Genotype modulates prenatal stress effects on aggression in male and female mice

Prenatal stress (heat and restraint) significantly increased postpartum aggression (proportion of animals fighting and/or the intensity of the behavior) in C57BL/6J female mice and reduced the behavior in DBA/2J females. For intermale aggression, prenatal stress increased the behavior (intensity of aggression) in C57BL/6J males but did not affect aggressive behavior in DBA/2J animals. Infanticidal behavior (the killing of young) exhibited by male mice was not influenced by prenatal stress in either strain. Relative anogenital distance measurements in neonates at birth did not serve as a reliable predictor of strain variation in prenatal stress effects. Prenatal stress did not influence this measure of prenatal androgen exposure in DBA/2J or C57BL/6J females. For males, prenatal stress elevated relative anogenital distance in C57BL/6J mice and decreased this measure in DBA/2J animals. Prenatal stress effects on aggressive behavior in male and female mice therefore depend upon genotype. Strain-dependent differences may be modulated by differences in endocrine reactivity to prenatal stress/and or differential central neural tissue sensitivity to hormones.     

The Y chromosome, social signals, and offense in mice

Offense is one type of aggression in mice (Mus musculus/Mus domesticus). Offense was measured in a panel of testers design for two congenic strains of mice. The two congenic strains were DBA1Bg and DBA1. C57BL10-YBg. These differ in the Y chromosome. Offense was measured for the following dyadic pairs: Group 1 (DBA1 tested against a DBA1 opponent); Group 2 (DBA1 tested against a DBA1.C57BL10-Y opponent); Group 3 (DBA1.C57BL10-Y tested against a DBA1.C57BL10-Y opponent); and Group 4 (DBA1.C57BL10-Y tested against a DBA1 opponent). Group 1 was more aggressive than Group 3, whereas Group 2 was no more aggressive than Group 4. Thus, when the experimental and opponent pairs have the same Y chromosome, the congenics differ in offense, whereas when the experimental and opponent pairs have different Y chromosomes, the congenics do not differ in offense. These findings are consistent with the hypothesis that these Y chromosomes affect the display of and response to social or other stimuli for offense of mice. These stimuli may be individual recognition chemosignals in urine.     

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.     

Sex differences in aggressive behaviour in various strains of mice

Two nonalbino inbred (C57 BL/6 and C3H/He) and one albino strain (Swiss) of mice were compared for female aggression toward intruders: 1 in period of lactation, 2 in nonlactating state and (3) in nonlactating state but previously rubbed with urine of lactating females; and for male aggression toward familiar or unfamiliar opponents. The results showed that resident females of the C57 and Swiss strain vigorously attack lactating intruders introduced into their cages. This effect was mediated by urinary cues emitted by the latter mice. It was also shown that Swiss residents displayed aggression towards nonlactating females, irrespective of their strain. Groups of C57 residents reacted most aggressively towards Swiss females, less aggressively towards C3H intruders, but did not show any aggression towards their own nonlactating conspecifics. In contrast, none of the C3H resident female groups displayed aggression towards intruding females of any category or strain. The results also showed that the males of the three strains displayed little (Swiss and C3H) or no aggression (C57) towards familiar opponents, whereas they directed increased aggressive responses towards unfamiliar ones. Comparisons among the three strains of mice revealed that Swiss males were the most aggressive in either situation. On the other hand, the finding that C3H males showed aggressive responses suggested that male and female aggression are, in this strain, under separate genetic or hormonal control.     

Strain-dependent modulation of memory by stress in mice

The effects of immobilization stress were investigated in Swiss Webster (Swiss), DBA/2 (DBA), and C57BL/6 (C57) mice, tested in a passive avoidance situation. Retention performance was impaired in Swiss and DBA mice, and improved in C57 mice, immobilized immediately, but not 2 hr, after training. These effects lasted for less than 7 days in DBA and Swiss mice, while they were still present, in the C57 strain, 14 days after training. The naloxone antagonism of the effects observed was also demonstrated. The results are discussed in terms of the possible role of endogenous opioids, stress hormones, and genetic makeup in the stress-induced modulation of memory processes in the mouse.     

