploratory Behavior Consumption/Elimination

Emotional Maturity Freezing Elimination

the equivalent factors obtained by Willingham (1956), who studied outbred mice that had considerable genetic variance (‘‘heterogeneous mice’’). See also Anderson (1938a, 1938b). Comment. Since there was no systematic source of genetic variance among the 16 ‘‘individuals’’ in our experiment, we may conclude that differential early experiences of mothers and offspring, in combination with differential housing histories, can generate a complex range of individual differences. Stated differently, independent of the genetic background, differing experiences during one’s development is another source of stable individual differences. Thus, in a genetically heterogeneous population growing up and developing in a multidimensional environment, the emerging individual differences would be the resultant of both long-term (genetic) and immediate (environmental) sources of variance. Maternal Behavior Is a Special Form of Early Experience Under normal circumstances genetic factors, maternal behavior, and environmental factors interact in an inextricable manner to form and shape the developing organism. Indeed, these forces probably act to mutually reinforce each other so that there is a high likelihood of producing young which will survive until they become functionally independent and start their own reproductive cycle. In order to understand the contributions made by each factor, singly and in combination, to the natural development of the offspring, it is necessary to interfere with nature. One method which we have found to be particularly effective is to have a maternal female from one species rear the offspring of a different species by fostering newborn mice to lactating rat mothers. In some experiments only mice were present; in others, both mice and rat pups were cared for by the rat mother. For a review of these studies, see Denenberg (1970b). The difficulty with the rat-mother preparation is that there is confounding between the rat’s maternal behavior and her milk, thus making it difficult to interpret our findings. To avoid this difficulty, virgin female rats that would engage in maternal behavior but could not lactate were used as rat ‘‘aunts.’’ The aunt, mouse mother, and the young stayed together in the cage

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

285

until weaning. During the course of these experiments some of the aunts did not act very maternally toward the mice, and the differences between controls and experimental mice were usually less when a rat aunt was used than when a rat mother was used. To generate an aunt preparation which was maximally maternal, the nipples were surgically removed from a virgin female (technically called thelectomy), who was then mated. Her pups were removed at parturition and the thelectomized female aunt was placed into a cage with a mouse mother and her pups. As a control, thelectomized virgin rats were also placed into cages with a mouse mother and her pups. Mice from two different strains, the C57BL/10J and the Swiss-Albino, were studied. The former is a genetically inbred strain, while the latter is genetically heterogeneous. The lactating Purdue–Wistar rat mother readily accepted newborn pups from either mouse strain and expressed appropriate maternal behavior, including grooming, licking the anal–genital region, nest building, nursing, and retrieving the young. The rat aunt also engaged in all of these behaviors, save nursing. Open-field activity. In all experiments mice were tested in the open field and their activity recorded. In all instances mice reared with rat mothers or rat aunts were less active than those reared by mouse mothers. The rat mother caused a greater decrease in activity than did the rat aunt. Aggression. Fighting among males is a species-specific behavior pattern in mice. Table 6 summarizes the findings from a number of experiments. The rat mother had a powerful effect upon aggressive behavior of the inbred mouse strain, reducing the incidence of aggression from approximately 45 to 4%. However, varying the maternal figure had no effect upon the SwissAlbino mice. Their fighting incidence remained at approximately 80%. Plasma corticosterone. The hormone corticosterone is secreted by the adrenal cortex and is critically involved in an animal’s response to novel or stressful situations. Swiss-Albino mice did not differ in basal levels, whether reared by a mouse mother, a rat mother, or in the presence of a rat aunt. However, there were marked differences in their physiological reactivity to TABLE 6 Incidence of Aggression in Two Mouse Strains as a Function of Being Reared by a Mouse Mother or a Rat Mother Strain C57BL/10J Swiss-Albino

Mouse mother

Rat mother

44.8% (96) 80.0% (40)

4.2% (71) 82.0% (17)

Note. The number in parentheses is the total number of pairs tested (from Denenberg, 1970).

