Environmental enrichment in male CD-1 mice promotes aggressive behaviors and elevated corticosterone and brain norepinephrine activity in response to a mild stressor

Housing rodents in an enriched environment (EE) has been typically considered to have positive effects on well-being and cognitive functioning of the animals. However, in some strains of mice, EEs have also been reported to elicit aggression and to promote stress-related outcomes. In the current investigation, we examined whether environmental enrichment would elicit aggression among CD-1 male mice and thus sensitize responses to a subsequent mild stressor. It was first observed that mice housed in an EE for 2 weeks displayed more aggressive behaviors than did mice that had been housed in a standard environment (SE). In the second experiment, it was noted that after 4 weeks of EE or SE housing, mice exhibited comparable plasma corticosterone concentrations as well as levels of brain norepinephrine and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the absence of a challenge. However, upon exposure to mild stressor (placement in a novel cage), relative to their SE counterparts, EE mice were more active and displayed higher plasma corticosterone concentrations and enhanced MHPG accumulation in the prefrontal cortex and hippocampus. It seems that enrichment in male CD-1 mice promotes aggression, and may sensitize biological processes, possibly increasing vulnerability to stressor-related outcomes.     

Differential effect of handling on adult aggression in male mice bidirectionally selected for attack latency

Individual variation in intermale aggression is to a significant degree based upon genetic variation, but environmental factors can also exert their influence on the level of aggression. Moreover, genotype–environment interactions are a well‐known phenomenon. In the present experiment, I tested whether cage size or handling during development had an influence on adult attack latency scores. To be able to study a genotype–environment interaction, mice from two bidirectionally on attack latency selected lines were used. The size of the cage in which the mice grew up had no long‐term effect on aggression, neither in the high‐ nor in the low‐aggressive line. Handling, however, significantly increased the adult aggression of males from the low‐aggressive line. Despite the differential effect of handling on genetically high‐ and low‐aggressive mice, handling was not able to undo the marked differences in attack latencies between mice from both lines. Aggr. Behav. 25:365–368, 1999. © 1999 Wiley‐Liss, Inc.     

Effects of environmental enrichment on spatial memory and neurochemistry in middle-aged mice

The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enriching objects. After the enrichment period, all mice were tested in a 1-day version of the Morris water maze, in which both spatial and nonspatial memory were assessed. Immediately after testing, the hippocampus and frontoparietal cortex were dissected, and GAD activity and synaptophysin levels were measured. Environmental enrichment reduced the age-related impairment in spatial acquisition and retention; relative to adult social controls, middle-aged enriched mice were unimpaired, whereas middle-aged social controls were impaired. This reduction was similar in middle-aged males and females. Enrichment did not affect cued memory in either sex. Although hippocampal GAD activity was increased by enrichment in males, all other neurochemical measurements were unaffected by enrichment or aging in either sex. These data suggest that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown.     

Subordinate male mice show long-lasting differences in spatial learning that persist when housed alone

In the wild, house mice live in social groups, whereas in the laboratory male mice are often singly housed. Environmental enrichment such as that provided by social housing has been argued to improve the cognitive performance of laboratory animals in experimental tests. The aim of the present study was to test the cost of aggressive social interactions on learning in male CD-1 mice. We found that subordinate mice from more aggressive dyads showed spatial learning impairment, measured as alternation on a T-maze. Learning impairments in subordinates have hitherto been presumed attributable to the animals' exposure to, and relative standing within, the social group. By contrast, the impairment we observed could not have been the result of recent social defeat because it persisted weeks later when the mice were housed alone. Elevated urinary corticosterone predicted later subordination, though paradoxically these abnormally high levels were reduced by pair housing.     

