Issues of Establishment, Consolidation, and Reorganization in Biobehavioral Adaptation

Brain and Mind 3: 53–77, 2002.© 2002 Kluwer Academic Publishers. Printed in the Netherlands.

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Issues of Establishment, Consolidation, andReorganization in Biobehavioral Adaptation

JEAN-LOUIS GARIÉPY1∗ and RAMONA M. RODRIGUIZ2

1Center for Developmental Science, Department of Psychology, University of North Carolina atChapel Hill, Chapel Hill, NC 27599-3270, USA; 2Department of Psychiatry and BehavioralSciences, Mouse Behavioral and Neuroendocrine Core, Duke University Medical Center, Durham,NC 27710, USA (∗author for correspondence, E-mail: [email protected])

(Received: 5 July 2001; in final form: 8 April 2002)

Abstract. Two strains of male mice have bred over forty generations, starting with the work ofRobert Cairns and his colleagues, one strain with a high level of intra-species aggression, the othera low level of aggression. The high-aggression mice tend to establish dominance hierarchies andparticularly fight in the presence of female mice. The low-aggression mice tend, in groups of theirown, to have a high degree of low-intensity, peaceful social contact, and to be more timid in initi-ating action than the high-aggression mice. Biochemical differences have been observed betweenthe two strains, and confirmed by the present data: the high-aggression mice have greater dopamineconcentrations (in the caudate nucleus and nucleus accumbens), lower levels of the stress hormonecorticosterone, and higher levels of testosterone than the low-aggression mice. The current exper-iments were designed to answer questions about the flexibility of adaptive behaviors: specifically,what is the effect of early daily maternal separation on adult stress response in each strain? Whatare the behavioral and hormonal mechanisms by which, as has been observed, low-aggressionmice achieve a dominant status when brought into situations where they compete for territory withhigh-aggression mice? Finally, what are the social and neurochemical mechanisms by which high-aggression mice can develop low-aggression behavior if brought out of isolation and into groups?Maternal separation was found to lead to decreases in stress levels, as measured by corticosterone, inthe low-aggression but not the high-aggression, mice – presumably because of the surplus of maternalcare the pups receive on returning to the nest. When a low-aggression mouse became dominant anda high-aggression mouse became submissive, their usual pattern of corticosterone and testosteronelevels was found to be reversed. The change to low-aggression behavior in high-aggression miceswitching from an isolation condition to a group condition, was mediated by a decrease in D1dopamine receptor densities. These results, like the ones on which they build, argue for substantialdevelopmental influences in expressions of the genes influencing aggressive or cooperative behavior.In this approach to evolution, epigenesis is treated not as a set of traits and behaviors predeterminedby the genome, but as a set of probabilistic tendencies toward certain traits and behaviors.

Key words: aggression, corticosterone, dominance, dopamine, handling, isolation, testosterone

General Introduction

According to the evolutionary synthesis, adaptive behaviors are shaped by naturalselection over the evolutionary history of the species, and their expression in

54 JEAN-LOUIS GARIEPY AND RAMONA M. RODRIGUIZ

the individual is supported by the genomic information thus accumulated. Fromthis perspective, individual development is propelled forward by genetic informa-tion that directs the formation of a neural substrate, which, in time, will supportthe expression of adaptive behaviors (Mayr, 1982). The behavioral scientist whoendorses this view generally bypasses the study of development and the object ofresearch is how behavior, as expressed in adult life, functions to promote adaptationto the species-specific context.

Developmental psychobiologists have proposed an alternative framework forexamining the origin of adapted behaviors, a perspective founded on the systemsapproach formulated by von Bertalanffy (1933, 1962) and earlier work in embry-ology (see Gottlieb, 1979 for review). Its central premise is that developmentproduces, through progressive differentiation, a hierarchy of nested systems inwhich there are bidirectional influences between all levels of organization, fromgenetic to behavioral activity and a structured environment. Accordingly, no levelof activity has special status from the standpoint of determination, and new infor-mation is generated at every step of the process as new contingencies between thedifferentiated parts emerge through developmental action. A logical implicationof this bidirectionality is that epigenesis is not predetermined as suggested bythe evolutionary synthesis, but is essentially probabilistic (Gottlieb, 1992). Fromthis perspective, species-specific end-points are achieved because developmentalactivity normally takes place in the presence of highly predictable and repeatableforms of stimulation. Thus, the very same processes that explain the attainment ofnormative end-points within the species also explain the origin of deviations fromthese universals during individual development (Gariépy, 1998).

Because the early stages of development are highly sensitive to variation instimulative conditions there is, early on, a vast potential for producing deviationsfrom the normative end-points. This plasticity is gradually lost, however, as thedifferentiated structures acquire specific functions (Gottlieb, 1983). At this point,subsequent development is said to be canalized – i.e., the acquisition of specificstructures and functions impose sharp limits on the future course of development.Although the developmental psychobiological framework explicitly recognizesthat development is a life long process, surprisingly little research has beenconducted from this perspective to examine questions of continuity and changeover development. As Cairns (1979) pointed out, beyond questions of establish-ment, the study of developmental phenomena also requires attention to questions ofconsolidation and reorganization over ontogeny. Importantly, the last two processesemphasize the notion that adaptive behavior and its underlying neurochemistry arealso adaptable. Any behavior that would become stereotyped or frozen by virtueof prior development would lose its most vital function of promoting flexible andreversible adaptations (Cairns, 1993). In these propositions, Cairns endorsed thebasic developmental psychobiological premises, but he also attributed behavioralactivity a special function in the establishment of mutually supportive relationships

BIOBEHAVIORAL ADAPTATION 55

between internal systems and a structured environment (Cairns, 1997; see Gariépy,1996 for further discussion).

This model has special relevance for social species in which interaction withothers is a central aspect of individual adaptation. Unlike activities directed at thephysical world, social actions involve other individuals that share the same psycho-logical and behavioral capacities. Accordingly, the basis for the organization ofaction in this context may be rapidly transformed as new constraints and opportu-nities emerge in the temporal flow of social interchanges. In the light of constantchanges in the properties and organization of the social environment, maintaining,consolidating, and establishing new organism-environment relationships requirethat activity within the different systems of the organism – genetic, hormonal,neurological, or cognitive – operate in ways that promote flexible and reversibleadaptations (Cairns, 1997). Although change is constrained by prior adaptations,together, these systems, along with the dynamic properties of the social environ-ment, provide multiples points of entry for negotiating new organism-environmentrelationships (Cairns et al., 1993).