286

VICTOR H. DENENBERG

the stress of the novel situation. Those reared with rat mothers or aunts had a lesser corticosterone response than control mice reared by mouse mothers. Strength of maternal behavior. Typically rat mothers had a greater impact upon the mice than did rat aunts. The rat mothers also engaged in more maternal behavior than did the aunts. To investigate the hypothesis that strength of maternal behavior was directly related to later performance, one group of Swiss-Albino mice was reared in the presence of thelectomized virgin rat aunts, and other mice were reared in the presence of thelectomized postparturient rat aunts. All mice, including controls, were nursed by SwissAlbino mothers (Rosenberg, Denenberg, & Zarrow, 1970). Two daily observations were made of each mouse cage and the amount of physical contact between the rat aunt and the mouse pups was recorded. As expected, the postpartum thelectomy group made significantly more pup contacts than did the virgin group. Table 7 shows open-field activity scores and corticosterone values after exposure to a novel environment (the groups did not differ in basal values). The aunt-reared mice had lower activity and corticosterone scores than those reared by mouse mothers, consistent with what was reported above. Further, mice reared in the presence of the more maternal postparturient aunt had their scores reduced significantly more than those reared by virgin aunts. Finally, within each group correlations were run between the summed maternal contact score and the pup’s 30-min corticosterone value obtained at weaning. Within the virgin group the correlation was ⫺.16 (not significant). However, within the postpartum group the correlation was ⫺.61 (p ⬍ .01). Thus, the greater the amount of maternal contact, the less was the pup’s corticosterone response. Recently, Liu et al. (1997) recorded maternal stimulation of handled rat pups. When adult, their corticosterone response to a stressful situation was measured. The correlation between the amount of maternal stimulation in infancy and offspring corticosterone values was ⫺.65. Given that Liu et al. TABLE 7 Open-Field Activity and Corticosterone of Swiss-Albino Mice Reared by a Mouse Mother or in the Presence of Thelectomized Rat Aunts Variable

Mouse mother

Thelectomized virgin rat

Thelectomized postpartum rat

Activity (squares) Corticosterone (µg/100 ml)

150.2 (16) 28.58 (17)

130.3 (10) 25.11 (10)

71.7 (20) 22.58 (24)

Note. The number of rats is shown in parentheses (from Rosenberg et al., 1970).

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

287

investigated rats, whereas Rosenberg et al. studied mice and that the studies are separated by almost 30 years, the similarity of results is striking. Comment. The findings clearly establish that rat mothers or aunts, through their behavioral interactions with the mouse pups, bring about changes in behavior and physiology which last well into adulthood. The most general statement is that locomotor activity is reduced for both strains. Assessment of the corticosterone response in the Swiss-Albino mouse revealed a marked reduction in adrenocortical activity to a novel situation, whether reared by a rat mother or a rat aunt. The impact of the maternal figure upon aggressive behavior, however, is genotype-specific. The rat mother virtually eliminated fighting behavior in C57BL/10J mice, but had no effect upon the Swiss-Albino animals. These findings reveal an important form of gene–environment interaction. The Uterine Environment Affects Later Cognitive Competence The procedure of having rat mothers or aunts care for mouse pups allows one to evaluate maternal behavior separated from the complex of confounded events present in any developmental situation. The same general strategy was used to investigate the role of uterine factors upon later behavior by transferring embryos from one uterine environment to another (Denenberg, Hoplight, & Mobraaten, 1998). Mice from the inbred BXSB strain (1) were left undisturbed; (2) were transferred, at the eight-cell stage, into the uteri of other BXSB females (in-strain transfer); or (3) were transferred at the eight-cell stage, into the uteri of hybrid females (out-strain transfer). At birth, the in-strain pups were fostered to lactating hybrid females, while the outstrain pups remained with their hybrid birth mothers. When adult, the three groups were tested on a variety of behavioral measures. Comparisons of the nontransfer mice with the in-strain transfer animals only found two significant effects, both on activity measures. The overall lack of significance indicates that (1) the procedures involved in transferring embryos and (2) being reared by a distinctly different postnatal mother had no measurable effect upon any cognitive variable. Therefore, any significant effects found when comparing the in-strain and out-strain mice may be attributed to the different uterine environments in which the embryos developed. The mice were tested on a simple water escape task, the hidden-platform Morris maze, the Lashley III maze, a visual discrimination task, and a twoway shuttlebox. Those mice reared in the uteri of hybrid females, when compared to those reared in the uteri of same-strain females, were superior in learning the Morris maze, the Lashley III maze, and the visual discrimination T-maze. Further, the out-strain mice made more escape responses and had more rapid escape times in the shuttlebox. In contrast, on the simple water escape task, the groups were reversed: the in-strain mice had the better scores.