Opposite strain-dependent differences for intermale aggressive behavior elicited by individual housing and housing with a female in the mouse

Male mice of the C57BL/6 strain show a significant increase in aggression toward a nonaggressive male conspecific following 72 hr of individual housing. However, this increase was no longer evident following 2 weeks of individual housing. When housed with a female, C57BL/6 mice show significantly more aggression than singly housed mice of the same strain after 72 hr as well as 2, 4, 8 weeks of differential housing. Male C57BL/6 mice housed with a female also show significantly higher levels of aggression than DBA/2 mice living in the same housing condition after 4 or 8 weeks of differential housing. Finally, male DBA/2 mice individually housed for 8 weeks are significantly more aggressive than mice of the same strain housed with a female for the same time. These results indicate that the increase in aggressive behavior observed following isolation and cohabitation with a female in the mouse is not the same phenomenon. © 1994 Wiley-Liss, Inc.     

Comparison between BALB/cJ and BALB/cByJ mice in tests of social behavior and resident-intruder aggression

The behavior of male mice from two BALB strains, the BALB/cJ strain and the BALB/cByJ strain, was examined with a social behavior test and a resident-intruder paradigm. Prior to testing, the animals were isolated for 0, 2, 5, or 10 days. In the social behavior test the pairs of BALB/cJ mice spent more time in active social interaction than pairs of BALB/cByJ mice, although the latter strain showed more locomotor activity. BALB/cJ mice isolated for 5–10 days, when tested in a familiar environment were more aggressive than mice from the BALB/cByJ strain. In the resident-intruder paradigm, in which a resident BALB mouse was confronted with an intruder NIH Swiss mouse, the BALB/cByJ mice showed more social investigation in their home cage towards the intruders, but there were no significant differences between the two strains in the amounts of aggressive behavior exhibited. The results of these experiments suggest that there are some differences in the social behavior of the genetically related BALB/cJ and BALB/cByJ mice. However, the differences appear subtle and paradigm-specific.     

The Effect of Stress on Spontaneous Nest Leaving Behavior in the Mouse: An Improved Model of Stress-Induced Behavioral Pathology

The present experiments were conducted to develop a more sensitive and reliable model of stress-induced behavioral pathology in the mouse. Male mice were housed singly in nest cages connected to either a circular tunnel, a recreational cage or a large box with food foraging apparatus. Spontaneous nocturnal out of nest activity or food foraging behavior in these environments was continuously monitored for a two week period during which time the effects of stress were examined. It was found that both repeated restraint and aggression stress markedly and persistently reduced out of nest nocturnal activity or food foraging behavior in all 3 environments but did not alter activity in a novel open field or plus maze or food or saccharin intake in the nest cage. In a preliminary experiment the reduction in out of nest activity by stress was attenuated by prior chronic treatment with the antidepressant, desmethylimipramine. Plasma corticosterone was elevated immediately after aggression stress but reduced 5 hr after chronic aggression stress. The reduction in activity did not appear the result of increased anxiety as measured by spontaneous risk assessment behavior in the nest. It is concluded that the decrease in out of nest activity after stress in the present studies models a withdrawn behavioral state and may be due to either or both a decrease in appetitive motivation to leave the nest or an increased aversion to the external environment which does not apparently involve anxiety.     

Aggressive behavior in inbred strains of mice during pregnancy

Female aggressive behavior toward adult male ICR/JCl mice was compared for virgin and pregnant mice of five inbred strains (BALB/c, C3H/He, C57BL/6, DBA/2J, and AKR/J). Pregnant females from four strains except BALB exhibited intense aggressive behavior, whereas only virgin AKR females were aggressive. Aggressive behavior began in early pregnancy, was highest in midpregnancy, and declined slightly thereafter until the day of parturition. The level of aggressive behavior showed significant strain differences. The topography of aggressive behavior was also different among the four strains. DBA females showed marked contrast with the other three strains in the temporal changes of aggression in the first phase of encounter. Furthermore, strain specific behavioral pattern of aggression was demonstrated based on six behavioral acts ( Darting , Chasing, Attack, Biting, Wrestling, and Boxing). Virgin and pregnant AKR females showed the identical behavioral pattern of aggression.     