Some 25 years ago, Robert B. Cairns produced by selective breeding two linesof mice that differed markedly in aggression toward conspecifics (Cairns et al.,1983). In a short (10-min) dyadic test conducted when the animals reach puberty,males in the high-aggressive line (NC900) lunge fierce attacks at the partner mouse,generally within the first minute of the test. By contrast, instead of attacking,low-aggressive mice (NC100) exhibit a strong tendency to freeze and to becomeimmobile upon social contact (Gariépy et al., 1988). Now in its 40th generation,this selective breeding program has consistently reproduced these differences. Wehave shown that dopamine concentrations are lower in the low line, in areas of thebrain – the caudate nucleus and the nucleus accumbens – that are associated withthe regulation of emotional responding, motivational states, and the initiation ofaction (Lewis et al., 1988). When exposed to challenging situations, corticosteroneactivation is higher in the low line and testosterone production is higher in the highline, and these differences augment in proportions that reflect the degree of chal-lenge imposed by the testing condition (Rodriguez et al., 1998). These biologicaldifferences directly parallel the observation that animals of the NC100 line, bycomparison to NC900, are less prone to initiate action and are more emotional andmore timid when exposed to novel social and nonsocial environments.

Given these potential constraints we have used the NC100 and NC900 mouselines to test various hypotheses concerning the flexibility of adaptive behaviors.The first experiment reported here examined the effects of early maternal separ-ation (i.e., handling) on adult stress response in these selected lines. In thiscontext we also examined how the established effects of this manipulation areeither consolidated or attenuated by subsequent experience in the adolescent peergroup. The second experiment examined behavioral and hormonal mechanismssupporting the attainment of a dominant status among low-aggressive males ininteractions with high aggressive males. The third experiment investigated the


social-ecological and neurochemical mechanisms that supported behavioral reor-ganization among high-aggressive males that were forced to communal livingcondition as adults after a prolonged period of social isolation.

Experiment 1: The Effects of Early Handling and Subsequent HousingConditions on Adult Stress Regulation

The procedure known as “handling” (i.e., the daily removal of pups from theirdam) has been widely used since Levine (1957) first demonstrated its surprisingdevelopmental effects. The adult subjects so treated as infants were less fearfulin novel environments and showed a better regulation of the stress hormone,corticosterone. The methods subsequently used to pursue this line of research havebeen remarkably consistent across laboratories. Most studies used rat or mousestrains where the effects were easily obtained; the subjects were handled dailyin the same manner for the first 2–3 weeks of life, then they were left undis-turbed under standard laboratory conditions until adult responses to stressors weremeasured.

The main conclusion of this research is that early experience permanently modi-fies the organization of the physiological systems regulating the response to stressin adulthood (Francis and Meaney, 1999; Meaney et al., 1996). The topic has drawnconsiderable resources in the last fifty years in part because early handling affectsthe organization of a system, the hypothalamo-pituitary-adrenal axis (HPA) that isof paramount importance to processes of adaptation and general health. Import-antly, this research established clear causal linkages between early developmentalevents and later adult behavioral and physiological functions. However, with theexception of earlier work by King and Eleftheriou (1959), Levine and Broadhurst(1963), and more recently by Fernandez-Teruel (1992) and Anisman et al. (1998),few investigators have examined how animals with different genetic backgroundsmay respond to the same neonatal treatment. Also, except for one report by Hughes(1971) we are not aware of research that examined whether the adult effects ofthis early experience could be either consolidated or attenuated as a result ofsocial experience beyond infancy and childhood. Given the emphasis placed on therelevance of the findings for human health, intervention and treatment, the relativeneglect of these issues is somewhat surprising.

To begin exploration of these questions, the present research examined the jointeffects of postnatal handling and subsequent rearing conditions on the adult stressresponse of mice selectively bred for high (NC900) and low aggression (NC900).To this end, males of each line were either handled or left undisturbed with theirmother for the first three weeks of life. Then, subjects of each neonatal conditionwere placed either in social isolation or in groups until corticosterone activationwas measured in adulthood. Given the evidence that NC100 is more emotionalthan NC900, we expected the establishment of more pronounced handling effectsin the low line. We also expected the line-specific effects to be either consolidated


or attenuated among animals subsequently exposed to communal living, dependingon the social ecological conditions prevailing among them.

METHODS

Subjects. A total of 88 male mice, 43 low-aggressive (NC100) and 45 high-aggressive (NC900) from the 30th and the 31st generations of the selectivebreeding program described above were randomly chosen from different litters toserve as subjects. The animals had access to food and water ad libitum, and werekept on a reverse light cycle (12 hr light: 12 hr relative darkness).

Neonatal handling. Seventy-two hours after parturition, 88 litters were culled toconsist of 4 females and 4 males. 19 NC100 and 21 NC900 litters were handledapproximately 7 hours into the dark cycle. Handling consisted of placing an entirelitter in a 500ml opaque plastic beaker for 30 sec once every 48 hours from day 3postpartum until weaning at 21 days. A control group consisting of 24 undisturbedNC100 and 24 NC900 litters was also constituted.

Postweaning rearing conditions. At 21 days of age, all male pups were weaned andassigned to either relative social isolation or group rearing. In the first condition,they were placed singly in standard mouse compartments and had no social contactother than exposure to the noises and odors in the colony room. Group rearingconsisted in housing four males of the same line, age and neonatal experiencetogether (i.e., handled or nonhandled) in a standard opaque mouse compartment.

Open field testing. The subjects were kept in their respective condition, socialisolation or group, until they reached 56 days of age when they were tested forcorticosterone (CORT) activation in an open-field arena. This compartment was asquare chamber (91 sq cm × 32 cm high) made of Plexiglass that was equippedwith a removable acrylic floor for easy cleaning between tests. The arena wasilluminated by a 25 watt incandescent light bulb placed 50 cm above the floorcenter. When the subjects reached the specified age for testing they were placedalone in the center of the arena, let free to explore the whole surface for 10 min,and returned to their home cage. Testing was conducted during the first 4 hours ofthe dark cycle from 0900h to 1300h. The order of testing was randomized acrosslines, neonatal experience, and rearing conditions.