Sex,strain, and housing: Variables influencing the effects of prior shock exposure on shock-induced aggression

A series of experiments was conducted to investigate sex, housing conditions, and strain as possible factors influencing the interference effect of prior exposure to shock on shock-induced aggression. In albino subjects, female rats and rats housed in community cages evidenced the greatest suppression in aggression following prior exposure to shock. In addition, ten sessions of prior exposure to shock produced a greater suppression in shock-induced fighting than 20 sessions of prior exposure to shock. The prior shock effect was not obtained with hooded subjects. Responsivity to shock was also investigated to determine whether the prior exposure to shock attenuation of shock-induced fighting was a consequence of reduced activity in response to shock. Responsivity to shock measured with an isometric platform accounted for less than 4% of the variance in shock-induced fighting in the single experiment that obtained a correlation between responsivity and shock-induced aggression.     

Cooperative social coordination and aggression: Sex and strain differences in the effects of housing on gonadectomized rats with hormone replacement

Laboratory rats were used to investigate sex and strain differences in the effects of aggression on a cooperative behavior in which pairs learned to coordinate shuttling in a rectangular chamber. The level of aggression was manipulated by comparing males and females of the aggressive S3 strain and a less aggressive Sprague-Dawley-derived strain and housing same-sex partners either together or individually (8 groups, n = 7 pairs per group). Hormone levels were stabilized by gonadectomy and daily injections of the appropriate sex hormone. The only serious coordination deficits were in individually housed males, associated with violent fighting and an extreme dominance/subordinance relationship that was not observed in females. All other groups readily learned and performed the coordination with evidence that low and moderate levels of aggression could facilitate coordination by evoking species-typical behaviors that increased proximity, synchrony, and differentiation within pairs. The discussion focused on models of affiliative behavior in the study of aggression and the compatibility between moderate levels of aggression and cooperation.     

Learning strategy selection in the water maze and hippocampal CREB phosphorylation differ in two inbred strains of mice

Learning strategy selection was assessed in two different inbred strains of mice, C57BL/6 and DBA/2, which are used for developing genetically modified mouse models. Male mice received a training protocol in a water maze using alternating blocks of visible and hidden platform trials, during which mice escaped to a single location. After training, mice were required to choose between the spatial location where the platform had been during training (a place strategy) and a visible platform presented in a new location (a cued/response strategy). Both strains of mice had similar escape performance on the visible and hidden platform trials during training. However, in the strategy preference test, C57BL/6 mice selected a place strategy significantly more often than DBA/2 mice. Because much evidence implicates the hippocampus and striatum as important neural substrates for spatial/place and cued/response learning, respectively, the engagement of the hippocampus was then assessed after either place or cue training by determining levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) in these two mouse strains. Results revealed that hippocampal CREB levels in both strains of mice were significantly increased after place in comparison to cued training. However, the relation of hippocampal pCREB levels to training was strain dependent; pCREB was significantly higher in C57BL/6 mice than in DBA/2 mice after place training, while hippocampal pCREB levels did not differ between strains after cued training. These findings indicate that pCREB, specifically associated with place/spatial training, is closely tied to differences in spatial/place strategy preference between C57BL/6 and DBA/2 mice.     

Strain and sex differences on olfactory discrimination learning in C57BL/6J and DBA/2J inbred mice (Mus musculus)

In this study, the authors explored potential strain and sex differences in nonspatial cognitive ability. Beginning around 90 days of age, male and female C57BL/6J (C57) and DBA/2J (DBA) inbred mice (Mus musculus) were tested on a task of simple odor discrimination learning with 3 repeated reversals. Males learned the task more readily than females, and DBA mice learned the task more readily than C57 mice. All differences became evident after repeated testing. Similarity of perseveration measures indicated the differences were not due to inhibitory deficits. Instead, a phase analysis localized differences to a transitional period of reversal learning. Females increased transitional errors that more likely indicated adaptive sampling strategies than memory failures. C57 females used this strategy indiscriminately, but DBA females sampled as a function of environmental uncertainty.     

Selective improvement of strain-dependent performances of cognitive tasks by food restriction

Temporary food restriction affects strain differences for behavioral phenotypes in the inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA). Since food restriction is a routine procedure to motivate learning, we evaluated its influence on differences for spatial and non-spatial discrimination between these strains of mice by using two non-associative tasks: the Spatial Novelty Test (SNT) and the Spontaneous Object Recognition Test (SORT). The results confirmed the poor performance of the DBA mice in SNT. Nonetheless, DBA mice were perfectly able to recognize the novel object in SORT. By contrast, C57 mice were good performers in SNT but failed to recognize a novel object in SORT. Finally, food restriction selectively improved C57 performance in SNT and DBA performance in SORT. These results support the view that a food restricting procedure enhances strain differences for discrimination of configurational information.     