High maternal aggression in dwarf hamsters (Phodopus campbelli and P. sungorus)

The defense of offspring, termed maternal aggression, is a highly conserved behavior in mammals, including rodents. This study examined relative levels of maternal aggression in two closely related dwarf hamster species, Phodopus campbelli and P. sungorus, that normally inhabit high latitude, boreal environments. When tested with first litters and with the breeder male remaining with the female (for P. campbelli the male is necessary for successful rearing of offspring), both species exhibited high levels of maternal aggression with average duration of aggressive behavior>80 sec for a 10 min test. For P. sungorus, males are not required to rear offspring. P. sungorus females with either one or multiple litters (singly housed after impregnation) exhibited significantly higher levels of aggression (>300 sec) relative to females co‐housed with the sires. In terms of species differences in attack style, P. campbelli exhibited a boxing or clawing strategy for ～50% of total attack time, but for P. sungorus, this form of attack occurred<5% of the time. For P. sungorus, attacks to the vulnerable belly and flank constituted>90% of all attacks, but these regions were attacked ～50% of the time for P. campbelli. A survey of levels of maternal aggression of rodents in other genera suggests that maternal aggression in Phodopus is at the high end of the spectrum. Results of this study suggest that the presence of the breeder male may actually suppress aggression in P. sungorus. This fact, as well as its high level of aggression and its distant relationship to mice and rats, suggest P. sungorus as a possible model for future studies on the neurobiological basis of maternal aggression. The relationship between the high rates of maternal aggression and life history strategy in Phodopus is discussed. Aggr. Behav. 00:000–000, 2005. © 2005 Wiley‐Liss, Inc.     

Repeated tests of intermale aggression in mice (Mus musculus) are influenced by housing and test conditions

Young adult male Binghamton Heterogenous (HET) mice were housed either individually or in groups of four, in two-tiered cages for 11 days before their agonistic behavior was observed. Pairs of male mice were tested 3 min each day for 9 consecutive days. Agonistic behavior was observed in two-tiered cages in which there were either clean pine shavings or shavings soiled by young adult female HET mice. Housing and shaving conditions interactively influenced aggression observed over the course of testing. That is, when individually housed mice were tested with clean shavings and when group-housed mice were tested with female-soiled shavings, agonistic behavior decreased over days, but when isolated mice were tested in soiled shavings and when group-housed mice were tested in clean shavings, aggression increased over the course of the 9-day test period.     

Effects of acute administration of nicotine and lobeline on agonistic encounters in male mice

The effects of acute administration of two nicotinic ligands, (‐)‐nicotine and (‐)‐lobeline were examined on isolation‐induced aggression in mice. Individually housed male mice confronted anosmic “standard opponents” in a neutral arena 10 min after drug administration. Encounters were videotaped and evaluated using an ethologically based analysis facilitating estimation of time allocated to 11 broad behavioral categories. Nicotine did not have significant effects on threat or attack but significantly diminished time allocated to digging. The lowest dose of lobeline significantly diminished attack and induced a slight increase of immobility without significantly diminishing other behaviors with motor components. The intermediate and highest dose of lobeline reduced time allocated to all behaviors with motor components. It is concluded that these two nicotinic agonists produce different behavioral profiles during agonistic encounters in mice but that this test may not facilitate assessing the impact of such drugs on irritability. Aggr. Behav. 26:376–385, 2000. © 2000 Wiley‐Liss, Inc.     

Maternal aggression toward infanticidal males of different social status in wild house mice (Mus musculus domesticus)

Maternal aggression was examined in wild female mice (Mus musculus domesticus) derived from animals trapped in Alberta, Canada. Lactating females were tested for their behavior toward intruder males during the time of postpartum estrus while housed in a two-cage apparatus containing a defensible nest area. Prior to being used as intruders, sexually naive males were screened for their behavior toward a newborn pup (83% exhibited infanticide). Only infanticidal males were then housed in pairs and allowed to establish a dominance hierarchy. Dominance status was further verified by a urine marking test. The dominant and subordinate infanticidal males were then placed into a lactating female's cage and observed for 1 hr. The test was terminated immediately when a male began to attack the pups. Lactating females attacked the males in both groups, but subordinate males received more intense attacks than dominant males. Dominant males elicited significantly more fear/defense behavior than subordinate intruders. All of the dominant males and only one submissive male attacked the pups. Females were thus successful in blocking infanticide only by infanticidal subordinate males. Since females do not persist in attacking males with high fighting ability, one function of maternal aggression could be to assess the fighting, and resource holding, potential of a future mate. © 1994 Wiley-Liss, Inc.     