Collection of serum. Subjects were anesthetized 20 min after completion of the testby Halothane (Halocarbon Laboratories, River Ridge, NJ) inhalation and blood wascollected by cardiac puncture. Blood samples were placed into 10 mL serum gel-separator (Microtainer, Becton Dickinson, Rutherford, NJ) and centrifuged at roomtemperature (25.5 ◦C). The serum was stored at –72 ◦C until assayed.


Figure 1. Effects of neonatal handling (handled, nonhandled) and rearing conditions (socialisolation, group ) on CORT activation following exposure to an open-field arena. Mean CORTconcentrations (ng ml−1 ± SEM). Left panel: NC100. Right panel: NC900.

Determination of hormonal concentrations. Serum samples were assayed induplicate for CORT concentration using the ImmuChem Double AntibodyCorticosterone 125I Kit (ICN-Biomedicals Costa Mesa, CA). The amount of [125I]-CORT bound for each sample was determined using a LKB gamma counter(Model 1272, CliniGamma). Concentrations were calculated as ng ml−1. Data areexpressed as means (± S.E.M.).

RESULTS

Serum CORT concentrations measured as a function of handling and housingconditions are presented in Figure 1 for NC100 (left panel) and NC900 (right panel)mice. As seen in this figure, in NC100 handling nearly halved CORT activation inthe open field but had no detectable effect in NC900 (Line × Handling, F(1,86) =3.74, p = 0.056). A separate analysis of variance confirmed the presence of asignificant handling effect in NC100, F(1,42) = 4.25, p < 0.02. In the undisturbedcondition, CORT concentrations among NC100 subjects were about 40% higherthan that measured among NC900 subjects. Essentially, the effect of handling inNC100 was to lower CORT activation levels to approximately those seen in NC900in the absence of handling.


The results presented in Figure 1 further indicate that the overall effect ofhousing conditions differed substantially between the two lines (Line × Housing,F(1,86) = 4.25, p < 0.04). As compared to the isolation condition, group rearingreduced CORT activation in NC100 (F(1,42) = 11.12, p < 0.01) but no housingeffect was evident in NC900. In the low line, this effect were especially pronouncedfor the handled subjects among whom CORT activation was further reduced bya factor of two as compared to similarly treated subjects reared in social isola-tion. The number of animals assigned to these experimental conditions, however,precluded testing the significance of this interaction. What these results suggest isthat in the NC100 line, handling and group housing had apparent additive effectson CORT response to novelty.

DISCUSSION

As shown in this study, neonatal handling failed to establish any adult differencesin stress regulation in the high-aggressive line. These animals exhibited moderateelevations of CORT in the open field and these levels were unaffected by neonatalhandling. By contrast, in the absence of handling, CORT levels were higher in thelow line, a finding consistent with previous research showing that these animalsare more emotional and more easily disturbed by changes in stimulative condition.Thus, the main effect of handling in this line was to reduce CORT activation tolevels comparable to that seen in the high line. Anisman et al. (1997) reportedsimilar differences in handling effects between the BALB and C57BL6 mousestrains. Specifically, they also observed that the least emotional of the two strains,the C57BL6, naturally exhibited a low CORT response to stress, and that only themore emotional BALB strain showed a reduction from naturally high levels as aresult of infantile handling.

This finding naturally begs the question: “How did differences in genetic back-ground interact with early experience to produce the line-specific effects that weobserved?” It has been demonstrated that the most likely experiential mediatorof handling effects is the surplus of maternal care that stressed pup receive upontheir return to the nest (Smotherman, 1983; Liu et al., 1999). On the basis of thismaternal mediation hypothesis, we have recently observed mother-pup interactionsin our selected line and showed that maternal care was unaffected by the dailyexperience of handling in the high-aggressive line, but was significantly augmentedin the low line (Gariépy et al., under review). We further determined that thisaugmentation in NC100 coincided with a tendency, more pronounced among pupsof this line, to emit ultrasonic distress calls (known to elicit maternal behaviors)when returned to nest. However, we also observed the disappearance of this differ-ence in outfostering experiments. Thus, it appears that elucidating how geneticbackground affects the contribution of early stimulation to development requirescareful examination of the behavioral characteristics that mothers and pups bringto their interaction, the particular ecology of postnatal care thus constituted, and the


differential immediate effects that similar forms of early stimulation may producegiven differences in that ecology.

With the discovery that the physiological mediation of handling effects involvedan upregulation of glucorticoid (GC) receptors in hippocampus and frontal cortex,the positive effects of the procedure were apparently fully explained becausethese receptors are critically implicated in the negative control feedback loop thatshuts down further HPA activity following its activation under stress (Meaneyand Aitken, 1985). These changes were shown to occur during the first fewweeks of life, at a time when the HPA axis undergoes developmental organization.According to a recent proposal, this change would be produced via the serotonergicrelease induced by maternal contact which stimulates in these areas the expres-sion of GC receptor mRNA and causes a permanent upregulation of this receptor(Meaney et al., 1996). The authors refer to this chain of physiological events asa form of “environmental programming” that reflects the unique openness of theearly developmental stages to modification by experience.

We have shown that in the low-aggressive line CORT activation was furtherreduced by approximately 50% beyond that induced by handling alone followinggroup housing. In other words, the experience of interacting with other low-aggressive animals consolidated the effects of infantile experience. This findingsuggests that the social ecology that low-aggressive males create for themselves– high frequency of low-intensity social contact, and the apparent absence of arigid dominance hierarchy (see Gariépy, 1994) – may be conditions that favor aconstant flow of serotonin and the expression of GC receptor mRNA in hippo-campal areas. After all, brain receptors are constantly replaced by new ones, and,consequently, mRNA coding for these proteins must be constantly expressed, evenfor maintenance. The absence of further change in this system among group-housed high-aggressive males may not reflect the lack of a receptive substrate,as these animals receive in infancy as much maternal care as do low-aggressivehandled pups. They do, however, constitute for themselves a harsh social ecologycharacterized by frequent conflicts and rigid control of individual action via strictdominance relations, conditions that may inhibit serotonin release.