288

VICTOR H. DENENBERG

Comments. There have been innumerable studies showing that, during gestation, many variables can have deleterious long-term consequences (e.g., poor nutrition, exposure to toxic substances, alcohol, smoking, stress, maternal age). Implicit in these findings is the assumption that the physiology of the uterus is optimal for maintaining pregnancy and supporting the developing embryo/fetus, but negative factors interfere with or degrade these functions. Those operating under this assumption would not ask the question: given a normal healthy uterine environment, are there things that can be done to improve the long-term biological and behavioral competence of the future individual? This study shows that different uteri are not equally effective in terms of long-term cognitive competence. The neural systems mediating these behaviors include the prefrontal cortex, the hippocampus, and the amygdala (Kandel, Schwartz, & Jessell, 1991). The breadth of the findings suggests that the central nervous system is affected early in its development. It is of interest to compare the findings described above with those of Tang, Shimizu, Dube, Rampon, Kerchner, Zhuo, Liu, and Tsien (1999). These researchers inserted a transgene for one of the NMDA receptors (NR2B) into the forebrains of mice, thereby causing an overexpression of the receptor. These mice and appropriate controls were then tested on the Morris maze, a novel object recognition task, and contextual fear conditioning. Mice with the transgene were superior to the controls on all three tasks, and Tang et al. concluded, ‘‘Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible’’ (p. 64). If the word ‘‘genetic’’ is replaced with the word ‘‘uterine’’ in the above quotation, the sentence applies equally as well to the Denenberg et al. (1998) uterus-transfer experiment. The Genome and Its Attendant Biological and Behavioral Systems Will Attempt to Compensate for Defects or Deficiencies It is apparent that development is a complicated process involving a multitude of interacting and overlapping systems which have to intermesh under highly constrained temporal parameters. That so many turn out so well may appear surprising, given the complexities involved. The reason for the high success rate appears to be because the organism uses a homeostatic, or systems, strategy to maintain its internal integrity and its competence to deal with the external world (Bertalanffy, 1969; Weiss, 1969). Thus, given some defect in the developing system, the organism will use its resources to try to fix the problem or, failing that, to find some way to compensate for the defect. This point is illustrated with two examples. Neocortical ectopias. Two inbred mouse strains, BXSB and NZB, have approximately a 50% incidence of neocortical ectopias (Sherman, Galaburda, Behan, & Rosen, 1987; Sherman, Morrison, Rosen, Behan, & Galaburda, 1990). These are cortical malformations which occur during cell mi-

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

289

gration around embryonic days 13–14. The majority of the ectopias are localized in the prefrontal/motor region in the BXSB mouse, and in the somatosensory region of the NZB. The ectopias are under genetic control with a distribution suggesting only a few genes are involved and are of interest because they are structurally similar to the neuropathology found in the brains of developmental dyslexics (Sherman et al., 1990; Sherman, Stone, Denenberg, & Beier, 1994). BXSB mice with ectopias have been found to be less competent than their littermates on spatial working memory tasks (Boehm, Sherman, Rosen, Galaburda, & Denenberg, 1996b; Hyde, Sherman, & Denenberg, 1996; Waters, Sherman, Galaburda, & Denenberg, 1997). This is not surprising since prefrontal cortex has been shown to be intimately involved in working memory processes in primates (Friedman & Goldman-Rakic, 1994; Goldman-Rakic, 1987). What may appear to be surprising is that these same mice are superior to nonectopics on learning and long-term retention of spatial reference memory tasks (Boehm et al., 1996a, 1996b; Denenberg, Sherman, Schrott, Waters, Boehm, Galaburda, & Mobraaten, 1996) and also on long-term retention of a nonspatial visual discrimination reference memory task (Balogh, Sherman, Hyde, & Denenberg, 1998). Knockout of the Ntan1 Gene. In eukaryotes, the N-end rule pathway is a part of the ubiquitin system. The Ntan1 gene encodes an amidase specific for N-terminal asparagine in mammals (Grigoryev, Stewart, Kwon, Arfin, Bradshaw, Jenkins, Copeland, & Varshavsky, 1996; Varshavsky, 1996, 1997). Behavioral studies have determined that knocking out this gene in the 129 mouse strain results in an animal defective in spatial learning but superior in S-R habit learning (Balogh, Denenberg, Varshavsky, & Kwon, 1999; Kwon et al., 2000). Comment. In both examples the adjustment made by the ‘‘defective’’ animal was in the same realm of behavior as the original insult. Spatial reference memory was enhanced as a consequence of difficulties with spatial working memory, and S-R learning was better in animals with a gene deletion which interfered with spatial relational learning. For this kind of behavioral plasticity to occur, it is necessary that there be multiple systems changes at all levels of the organism. An understanding of how these changes occur is one of the great challenges facing neuroscience. Genes Do Not Act in Isolation Many of the studies described above establish that genes interact with their environment. Rats handled in infancy have lateralized brains, whereas those not handled have symmetrical brains. Newborn chicks exposed to light while in the egg have lateralized brains, whereas chicks deprived of light exposure in ovo are not lateralized. C57 and Swiss-Albino mice reared by rat mothers or in the presence of