Cooperative social coordination and aggression: Sex and strain differences in the effects of housing on gonadectomized rats with hormone replacement

Laboratory rats were used to investigate sex and strain differences in the effects of aggression on a cooperative behavior in which pairs learn to coordinate shuttling in a rectangular chamber. The level of aggression was manipulated by comparing males and females of the aggressive S3 strain and a less aggressive Sprague-Dawley-derived strain and by housing same-sex partners either together or individually (eight groups, n = 7 pairs per group). Hormone levels were stabilized by gonadectomy and daily injections of the appropriate sex hormone. The only serious coordination deficits were in individually housed males, associated with violent fighting and an extreme dominance/subordinance relationship that was not observed in females. All other groups readily learned and performed the coordination, with evidence that low and moderate levels of aggression could facilitate coordination by evoking species-typical behaviors that increased proximity, synchrony, and differentiation within pairs. The discussion focused on models of affiliative behavior in the study of aggression and the compatibility between moderate levels of aggression and cooperation.     

Strain-dependent interactions between MK-801 and cocaine on retention of C57BL/6 and DBA/2 mice tested in a one-trial inhibitory avoidance task: involvement of dopaminergic mechanisms

Two sets of experiments were carried out with C57BL/6 (C57) and DBA/2 (DBA) mice tested in a one-trial inhibitory avoidance task. In the first set C57 and DBA mice were injected posttraining with saline or with the D1 DA receptor antagonist SCH 23390 and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Cocaine enhanced retention in the C57 strain and impaired it in the DBA strain, and MK-801 potentiated the effects of cocaine in both strains. Furthermore, pretreatment with SCH 23390 completely antagonized the potentiation of the effects of cocaine exerted by MK-801. In the second set of experiments mice belonging to these same two strains were injected posttraining with vehicle or with the D2 DA receptor antagonist (-)-sulpiride and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Pretreatment with the D2 DA receptor antagonist completely antagonized in both strains the potentiation of the effect of cocaine exerted by MK-801. The results of the present research show that the noncompetitive NMDA receptor antagonist MK-801 enhances the effect of cocaine on retention performance in C57 and DBA mice and that dopaminergic mechanisms are involved in this potentiation.     

Anxiety and maternal aggression in house mice (Mus musculus): a look at interindividual variability

The hypotheses were tested that mouse motherhood is accompanied by decreased reactivity to aversive stimuli and that female anxiety is inversely related to the probability of displaying intense forms of postpartum aggression. Outbred Swiss female mice were tested for anxiety in a light/dark choice test when virgin, pregnant, or lactating, and then tested for maternal aggression (5-min exposure to a male intruder) on postpartum Day 7. Anxiety declined in pregnant and lactating females when compared with virgin animals. Furthermore, females who displayed higher scores of postpartum fighting were less anxious in the previous test regardless of reproductive stage. Part of interindividual variability in postpartum aggression might thus be related to differences in the extent to which individuals perceive and react to anxiogenic situations. In addition, the higher emotionality characterizing the C57BL/6 and DBA/2 inbred strains may be responsible for the lack of a clear-cut exhibition of maternal aggression in these two strains.     

A genetic analysis of stereotypy in the mouse: dopaminergic plasticity following chronic stress

After repeated stressful experiences, DBA/2 (DBA) mice showed an increase in apomorphine-induced climbing while C57BL/6 (C57) mice showed a clear-cut decrease of this behavior. Genetic analysis involving F1 and F2 hybrids and the backcross populations (F1 X C57; F1 X DBA) indicated complete dominance of the C57 genotype and a significant genotype X environment interaction. These findings are discussed in terms of dopaminergic plasticity and of the heuristic value of this animal model in relation to disturbed behaviors triggered by stressful experiences.     