Further research will be necessary to determine whether the consolidationeffects reported here are mediated via further upregulation of GC receptors orsome other central mechanism, and whether serotonin is the inductive factor.Whatever the exact mechanism, the present results clearly indicate a consolidationeffect on a biobehavioral system whose organization was thought to be fixed byevents taking place in infancy. On this issue, our results demonstrate that criticalsystems supporting adaptive activity remain open to experiential effects throughoutdevelopment, although the pathways for these effects may change over ontogeny(Cairns, 1979). The present case suggests that the stress regulation system, modifi-able early in infancy by maternal care, remains alterable later in ontogeny throughexperience with peers.


Experiment 2: The Reversibility of Line-specific Patterns of Behaviors andHormonal Activation

Throughout the NC selective breeding program, the 45 day-old males in the high-aggressive line that attacked the least in a brief 10 min dyadic encounter after 24days in social isolation were identified and removed from the gene pool of that line(ca. 20% in every generation). In the low-aggressive line the reverse procedure wasconsistently employed. This selective breeding strategy created males in the highline who, when tested under these conditions, respond reactively to novel socialstimulation and attack rapidly and fiercely. The males in low line, by contrast, areless reactive, they rarely initiate attacks and they freeze instead. As long as testingand rearing conditions remain constant these line differences are always observed(Gariépy et al., 1988).

Although the line differences were very robust by the fourth generation, Cairnset al. (1983) showed that repeatedly exposing the low-aggressive animals to dyadictesting at different points in ontogeny caused them to initiate attacks in late adult-hood as rapidly as males of the high line. The same effect was observed in thethirteenth generation, with no indication that continued selective breeding hadchanged the capacity of this experiential input to bring about change in behavi-oral organization (Gariépy et al., 2001). Similarly, placing the males in groups atweaning instead of isolation abolished all the behavioral differences seen betweenthe lines under the conditions used for selective breeding. When group-reared, themales of both lines show little reactivity in a dyadic test, the high-aggressive onesdo not tend to initiate attacks and low-aggressive animals no longer freeze uponsocial contact (Gariépy et al., 1995; see also Experiment 3). Across the severalgenerations of the selective breeding program, this powerful effect has been usedto obtain partner animals who are unreactive in dyadic testing and who have a verylow propensity to attack, so that attack measures can be taken to reflect the truepropensity of the selected subjects.

The present research was conducted to determine whether the same experien-tial effects could take place over intervals of hours instead of weeks and months.Specifically, we tested the hypothesis that previously isolated low-aggressive maleswould attack and that a sizable proportion of them could even achieve full domin-ance over a high-aggressive male, if two conditions were met. The first was toextend the duration of the test to several hours, and the second was to provide aninteractive context that could produce interruptions in otherwise long and sustainedbouts of attack by the high-aggressive partner. To create such a context we intro-duced a female in the test arena, thus transforming the test situation from a dyadicto a triadic one. Only the interactions involving the two males are presented in thisreport.

In previous research, we determined that when exposed to an open field or toanother male behind a wire mesh for 10 minutes, or when social interactions werepermitted to occur, but only for 20 seconds (i.e., prior to the occurrence of any


attacks), the following pattern of activation was observed: Testosterone (TEST)augmented in subjects of both lines across the graded series, but to a greater extentin the high line, and corticosterone (CORT) was higher in the low line, especially astesting conditions became more challenging (Rodriguiz et al., 1998). These differ-ences were deemed very similar to those naturally found in stable groups of animalsbetween their dominant and submissive members (Blanchard et al., 1993; Henry,1992). We hypothesized that the characteristic pattern of activation of these twosteroids ordinarily observed in our selected lines would be reversed among thosepairs of high- and low-aggressive subjects in which the low-aggressive memberwould achieve, by the end of the test, stable and uncontested dominance over hishigh-aggressive partner.

METHODS

Subjects and test conditions. The subjects used in this experiment were 30 high-aggressive and 30 low-aggressive subjects born in the 22nd generation of theselective breeding program. Extended triadic tests involving a NC100 male, aNC900 male, and a female from our unselected line (NC600) were conducted byplacing the three animals in a 24′′ × 24′′ enclosure and letting them free to interactfor six hours. In all tests the males were approximately 72 days of age (+ 4 days)and had been matched so that their weights were roughly the same (± 1.5 grams).All subjects had been kept in social isolation until the time of testing, and hadhad no prior social experience. Social interactions between the three animals werecoded continuously over the first 2 and the last 2 hours of the tests.

Determination of social status. For every pair of high- and low-aggressive subjects,a time point was determined at which dominance relationships were considered tobe clearly established. To this end, a candidate time point was considered whenone of the males responded submissively to the attack of the other (upright boxposture/vocalize, or escape/vocalize). We considered this point as the momentwhen clear status differentials had been achieved, only if for the remainder ofthe test the submitting male was not observed counter-attacking again or initiatingattacks. Statuses were considered contested or unresolved if counterattacks werestill observed by the end of the test, or if the time point identified using these twocriteria occurred in the last hour of the test.

Hormonal concentrations. Immediately upon completion of the test, the two maleswere sacrificed by rapid decapitation, trunk blood was collected and stored at –72 ◦C until assayed for CORT and TEST. The assay techniques have been describedin the preceding experiment.


Figure 2. Effects of line (Left panel: NC100, NC900) and social status (Right panel:Dominant, Submissive) on TEST activation following an extended triadic test. Mean TESTconcentrations (ng ml−1 ± SEM).

RESULTS

Dominance/subordination outcomes. As expected, the NC900 subjects were invari-ably the first to attack in all 30 tests. On average, the first attack occurred within 10min following the introduction of the animals in the test arena (SD = ± 21 min).In all but 2 cases, NC100 males eventually counterattacked, generally within thefirst 2 hours (i.e., 23 subjects). Among those subjects the average latency to coun-terattack was 40 min (SD = ± 33 min). The first counterattack among the fiveremaining NC100 subjects was observed during the last two hours of the test.In these cases, mean latency and standard deviation were not calculated becausethe first counterattack may have occurred during the two-hour window when theanimals were not observed. By the criteria described in the method section, outof 30 pairs of males, 16 NC900 achieved full dominance over the low-aggressivemale. NC100 males achieved the same status in 12 cases. Thus, in the comple-mentary, submissive role, there were 16 NC100 and 12 NC900, respectively. In two


cases, dominance/subordination roles could not be determined by the same criteria,as statuses were still contested by the end of the tests. Thus, under the conditions ofthis extended triadic context, a full 40% of all NC100 subjects (12/16) successfullyachieved dominance over their NC900 opponent.