290

VICTOR H. DENENBERG

rat aunts have lower activity scores than genetically equivalent animals reared by mouse mothers. Swiss-Albino mice give a lesser corticosterone response to novel stimuli if reared by rat mothers or in the presence of rat aunts than genetically equivalent animals reared by mouse mothers. C57BL/ 10J mice normally have around a 45% fighting incidence, but when reared by rat mother the incidence drops to 4%, even though the genetics of those reared by rat mothers are identical to those reared by mouse mothers. BXSB mice reared in the uteri of hybrid females are superior to genetically identical mice reared in the uteri of BXSB females on four of five cognitive tasks. BXSB mice with and without neocortical ectopias are genetically identical with about a 50% expression rate of the ectopias; those without ectopias are superior on spatial working memory measures, whereas those with ectopias are superior on spatial and nonspatial reference memory tasks. Mice from the 129 strain with the Ntan1 gene knocked out are inferior to genetically equivalent control mice on spatial learning measures but are superior on a nonspatial discrimination learning task. One exception to the rule that genes do interact with their environment is the aggression findings for the Swiss-Albino mice: those reared by rat mothers have as great a fighting incidence as those reared by mouse mothers. However, this does not preclude the possibility that some other set of environmental conditions might reduce their aggression scores. Note also that those reared by rat mothers or in the presence of rat aunts have changed activity and plasma corticosterone levels. Comment. In his review, Wahlsten (1999) cites a number of examples of interaction effects. The most dramatic is the finding that the mutation of a single gene in yeast altered the expression of 355 other genes (DeRisi, Iyer, & Brown, 1997). Since yeast has 6297 genes, more than 5% of the entire genome was affected by one mutation. An important corollary of the interaction concept is that it does away with the fruitless nature–nurture controversy. At one time, when we had much less knowledge, the question concerning the relative proportion of variance to be attributed to heredity and to environment appeared reasonable. That question is based upon an additive model which is incompatible with current research findings which compel the use of an interactive systems model (Wahlsten, 1999). The flavor of present-day thinking about genes and environment is well expressed in Wahlsten’s (1999) recent review: ‘‘The era of examining single-gene effects from a reductionistic perspective is waning, and research with interacting arrays of genes in various environmental contexts is demonstrating a need for systems-oriented theory’’ (p. 599). DISCUSSION

This article started with the statement that there are intimate links between adaptation during development and species survival. This was followed by

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

291

TABLE 8 Summary of Reviewed Research Genome Knocking out Ntan1 gene Neocortical ectopias Conception-birth In-strain embryo transfer Out-strain embryo transfer Asymmetrical light input Birth-weaning Handling

Rat mother/aunt for mouse pups

Postweaning Enriched environment

Inter generational Handling of mothers and grandmothers ⫹ enrichment pre- and postweaning

↓ ↑ ↓ ↑

Spatial learning of KO Nonspatial (S-R) learning of KO Spatial working memory Reference memory

0 Behavioral effects ↑ Adult cognitive competence ↑ Brain laterality (chicks) ↑ Brain laterality (rats) ↓ Emotionality to novel stimuli ↓ Corticosterone response to novel stimuli ↑ Corticoterone to distinctly noxious stimuli ↑ Number of corticosterone receptors in hypothalamus ↓ Open-field activity (C57, SA) ↓ Corticosterone response to novel stimuli (SA) ↓ Intramale aggression (C57) 0 Intramale aggression (SA) ↑ Rat aunt–mouse pup contact → ↓ corticosterone response of mice to novel environment ↑ Learning, problem solving, perception ↑ Dendritic growth, cortical thickness ∆ Brain chemistry ↑ Body weight ↑ Open-field activity ↑ Systematic ‘‘individual differences’’