Some adrenal correlates of aggression in isolated female mice

Forty-six female mice (CFW) were isolated for a period of 23 weeks. The effect of isolation on fighting behavior was tested weekly by introducing a naive brown female mouse into the subject's home cage. Total leucocyte counts were obtained at 8 and 14 weeks of isolation. The appearance of leucopenia was used as an index of elevated adrenocortical activity. After 23 weeks of isolation all animals were sacrificed by decapitation. Plasma was collected for corticosterone assay, and paired adrenals were used to assay catecholamine levels. On the basis of the frequency and/or the absence of fighting, the mice were segregated into fighters (n = 22) and non-fighters (n = 17). Analysis of the data by Pearson's product moment correlation and Student's t-test showed that elevated sympathetic-adrenal activity was positively correlated with aggression and that elevated adrenocortical activity was negatively correlated with aggression.     

Are there preexisting behavioral characteristics that predict the dominant status of male NIH Swiss mice (Mus musculus)?

The behavior of isolated Cr:NIH(S) mice (Mus musculus) was studied in a holeboard test of exploration, in a plus-maze test of anxiety, in the resident-intruder paradigm of aggression, and in the swim test. Thereafter, mice that were matched for body weight were housed together in groups of 4-5. Within a week, 1 mouse per cage (the alpha) had attacked all its subordinate cagemates but lacked any signs of attack itself. Subordinate mice had bite marks on their tails and backs. When mice were isolated, no differences were found between the behavior of those that later became alphas and those that became subordinates. In contrast, after the establishment of the social hierarchy, alpha mice spent less time immobile in the swim test and had higher locomotor activities than did the subordinate mice. The results suggest that the differences in behavior between the alpha and subordinate mice result from aggressive social interactions in the home cage.     

Gender-specific social experiences and the development of aggressive and sexual behavior in male mice

This study examined influences of gender-specific social experiences on the development of aggressive and sexual behavior in male mice. To determine the effects of gender-specific social experience three different types of groups were constituted after the animals had been weaned. The subjects were randomly assigned to different treatments. Female groups were composed of one experimental male and three female cohabitants. Male groups were composed of five experimental males each, and the mixed-sex groups were composed of two experimental males and of two females. The experimental subjects stayed in these groups until the age of approximately three months, when the testing for sexual and aggressive behavior commenced. For the sexuality tests, a receptive female was placed in the home cage of the experimental male for ten minutes. A nonaggressive male was placed in the home cage of the experimental male for seven minutes for the aggression tests. The experimental males were administered both sexuality and aggression tests, the sequence of testing sexual and aggressive behavior was systematically varied in order to control the influence of the two different types of behavioral tests. The results showed that males with only male social experiences showed fewer responses and were less active in both the aggression and sexuality tests than the males from the two other types of groups. Significant positive correlations between activity during aggression and sexual tests were obtained for all three groups. © 1994 Wiley-Liss, Inc.     

Effect of MAO A deficiency on different kinds of aggression and social investigation in mice

Monoamine oxidase A (MAO A) degrades serotonin, dopamine and noradrenaline, factors critically involved in the regulation of aggression. Different kinds of aggression were investigated in Tg8, a transgenic mouse strain lacking a functional MAO A gene. MAO A-deficient mice differ from wild-type C3H/HeJ (C3H) in terms of showing higher territorial, predatory and isolation-induced aggression. Tg8 demonstrated shorter latencies to cricket killing and to the first attack after 6 weeks isolation than C3H mice. In the resident-intruder paradigm, MAO A-lacking mice were more aggressive than C3H when tested as intruders. In contrast to C3H, attack in Tg8 mice did not depend on different aggressiveness of intruders of BALB/c, A/Sn and C3H strains. Tg8 mice displayed no increase in aggression but demonstrated reduced social investigation towards anesthetized, as well as towards juvenile BALB/c males. Thus, MAO A deficiency in Tg8 mice is accompanied by increased expression of different kinds of aggression, as well as by disruption of normal pattern of social interaction.     