Hormonal outcomes. TEST concentrations measured after the tests are presentedin Figure 2 as a function of line and social status. As seen on the left panel of thisfigure, no line difference was apparent when measures of this steroid were pooledas function of line. By contrast, pooling these values as function of social status,dominant or submissive, revealed large differences, F(2,26) = 7.50, p < 0.01. Inthis case, average concentrations among the dominant animals were substantiallyhigher than those measured among the submissive subjects. This global pattern wasobserved in every dominant/subordinate pair without exception, irrespective of theline of the animals. For the two cases where statuses were still contested by theend of the tests these values were about the same within pairs, with concentrationsslightly higher than that found among submissive subjects (data not shown). Thesetwo cases suggest that among dominant subjects, concentrations of this hormonebegun rising sometime after the establishment of their status.

CORT concentrations measured following the test are presented in the samemanner in Figure 3. Again, pooling these measures as a function of line (left panel)indicated similar values for NC100 and NC900 subjects. As it did for testosterone,social status strongly affected the concentrations of this steroid, F(1,26) = 21.46,p < 0.001. Mean CORT values were substantially higher among submissive thanamong dominant animals. Inspection of the values measured within the 28 dyadsfor which clear status differentials could be determined revealed no exception tothis pattern. For the pairs of subjects where social statuses were contested themagnitude of the difference among the males was smaller than that measured inthe other dyads, and absolute values hovered between those obtained for dominantand submissive males.

DISCUSSION

Our laboratory produced mouse lines that show large differences in attack behaviorwhen the males are tested under the conditions used for selective breeding. Thisresearch tested the hypothesis that an extended period of interactions involving ahigh- and a low-aggressive male and a female may create conditions under whichNC100 males could exhibit aggressive behavior and even dominate a NC900 male.The fact that NC900 males were, in all 30 tests, the first to attack reflects thepowerful effects of selective breeding. On the other hand, the observation that mostNC100 males eventually counterattacked showed that the main effect of selectionin this line was not to eradicate the capacity to attack but to create animals that donot tend to initiate attacks. It is unlikely that the present results could be explainedby the fact that our subjects were 72 days old instead of the standard 45 days


Figure 3. Effects of line (Left panel: NC100, NC900) and social status (Right panel:Dominant, Submissive) on CORT activation following an extended triadic test. Mean CORTconcentrations (ng ml−1 ± SEM).

in dyadic tests, as the tests conducted at this age regularly yield the largest linedifferences (Gariépy et al., 2001).

Not only did most of the NC100 males eventually counter-attack under thepresent testing conditions, but a substantial number of them even achieved fulldominance over their high-aggressive partner. Since all social interactions werecoded during the first two hours, it was observed that in these cases of line reversal,the initial inhibition/avoidance typical of the low-aggressive subjects was graduallyreplaced by more frequent approaches, and attacks were initiated at a higher ratewhen some of the high-aggressive partners, because they had been counterattackedeffectively (i.e., they had been harmed), decreased their own rate of aggressiveinitiation and became more reactive. We have not yet systematically analyzed therole that the presence of a female in the test arena may have played as a facilitatorof this reversal. The hypothesis was that her initiation of approaches toward themales, as well as the approaches she would elicit, would create a divided focusof attention. This situation, it was reasoned, may constitute for NC100 males a


window of opportunity for achieving dominance by creating delays between attackbouts that would permit recovery and organization of action. Although this was notdirectly tested here, another series of twelve extended tests that only involved thetwo males did not yield a single dominant NC100. At best, two of them were stillcontesting for dominance by the end of the test (unpublished data).

As Cairns (1979) suggested, the social interactive context is a powerful sourceof behavioral regulation that may either serve to consolidate or to reorganize previ-ously established patterns of social adaptation. Here we have seen that the initialresponse of the subjects to the test condition was highly predictable. Behaviors atthe onset of social interactions reflected line-specific propensities, and, as such,were internally regulated. With further interactions, however, new constraints onbehavioral organization emerged, and from this point on, factors external to theorganism acquired fresh regulatory power in behavioral organization. Withoutassuming higher cognitive capacities in these animals, it is reasonable to think that,as the social context departed from its initial configuration, so did the perception ofopportunities, the motivation to attack or flee, in sum, the basis for the organizationof action.

This shift from internal to external regulation caused what in Piagetian termscould be called behavioral “accommodations.” These accommodations were, inthe early phase of behavioral reorganization, externally supported by changes inthe behavior of the other animal. One hypothesis that was central to this work wasthat given their own time-frame for reorganization, changes in critical biologicalsystems would also occur that would provide internal support for the new adaptivedirections (Cairns, 1993). At least partial support was obtained for this view inthe strong correlations observed between social statuses and the patterns of TESTand CORT activation measured by the end of the test. Within every male pair,TEST was high and CORT was low for the dominant member of the dyad with thereversed pattern for the submissive member.

These correlations between social statuses and hormonal concentrations mayseem unremarkable given the abundant reports of similar patterns among dominantand submissive members of natural or laboratory maintained populations ofanimals (e.g., Blanchard et al., 1993; Henry, 1992; Sapolsky, 1990). Recall,however, that the typical hormonal response to novel social stimulation in ouranimals revealed a classic submissive pattern in NC100 and a classic dominantpattern in NC900 (Rodriguiz et al., 1997). Recall also that these line-specificpatterns were observed prior to social interactions, that is, before any status differ-ential could be clearly established. There is no reason to believe that the initialconcentrations of these steroids deviated from this pattern at the onset the triadictests. Given the perfect concordance between steroid concentration levels and thestatus differentials achieved during the tests, its seems reasonable to conclude thatthe twelve cases of behavior reversal seen in the present experiment were accom-panied by a similar reversal in characteristic patterns of hormonal activation. Assuggested by the unresolved cases, these changes would have occurred after the


establishment of status differentials, that is, in support of a new mode of socialadaptation. It is possible to argue that the rise of TEST among the dominant maleswas triggered by the presence of the female and sexual arousal. The fact remains,however, that such a rise was primarily conditioned by the social status achievedby the males.