Note. Symbols and abbreviations are as follows: ↑, increase; ↓, decrease; →, lead to; ∆, change; 0, no effect; C57, C57BL/10 mice; SA, Swiss-Albino mice; KO, knockout.

brief summaries of a wide range of experimental findings involving manipulations of environmental and social parameters during early development. These findings are summarized in Table 8, ordered roughly along a developmental continuum starting with the genome. This list is not inclusive, but is sufficient to establish that differing forms of early experience influence a vast number of behavioral and biological endpoints. There are several implications from this research. First, where one can place a value judgment on the measures, most of the changes observed are ‘‘good’’ in the sense that they facilitate the animal’s adaptation and ability to survive. At the behavioral level, appropriate stimulation during different developmental periods can increase exploratory behavior, reduce emotionality, allow the organism to have a more modulated response to novel and noxious stimuli, enhance learning and memory along multiple cognitive di-

292

VICTOR H. DENENBERG

mensions, and increase perceptual competence. At the biological level, there are permanent changes in brain laterality, brain morphology, brain chemistry, corticosterone receptors, and corticosterone responsivity. The second implication is that nondisturbed controls (i.e., nonhandled or nonenriched) are usually found to be the least adaptive. This suggests that variability of experience during early development is a critical factor in facilitating the adaptive competence of the organism (Denenberg, 1975). This conclusion is based on the assumption that the organism will encounter, in later life, environmental conditions and contingencies different from those present while growing up. When one considers the vast range of physical conditions on this planet, and realizes that complex life can survive and reproduce successfully under most of these conditions, one comes to appreciate that species have evolved biological and behavioral systems competent to cope with a multitude of environmental events. Early postnatal experiences inform the organism about the immediate demands of the environment and adaptive mechanisms are brought into play. If the early environment is complex and varied, a wider range of mechanisms is needed. Once these mechanisms have been activated, they can be called upon in later life when unexpected and changed environmental contingencies occur. This leads to a discussion of the contributions that developmental experiences make to evolutionary processes. These can be highlighted by considering two processes, among many, that are necessary for species survival: (1) the homeostatic competence of the species must be sufficient to adapt to the exigencies of the environment; and (2) if a catastrophe occurs, there must be sufficient variability in the population so that some members will survive and reproduce. The first statement pertains to the population mean and the second to the population variance. Experiences during early development can permanently affect both parameters. Table 8 lists a number of behavioral and biological endpoints affected by early experiences which aid in survival. Thus, if all or most members of a population are exposed to appropriate experiences at the right time in development, their mean level of performance will be raised, thereby increasing the likelihood that they can adapt and survive extreme environmental challenges. A shift in mean level says, in theory, that all or most of the members of the population have been exposed to the extra stimulation in early life and, because of that exposure, their performance has been permanently changed. In such a situation, the shift in mean level is not accompanied by a change in variance. Consider, however, a situation where only some of the individuals from the population received the extra early exposure. Their behavior would be incremented, thus bringing about an increase in population variance (there would also be a slight increase in the mean). Thus, differential early experiences are a way of generating stable individual differences, thereby enhancing the within-population variance.