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2?h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, na?ve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33?mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.     

Does fear modulate defensive and offensive types of maternal attack in mice?

Swiss CD‐1 lactating mice show a different pattern of attack toward intruders of differing sex, displaying defensive attack against the male (bites on the head and ventrum associated with fear) and offensive attack against the female (bites on the back and flanks with no elicitation of fear). This dichotomy may reflect diverse functions of maternal aggression: the attack toward males (the more infanticidal gender in laboratory strains) has been interpreted as a counterstrategy to infanticide, whereas the attack toward females may serve to establish a social hierarchy or to space rivals of the same sex. In terms of proximal mechanisms, fear may be a key factor involved in the modulation of the different patterns of attack. In Experiment 1 we compared the pattern of attack of lactating females in Swiss CD‐1 and Wild mice toward male and female intruders in relation to fear components of behavior of the attacking dams. Results showed that in Swiss mice, male intruders were attacked with a defensive type of attack accompanied by high levels of fear, whereas female intruders did not elicit fear in the attacking animal but were attacked with an offensive pattern. In Wild mice, both types of intruders were attacked with a defensive pattern; notwithstanding, fear was evident only toward male intruders. This suggests that fear is not totally responsible for the expression of the defensive type of attack. To test the hypothesis that defensive attack toward male and female intruders may be related to the infanticidal potential of the intruder, Experiment 2 examined levels of infanticide in both male and female Swiss CD‐1 and Wild mice. Swiss female mice showed virtually no infanticidal behavior, whereas Swiss males and both sexes of Wild mice showed similarly high levels of infanticide (55%–75%). From a game theory perspective, the defensive pattern of maternal attack toward female intruders in Wild mice is discussed as “extreme” defense of a high value resource and thus, functionally, a competitive form of aggression. Aggr. Behav. 26:193–203, 2000. © 2000 Wiley‐Liss, Inc.     

Genetic analysis of “Spontaneous” intermale aggression in mice

“Spontaneous” intermale aggression was investigated in seven inbred strains of mice. A positive interstrain correlation and cross-correlation was found for two indices of fighting intensity, ie, accumulated attacking time and number of attacks. The strain aggressiveness level (percent of mice fighting in each strain) does not correlate with the intensity of aggressive behavior. It has been shown by using a genetical analysis performed on C57BL/6 and BALB/c strains, their reciprocal F₁ hybrids, and back-crosses that these indices of intermale aggression are under different genetic control. Aggressive behavior intensity depends on the additive effects of genes. The control of strain aggressiveness level revealed that a high level of aggressiveness was dominant. No reciprocal effects were found. The level of aggressiveness and the intensity of fighting seem to represent different aspects of aggression and may be controlled by different genetic mechanisms.     

Inseminated female mice (Mus musculus) investigate rather than avoid novel males that disrupt pregnancy, but sires protect pregnancy

Experiment 1 replicated the Bruce effect, showing pregnancy termination in CF1 strain female mice (Mus musculus) housed underneath novel heterogeneous strain (HS) males. In a 4-arm maze in Experiment 2, inseminated CF1 females approached novel HS males more often than CF1 sires or unfamiliar CF1 males. In Experiment 3, inseminated females showed random nesting sites when housed continuously underneath 4 compartments containing the sire, a novel CF1 male, a novel HS male, and no stimulus. In Experiment 4, when inseminated females were housed with or without the sire below novel HS males, the sire's presence decreased female interaction with novel males and mitigated the Bruce effect. Inseminated females do not reliably avoid males that disturb pregnancy unless the sire is immediately present.