Experiment 3: Behavioral Accommodations and the Reorganization ofDopaminergic Functions

In the preceeding experiment, we mentioned that group rearing produces males thathave a low propensity to initiate attacks. It has been proposed that the low rates ofattack initiated by these animals may reflect the inhibiting mechanisms acquired inthe social group to achieve and maintain communal living (Brain and Benton, 1983;Siegfried et al., 1981; Vandershuren et al., 1995). Male mice reared in isolation,by contrast, would be deprived of the social conditions that favor the acquisition ofsuch mechanisms. Group-reared and isolation-reared males also differ in anotherimportant respect. Typically, social isolation induces a high propensity to reactstrongly to novel stimuli, a propensity that is greatly reduced among male micereared in groups (Cairns et al., 1985; Gendreau et al., 1997; Valzelli, 1973). Inan interpretation of these behavioral differences, Brain et al. (1989) compared thecharacteristics of the isolated subject to those of the dominant male who isolateshimself from the rest of the colony to defend his exclusive access to a limitedterritory. By prompting rapid attacks, a propensity to react strongly to novel stimulimay be considered an adaptive trait among territorial animals.

Research conducted in our laboratory suggested an important role for thedopaminergic function in the regulation of isolation-induced behaviors. It wasinitially observed that administration of the full efficacy D1 dopamine agonist,dihydrexidine, dose-dependently increased reactivity to the mild social stimulationprovided by the partner mouse (Lewis et al., 1994). In an independent experimentit was demonstrated that administration of D1, but not D2 dopamine receptor antag-onist significantly antagonized the subsequent treatment with dihydrexidine. Takentogether, the results suggested that the reactive response of the isolated subjects ina novel social environment may be mediated at least in part by an increase in thedensity of the D1 dopamine receptor.

A partial test of this hypothesis involved treating isolated and group-housedmice of each line with dihydrexidine prior to a dyadic test, and contrasting theeffects to vehicle treatment. As expected, the drug had no detectable effect onthe social interactions of group reared animals. By contrast, isolated animalsresponded to the same treatment with a marked increase in reactive behaviors(Gariépy et al., 1995). A more direct test of the same hypothesis was the demon-stration in radioligand binding studies that D1 dopamine receptor densities weresignificantly higher among isolated than among group-reared subjects. Densityvalues were virtually the same in the two lines when the subjects were reared in


groups. By contrast, high-aggressive animals reared in isolation had density values20% higher. The slight change (6% increase) observed in the low-aggressive line(Gariépy et al., 1995) was found consistent with the absence of isolation-inducedaggression in this line, and with the fact that across generations the most extremeforms of reactivity, jumping and escaping when mildly stimulated, have beenobserved most exclusively in the high-aggressive line (Gariépy, 1994). The fact thatthis increase was observed in the caudate-putamen complex was consistent with theknown functions of this area as an interface between sensory input and responsesystems (Beninger, 1983). As such this complex was found to be an importantmediator in the initiation of action such as responses to novelty in the environment(Cigrang et al., 1986; Thullier et al., 1997).

By its very nature, most of the research on social isolation consisted in assessingthe effects at some predetermined developmental end-point. Accordingly, less isknown concerning the reversibility of isolation-induced behaviors. In one studydesigned to address this question, Cairns and Sholz (1973) observed that thenumber of attacks directed by isolated animals against an intruder was sharplyreduced after their placement into groups. A similar change was reported by Lager-spetz and Sandnabba (1981) for isolated males which experienced repeated defeatsduring daily exposures to aggressive males. The rapidity of the effects reported inthese experiments is consistent with the view that flexible changes in behavior andphysiology are necessary for continued adaptation under natural conditions of rapidchange in social organization (Blanchard et al., 1993; Cairns, 1993; Mackintosh,1981). To document further these processes, the current research examined someof the behavioral and physiological concomitants of adjustment to conditions ofcommunal living among male mice with a prior history of social isolation.

It was hypothesized that flexible changes in the density of the D1 dopaminereceptor should be observed when situations are created in which social reactivityand dyadic escalation are no longer adaptive. To verify this hypothesis we createdexperimental conditions in which, during a first phase initiated at weaning, high-aggressive (NC900) and low-aggressive (NC100) males were housed individuallyfor 24 days. Then, in a second phase, groups of four animals were formed usinghalf of the subjects while social isolation was maintained for the other half. All testswere conducted 24 days later. It was expected that forming groups of previouslyisolated animals would reduce isolation-induced reactivity in a dyadic encounterwhere it would also attenuate the effects of a dihydrexidine treatment. A corollaryof this hypothesis was that previously isolated animals living in groups wouldexhibit a significant reduction of D1 dopamine receptor densities as compared tosubjects continuously kept in social isolation.

METHODS

Subjects, rearing, and testing conditions. When the progeny of the 27th generationreached the age of 21 days, 102 males from each line were separated from their


litter of origin and housed in isolation for the next 24 days. At this point, 60 ofthe 45 day-old subjects were used to form 15 groups, each composed of 4 same-age males. The remaining 42 animals were left undisturbed in their home cages. Allsubjects were kept in their respective conditions – isolation-to-group, or continuousisolation for an additional 24 days before testing began on day 69. Social conditionsamong the communally living subjects were assessed daily until testing. In mostgroups, fighting declined sharply after the first half hour and eventually approachedthe low levels observed among animals reared in groups since weaning. In somegroups, higher frequencies of attacks were maintained for longer periods, creatingdifficult conditions for the animals. Five groups were removed from the study forthis reason.

At age 69 days, all subjects were randomly assigned to one of three experi-mental conditions. Those assigned to the first condition served as vehicle injectedcontrols (VEH) in a dyadic test (see Gariépy et al., 1988 for a full description ofthe procedures). In the second condition, they were injected (SC) with 10 mg/kg ofdihydrexidine (DHX) prior to a dyadic test. This dose was determined on the basisof a previous experiment where it has been shown to induce high levels of socialreactivity without disturbing activity rates or inducing stereotypies (Lewis et al.,1994). Finally, animals in the third condition were sacrificed without testing andstriatal tissue was removed for receptor study.