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

293

Further, this form of individual differences is based upon the immediate and local characteristics of the subjects’ developmental environment, in contrast to genetically based individual differences which are a consequence of long-term evolutionary history. The findings that experiences females had during their early life can affect their offspring and grandoffspring are particularly relevant in this regard because it involves a social communication system whereby information acquired by one generation as a function of environmental events is transmitted by nongenetic mechanisms to a later generation (Denenberg & Whimbey, 1963). Thus, nongenetically derived individual differences facilitates short-term generational adaptation, which can, in the long run, help enhance survival of the species. Because variability is an imperative for survival, there may well be multiple mechanisms in early development which have the purpose of generating individual differences (Denenberg, 1999). In conclusion, biologists talk about developmental stability, or canalization, as a genetic process to buffer developmental pathways against mutational or environmental perturbations (Wilkins, 1997). This is what Weiss (1969) calls a microdeterministic level. At a macrodeterministic level, developmental stability requires that genotypes be expressed as phenotypes which are capable of growing up, adapting, and procreating in the worlds within which they are born. Evolution preserves those genes whose phenotypic expression survives, and this is the link between adaptation during development and species survival. REFERENCES Anderson, E. E. (1938a). The interrelationship of drives in the male albino rat. II. Intercorrelations between 47 measures of drives and learning. Comparative Psychology Monographs, 14, No. 6:119. Anderson, E. E. (1938b). The interrelationship of drives in the male albino rat. III. Interrelationships among measures of emotional, sexual, and exploratory behavior. Journal of Genetic Psychology, 53, 335–352. Andrew, R. J. (1988). The development of visual lateralization in the domestic chick. Behavioral Brain Research, 29, 201–209. Balogh, S. A., Denenberg, V. H., Varshavsky, A., & Kwon, Y. T. (1999). Behavioral characterization of mice lacking the asparagine-specific branch of the N-end rule pathway. Society for Neuroscience Abstracts, 25, 635. Balogh, S. A., Sherman, G. F., Hyde, L. A., & Denenberg, V. H. (1998). Effects of neocortical ectopias upon the acquisition and retention of a non-spatial reference memory task in BXSB mice. Developmental Brain Research, 111, 291–293. Bennett, E. L. (1976). Cerebral effects of differential experience and training. In M. R. Rosenzweig & E. L. Bennett (Eds.), Neural mechanisms of learning and memory (pp. 279– 287). Cambridge, MA: MIT Press. Bertalanffy, L. V. (1969). Chance or law. In A. Koestler & J. R. Smythies (Eds.), Beyond reductionism (pp. 56–76). Boston: MacMillan. Boehm, G. W., Sherman, G. F., Hoplight, B. J., Hyde, L. A., Waters, N. S., Bradway, D. M., Galaburda, A. M., & Denenberg, V. H. (1996a). Learning and memory in the autoimmune

294

VICTOR H. DENENBERG

BXSB mouse: Effects of neocortical ectopias and environmental enrichment. Brain Research, 726, 11–22. Boehm, G. W., Sherman, G. F., Rosen, G. D., Galaburda, A. M., & Denenberg, V. H. (1996b). Neocortical ectopias in BXSB mice: Effects upon reference and working memory systems. Cerebral Cortex, 6, 696–700. Comery, T. A., Shah, R., & Greenough, W. T. (1995). Differential rearing alters spine density on medium-sized spiny neurons in the rat corpus striatum: Evidence for association of morphological plasticity with early response gene expression. Neurobiology Learning Memory, 63, 217–219. Denenberg, V. H. (1967). Stimulation in infancy, emotional reactivity, and exploratory behavior. In D. C. Glass (Ed.), Neurophysiology and emotion (pp. 161–190). New York: Rockefeller Univ. Press. Denenberg, V. H. (1969a). Open-field behavior in the rat: What does it mean? Annals New York Academy Sciences, 159, 852–859. Denenberg, V. H. (1969b). The effects of early experience. In E. S. E. Hafez (Ed.), The behaviour of domestic animals (pp. 95–130). London: Bailliere, Tindall and Cassell. Denenberg, V. H. (1970a). Experimental programming of life histories and the creation of individual differences: A review. In M. R. Jones (Ed.), Effects of Early Experience, 1968, Miami Symposium on the Prediction of Behavior (pp. 61–91). Coral Gables, FL: Univ. of Miami Press. Denenberg, V. H. (1970b). The mother as a motivator. In W. J. Arnold & M. M. Page (Eds.), Nebraska Symposium on Motivation (pp. 69–93). Lincoln, NE: Univ. of Nebraska Press. Denenberg, V. H. (1975). Effects of exposure to stressors in early life upon later behavioural and biological processes. In L. Levi (Ed.), Society, stress and disease. Vol 2: Childhood and adolescence (pp. 269–281). New York: Oxford Medical. Denenberg, V. H. (1977). Assessing the effects of early experience. In Methods in psychobiology (Vol. III, pp. 127–147). New York: Academic Press. Denenberg, V. H. (1980). General systems theory, brain organization, and early experiences. American Journal of Physiology (Regulatory, Integrative Comparative Physiology), 7, R3–R13. Denenberg, V. H. (1981). Hemispheric laterality in animals and the effects of early experience. Behavioral and Brain Sciences, 4, 1–49. Denenberg, V. H. (1999). Commentary: Is maternal stimulation the mediator of the handling effect in infancy? Developmental Psychobiology, 34, 1–3. Denenberg, V. H., Brumaghim, J. T., Haltmeyer, G. C., & Zarrow, M. X. (1967). Increased adrenocortical activity in the neonatal rat following handling. Endocrinology, 81, 1047– 1052. Denenberg, V. H., Hoplight, B. J., & Mobraaten, L. E. (1998). The uterine environment enhances cognitive competence. NeuroReport, 9, 619–623. Denenberg, V. H., & Rosenberg, K. M. (1967). Nongenetic transmission of information. Nature, 216, 549–550. Denenberg, V. H., Sherman, G., Schrott, L. M., Waters, N. S., Boehm, G. W., Galaburda, A. M., & Mobraaten, L. E. (1996). Effects of embryo transfer and cortical ectopias upon the behavior of BXSB-Yaa and BXSB-Yaa⫹ mice. Developmental Brain Research, 93, 100–108. Denenberg, V. H., & Whimbey, A. E. (1963). Behavior of adult rats is modified by the experiences their mothers had as infants. Science, 142, 1192–1193. DeRisi, J. L., Iyer, V. R., & Brown, P. O. (1997). Exploring the metabolic and genetic control of gene expression on a genomic scale. Science, 278, 680–686.

EVOLUTION PROPOSES AND ONTOGENY DISPOSES

295

Francis, D., Diorio, J., Liu, D., and Meaney, M. J. (1999). Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science, 286, 1155–1158. Friedman, H. R., & Goldman-Rakic, P. S. (1994). Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the Rhesus monkey. The Journal of Neuroscience, 14, 2775–2788. Goldman-Rakic, P. S. (1987). Development of cortical circuitry and cognitive function. Child Development, 58, 601–622. Greenough, W. T. (1976). Enduring brain effects of differential experience and training. In M. R. Rosenzweig & E. L. Bennett (Eds.), Neural mechanisms of learning and memory (pp. 255–278). Cambridge, MA: MIT Press. Grigoryev, S., Stewart, A. E., Kwon, Y. T., Arfin, S. M., Bradshaw, R. A., Jenkins, N. A., Copeland, N. G., & Varshavsky, A. (1996). A mouse amidase specific for N-terminal asparagine. Journal of Biological Chemistry, 271, 28521–28532. Hebb, D. O. (1949). The organization of behavior. New York: Wiley. Hyde, L. A., Sherman, G. F., & Denenberg, V. H. (1996). Radial-arm maze learning in BXSB mice: Effects of neocortical ectopias. Society for Neuroscience, 22, 485. Juraska, J. M., Henderson, C., & Muller, J. (1984). Differential rearing experience, gender, and radial maze performance. Developmental Psychobiology, 17, 209–215. Kandel, E. R., Schwartz, J. H., & Jessell, T. M. (1991). Principles of neural science (3rd ed.). New York: Elsevier. Krech, D., Rosenzweig, M. R., & Bennett, E. L. (1962). Relations between brain chemistry and problem solving among rats raised in enriched and impoverished environments. Journal of Comparative and Physiological Psychology, 55, 801–807. Kwon, Y. T., Balogh, S. A., Davydov, I. V., Kashina, A. S., Yoon, J. K., Xie, Y., Hyde, L. A., Denenberg, V. H., & Varshavsky, A. (2000). Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the Nend rule pathway. Molecular and Cellular Biology, in press. Levine, S. (1975). Psychosocial factors in growth and development. In L. Levi (Ed.), Society, stress and disease (pp. 43–50). London: Oxford Univ. Press. Liu, D., Diorio, J., Tannenaum, B., Daldji, C., Francis, D., Freedman, A., Aharma, S., Pearson, D., Plotsky, P. M., & Meaney, M. J. (1997). Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal response to stress. Science, 277, 1659– 1662. Meaney, M. J., Aitken, D. H., Bodnoff, S. R., Iny, L. J., Tatarewicz, J., & Sapolsky, R. M. (1985). Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions. Behavioral Neuroscience, 99, 765–770. Meaney, M. J., Aitken, D. H., Viau, V., Sharma, S., & Sarrieau, A. (1989). Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal Type II glucocorticoid receptor binding in the rat. Neuroendocrinology, 50, 597–604. Mench, J. A., & Andrew, R. J. (1986). Lateralization of a food search task in the domestic chick. Behavioral Neural Biology, 46, 107–114. Rogers, L. J. (1990). Light input and the reversal of functional lateralization in the chicken brain. Behavioural Brain Research, 38, 211–221. Rogers, L. J., (2000). Evolution of hemispheric specialization: Advantages and disadvantages. Brain and Language, 73, 236–253. Rogers, L. J., & Anson, J. M. (1978). Cycloheximide produces attentional persistence and slowed learning in chickens. Pharmacology Biochemistry Behavior, 9, 735–740. Rogers, L. J., & Anson, J. M. (1979). Lateralisation of function in the chicken forebrain. Pharmacology Biochemistry Behavior, 10, 679–686.