Treatment of behavioral data. For the present purposes, only measures of socialreactivity observed in the dyadic test are reported. This reactivity is expressed asa tendency to react strongly to the mild social stimulation provided by the partneranimal (i.e., startle, kicking, jumping or escaping; see Gariépy et al., 1998 for defin-itions). The frequency of these behaviors was calculated over the first two minutesof interactions or before the initiation of an agonistic action (e.g., feint, bite, chase,attack) by one of the animals. Thus rates per minute of preagonistic reactivity werecalculated to permit comparisons across test sessions and to disentangle rearingand drug effects from agonistic effects. In the following analyses, two categoriesof social reactivity were distinguished on the basis of factor analysis – stationaryreactivity, which included the sum of startles and kicks, and locomotor reactivity,the sum of escapes and jumps. In the first case, the reactive subject maintains itsproximity to the partner mouse, while in the second, a rapid distance is taken fromthe other animal (Gendreau et al., 1997).

D1 Dopamine receptor binding. The subjects assigned to receptor binding studywere sacrificed by decapitation at day 69 without being exposed to a social inter-action test. Their brains were rapidly removed, frozen on powdered dry ice withcare taken to avoid compression of the dorsal or ventral surface, and stored at –80 ◦C until assayed. Estimates of the relative affinity (KD) and density (Bmax) ofD1 dopamine receptor sites in the corpus striatum (caudate nucleus and putamen)were determined using Scatchard analyses of saturation isotherms generated from


Figure 4. Effects of rearing conditions (continuous isolation, isolation-to-group) on dihydrex-idine (DHX; 10 mg/kg) – induced increases in stationary reactivity in mice selectively bredfor high (NC900) and low (NC100) levels of aggression.

radioligand studies. Using three to four nonlittermates from each line per assay,three Scatchard plots were generated for each condition in the low-aggressive lineand five per condition in the high-aggressive line (See Gariépy et al., 1998 forfurther details).

RESULTS

Effects of rearing experience on dihydrexidine-induced reactivity. The frequenciesof social reactivity observed under the specified conditions of rearing and drugtreatment closely matched those reported in a similar study conducted by Gariépyet al. (1995). The effects of rearing conditions and drug treatment on stationaryreactivity are presented in Figure 4. As observed in a number of generations, thisform of reactivity occurred at a higher rate in the current low-aggressive line,F(1,75) = 10.95, p < 0.01. Overall, stationary reactivity was significantly higheramong singly caged animals, F(1,75) = 10.95, p < 0.01, and was independentlyincreased in both lines by dihydrexidine, F(1,75) = 15.50, p < 0.001. The strong3-way interaction indicated that the effects of rearing conditions on dihydrexidine-induced reactivity were line specific, F(1,75) = 7.86, p < 0.01. In the tests involvingNC100 mice, the drug induced high levels of stationary reactivity among the isol-ated subjects, and had no detectable effect on those reared in groups. In NC900,this form of reactivity was globally low and rearing conditions did not affect theresponse to a dihydrexidine treatment.


Figure 5. Effects of rearing conditions (continuous isolation, isolation-to-group) on dihydrex-idine (DHX; 10 mg/kg) – induced increases in locomotor reactivity in mice selectively bredfor high (NC900) and low (NC100) levels of aggression.

As shown in Figure 5, locomotor reactivity was not expressed among isolatedsubjects of either line when treated with vehicle. The S28 generation was one of thefew where this form of reactivity was not observed in the dyadic tests involvingisolated animals. However, dihydrexidine induced relatively high levels of loco-motor reactivity, F(1,75) = 6.37, p < 0.05, generally within the first 30 sec ofthe test. Among NC100 mice, the drug induced comparable levels of locomotorreactivity in both rearing conditions. In NC900, by contrast, the drug potentiatedhigh levels of escapes and jumps among isolated subjects and had no detectableeffect in the isolation-to group condition. A separate analysis of variance conductedfor the NC900 line revealed a marginal drug by rearing interaction, F(1,33) = 2.72,p = 0.10.

Effects of rearing experience on dopamine receptor function. It was hypothesizedthat the differential effects of dihydrexidine in the continuous isolation and theisolation-to-group conditions would be reflected in correlated differences in D1

dopamine receptor densities. This hypothesis was directional in that lower densitieswere expected among animals in the isolation-to-group condition relative to thosekept in continuous isolation. The average densities measured across independentScatchard analyses conducted for each line and each rearing history are presentedin Table I. As predicted, continuously isolated animals of both lines had higherD1 dopamine receptor densities than those who experienced group housing afteran initial period of isolation. Among NC100 mice, the mean decrease in density


Table I. Comparison of striata/D1 dopamine receptor function between the continuous isolationand the isolation-to-group conditions as a function of line

NC100 NC900

Cont. isol Isol.-to-group Cont. isol Isol.-to-group

BMax KD BMax KD % Decr. BMax KD BMax KD % Decr.

Mean∗ 99.7 0.28 79.2 0.32 20.6% 104.2 0.29 70.7 0.30 32.0%

SEM 1.6 0.01 7.4 0.03 10.3 0.01 10.0 0.02

Average of three Scatchard analyses per housing condition in NC100 and five Scatchard analysesper condition in NC900.

was 20.6%, t(4) = 2.70, p < 0.05 (one tailed), and was as large as 32.1% amongNC900 mice, t(8) = 2.33, p < 0.05 (one-tailed). The density values obtained inthe continuous isolation condition were virtually the same for the two lines. Asexpected, no effect of selected line or rearing condition was found for affinity. Thisis reflected in the narrow range of variation obtained for the mean Kd values (0.28to 0.32) presented in Table I.

DISCUSSION

In a previous study, it was demonstrated that the high rates of social reactivityexhibited by isolated male mice in a dyadic test are mediated, at least in part,by an increased sensitivity of D1 dopamine receptors (Lewis et al., 1994). Thepresent research was guided by the hypothesis that the behavioral effects of isol-ation are reversible, and that flexible changes in dopaminergic function supportthis reversibility. Specifically, it was expected that forming groups of previouslyisolated animals would reduce isolation-induced behaviors, attenuate the effects ofdihydrexidine treatment in a dyadic encounter, and reduce striatal densities of theD1 dopamine receptors.

As expected, rates of locomotor reactivity were reduced in the dyadic testsinvolving high-aggressive animals of the isolation-to-group condition. In the low-aggressive line, a similar effect was obtained for stationary reactivity. Theseobservations are consistent with those made by Cairns and Sholz (1973) in acomparable experiment, and provided further confirmation that the behavioraleffects of isolation are reversible. The same reversibility was observed in theresponse to dihydrexidine treatment. The drug potentiated relatively high rates ofsocial reactivity among animals kept in continuous isolation but had no detect-able effects in the isolation-to-group condition. Finally, homogenate binding datasupported the hypothesis that the reversibility of isolation effects is mediated, atleast in part, by a reduction of striatal D1 dopamine receptor densities. In spiteof their prolonged experience of isolation, isolation-to-group subjects had density


values on day 69 as low as those previously measured for 45 day-old subjectswhose only experience had been group living (Gariépy et al., 1995).

This experiment provided evidence for the plasticity of the neurobiologicalsystem supporting reactive responses and confirmed the view that its functionalorganization is open to experiential input. Given that fluctuations occur naturallyin population densities and social conditions during the life time of individualanimals, it is difficult to think that the dopaminergic function could be crystallizedby early experience. In the present case, adult animals were challenged to adjustto social conditions for which they were behaviorally and biologically unprepared.Following Brain’s (1989) analysis, upon their entry into groups, the previouslyisolated high-aggressive subjects carried with them the behavioral characteristicsof an established territory holder and a corresponding tendency to respond aggress-ively to the presence of conspecifics. Our observations of the previously isolatedanimals showed that social interactions during the first half hour of group formationwere characteristically intense and that reactive responses and attacks predomin-ated. However, these behaviors progressively vanished when one of the membersestablished its dominance over the other males. As the new social order precludedthe expression of reactive behaviors, these responses became less frequent and weregradually replaced by the less provocative and more submissive upright posture.

Studies in which subjects are removed from the testing conditions at parametricintervals would be necessary to determine a precise time frame for the consolid-ation of new behavioral patterns via attenuated dopaminergic functions. On thebasis of the extended test described previously, we have reasons to think that inthe early stage, behavioral reorganization in the present experiment was supportedin part by rapid endocrinological changes. Accordingly, we can speculate thatit is the relative stability of the relationships established in the groups and themaintenance of the related endocrinological states that set the stage for the eventualchange in dopaminergic functions. In this scenario, receptor downregulation wouldoccur as a result of the bidirectional influences between the neurochemistry of thedopaminergic system and a neurological environment altered by a new pattern ofendocrinological activity (Brown, 1994). Parallel comparisons with animals whofail to show the plasticity to adjust to new living conditions, as those involved inthe groups where communal living had to be interrupted (see methods) would alsobe informative. Research on these processes should further our understanding ofhow, within their own time frame for reorganization, different biological systemsbecome functionally aligned with behavioral accommodations to enduring changesin social conditions.

Concluding Comments

The task of the behavioral neurosciences, in the broadest sense, is to explain whyorganisms behave the way they do. Following the evolutionary synthesis, this ques-tion has been addressed from the standpoint of both ultimate (evolutionary) and


proximate (developmental) causation (Mayr, 1964). In both cases the goal is toexplain how a set of antecedent events or conditions may explain some presentend-state in biobehavioral organization. While these two approaches may providesatisfactory explanations for the establishment of individual differences at somepredefined end point in development, they typically bypass questions of mainte-nance and reorganization over ontogeny. We think that there are two major reasonsfor the relative neglect of these two phenomena of development. The first, is theadoption of an epistemological framework that forces upon the life scientist anagenda – the search for cause-effect relationships – borrowed from the physicalsciences. This framework, although a necessary one for the conduct of any science,has encouraged in developmental research a tradition that consists in looking forantecedent conditions that produce and preserve individual differences in biobeha-vioral organization. The second reason for this neglect is that it is, indeed, possibleto demonstrate the existence of such simple cause-effect relationships, and therebyto “explain” development.

The conceptual framework that inspired conducting the three experimentsreported in this article places a special emphasis on the role that organismic activityplays at the interface between intra-and extra-organismic systems. This emphasisis directly related to the notion that living organisms are open system and thateven for maintenance it is necessary to assure a constant throughput of energyextracted from the environment. In this respect, we concur with Baldwin that inthe most general sense, the goal of adaptive behavior is to establish or maintainconditions (by acting and transforming the environment) that favor the recurrenceof vital stimulation (Baldwin, 1894; see also Piaget, 1967). Accordingly, systemswithin and systems without tend to become correlated over time. That is, theorganizational features of the two systems become co-dependent and mutuallysupportive. To illustrate, Cairns et al. (1993) wrote: “It should not be surprisingto find hot-tempered, impulsive children growing up with family members whothemselves exhibit and reward these traits, or subcultures of aggressive adoles-cents in which aggressive behavior is viewed as an asset rather than a liability. Inmost accommodations, nature and nurture collaborate rather than compete. Morebroadly, social systems are usually formed in ways that are correlated with andsupport bio-behavioral dispositions.”

One advantage of this conceptual framework is its capacity to explain bothcontinuity and change in development. Organismic activity is, in a sense, extremelyconservative as its seeks to maintain and consolidate already established functionalrelationships with a structured environment. Given that this tendency is observ-able over both evolution and development (Gerhart and Kirschner, 1997) it is notsurprising that organisms that share a common genetic background behave in asimilar way, or that early developmental events predict later biobehavioral adapta-tion. The two factors, genetic makeup and early stimulation, acquire their predictivepower only to the extent that there is continuity in the relationships established withan environment that both supports and validates these adaptations, over evolution


in the first case and over development, in the second. When circumstances arise,however, that compromise the functionality of established organism-environmentrelationships, organismic activity naturally seeks to establish new ones. A strictfocus on continuity in development, on the predictive value of antecedent factors,be they genetic, neurohormonal, or having to do with the effects of early stim-ulation, miss on this dynamic aspect of the process of adaptation. By creatingsocial-ecological conditions that were uncorrelated with those which over genera-tions and development served to establish the biobehavioral characteristics of ouranimals selectively bred for high and low aggression, our goal what to highlightthis dynamic aspect of the adaptive process. Together, these experiments suggestthat the study of continuity and change through time begins with an analysis of thebehavioral accommodations observed in the short-term, along with appropriatelytime-framed analyses of the supportive changes taking place in the other systemsof the organism and the environment.

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Issues of Establishment, Consolidation, and Reorganization in Biobehavioral Adaptation

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