296

VICTOR H. DENENBERG

Rogers, L. J., Zappia, J. V., & Bullock, S. P. (1985). Testosterone and eye–brain asymmetry for copulation in chickens. Experientia, 41, 1447–1449. Rosenberg, K. M., Denenberg, V. H., & Zarrow, M. X. (1970). Mice reared with rat aunts: The role of rat-mouse contact in mediating behavioural and physiological changes in the mouse. Animal Behaviour, 18, 138–143. Rosenzweig, M. R. (1971). Effects of environment on development of brain and behavior. In E. Tobach, L. R. Aronson, & E. Shaw (Eds.), The biopsychology of development (pp. 303–342). New York: Academic Press. Rosenzweig, M. R., Bennet, E. L., & Diamond, M. C. (1972), February. Brain changes in response to environment. Scientific American, 22–30. Schaefer, T., Weingarten, F. S., & Towne, J. C. (1962). Temperature change: the basic variable in the early handling phenomenon? Science, 135, 41–42. Sherman, G. F., Galaburda, A. M., Behan, P. O., & Rosen, G. D. (1987). Neuroanatomical anomalies in autoimmune mice. Acta Neuropathology (Berlin), 74, 239–242. Sherman, G. F., Morrison, L., Rosen, G. D., Behan, P. O., & Galaburda, A. M. (1990). Brain abnormalities in immune defective mice. Brain Research, 532, 25–33. Sherman, G. F., Stone, L. V., Denenberg, V. H., & Beier, D. R. (1994). A genetic analysis of neocortical ectopias in New Zealand Black autoimmune mice. NeuroReport, 5, 721– 724. Tang, Y-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., & Tsien, J. Z. (1999). Genetic enhancement of learning and memory in mice. Nature, 401, 63–69. Vallortigara, G. (2000). Comparative neuropsychology of the Dual Brain: A stroll through animals’ left and right perceptual world. Brain and Language, 73, 189–219. Varshavsky, A. (1996). The N-end rule: Functions, mysteries, uses. Proceedings of the National Academy of Sciences, 93, 12142–12149. Varshavsky, A. (1997). The ubiquitin system. Trends in Biological Science, 22, 383–387. Volkmar, F. R., & Greenough, W. T. (1972). Rearing complexity affects branching of dendrites in the visual cortex of the rat. Science, 176, 1145–1147. Wahsten, D. (1999). Single-gene influences on brain and behavior. Annual Review of Psychology, 50, 599–624. Wallace, C. S., Kilman, V. L., Withers, G. S., & Greenough, W. T. (1992). Increases in dendritic length in occipital cortex after 4 days of differential housing in weanling rats. Behavioral Neural Biology, 58, 64–68. Waters, N. S., Sherman, G. F., Galaburda, A. M., & Denenberg, V. H. (1997). Effects of cortical ectopias on spatial delayed-matching-to-sample performance in BXSB mice. Behavioral Brain Research, 84, 23–29. Weiss, P. A. (1969). The living system: Determinism stratified. In A. Koestler & J. R. Smythies (Eds.), Beyond Reductionism, pp. 3–42. Boston: Beacon. Whimbey, A. E., & Denenberg, V. H. (1967). Experimental programming of life histories: The factor structure underlying experimentally created individual differences. Behaviour, 29, 296–314. Wilkins, A. S. (1997). Canalization: A molecular perspective. BioEssays, 19, 257–262. Willingham, W. W. (1956). The organization of emotional behavior in mice. Journal of Comparative and Physiological Psychology, 49, 345–348. Zappia, J. V., & Rogers, L. J. (1987). Sex differences and reversal of brain asymmetry by testosterone in chickens. Behavioral Brain Research, 23, 261–267.