Effects of age at differential housing and the duration of individual housing/grouping on lntermale fighting behavior and adrenocortical activity in TO strain mice

A study of the effects of the duration of individual and group housing on intermale fighting and adrenocortical activity was conducted in TO strain mice. It was found that fighting and threat increased with progressive isolation up to an asymptote at 56–58 days. ‘Basal’ adrenocortical function differed little under the 2 housing conditions, but after ‘stress,’ mice isolated for short periods, which had not fought when tested for aggression, had lower titers than group-housed counterparts. However, mice that had been isolated for longer periods, and had fought in aggression tests, had higher corticosterone titers than comparable group-housed animals. The effects of a short duration (28–30 days) of differential housing, commencing at different ages, were also studied. The shorter duration adrenocortical changes were largely confirmed. In general, the earlier the age at which the differential housing was imposed, the greater the behavioral differences between animals under each housing condition. It is suggested that this is largely a consequence of a loss of behavioral plasticity in older mice. The data provides little support for the concept of the “isolation stress syndrome,” or for the view that the characteristic fighting exhibited by individually housed mice is a consequence of “social deprivation”.     

The influence of the Y-chromosome of Rb/1Bg mice on agonistic behaviors

Males of the Rb/lBg and C57BL/10Bg strains, as well as of the Bl0RblF, and RblBlOF1, reciprocal hybrids, were tested for aggression over three daily trials beginning at 50 days of age. The BlORblF, hybrids were sired by Rb/lBg males, and the RblBlOF, hybrids were sired by C57BL/10Bg males. The mean scores for the agonistic acts of chase, wrestle, flank-bite (but not tail rattle or attack), and the mean “aggression” score (but not mean latencies to first agonistic act or first attack) were significantly higher for BlORblF, than for RblBlOF, hybrids. These findings are consistent with the hypothesis that some aspect(s) of the Rb/lBg Y-chromosome strain can influence the occurrence of some of the motor patterns of offense but not defense. The Y-chromosomes of the DBA/1, DBA/2, CBA, and PHH inbred strains have a similar effect on agonistic behaviors.     

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.     

Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice

Many studies have used "reverse" genetics to produce "knock-out" and transgenic mice to explore the roles of various molecules in long-term potentiation (LTP) and spatial memory. The existence of a variety of inbred strains of mice provides an additional way of exploring the genetic bases of learning and memory. We examined behavioral memory and LTP expression in area CA1 of hippocampal slices prepared from four different inbred strains of mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J. We found that LTP induced by four 100-Hz trains of stimulation was robust and long-lasting in C57BL/6J and DBA/2J mice but decayed in CBA/J and 129/SvEms-+(Ter?)/J mice. LTP induced by one 100-Hz train was significantly smaller after 1 hr in the 129/SvEms-+(Ter?)/J mice than in the other three strains. Theta-burst LTP was shorter lasting in CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J mice than in C57BL/6J mice. We also observed specific memory deficits, among particular mouse strains, in spatial and nonspatial tests of hippocampus-dependent memory. CBA/J mice showed defective learning in the Morris water maze, and both DBA/2J and CBA/J strains displayed deficient long-term memory in contextual and cued fear conditioning tests. Our findings provide strong support for a genetic basis for some forms of synaptic plasticity that are linked to behavioral long-term memory and suggest that genetic background can influence the electrophysiological and behavioral phenotypes observed in genetically modified mice generated for elucidating the molecular bases of learning, memory, and LTP.     

Place avoidance learning and stress-induced analgesia in the attacked mouse: role of endogenous opioids

In this study, mechanisms of pain inhibition (tail-flick test) and memory (place avoidance paradigm) were investigated in attacked, DBA/2 and C57BL/6, mice. During training, exposure of test animals to 10 or 30 bites by an aggressive, isolated ICR mouse situated in the dark half of a bright/dark conditioning box induced a significantly higher social conflict analgesia in DBA than in C57 mice. Naltrexone (0.5 and 2.0 mg/kg) reduced this response in DBA mice that received 30, but not 10, bites and was ineffective in C57 mice. This points to different, opioid versus naltrexone-insensitive nonopioid, analgesic mechanisms. During place choice testing in the same box 24 h later, DBA mice that had received 30, but not 10, bites showed a significant, naltrexone-reversible, avoidance of the attack place. No place avoidance learning was observed in C57 mice. The data provided unequivocal evidence that place avoidance learning was a result of associative conditioning, in that neither pairing nor social conflict per se significantly changed the preference for the dark side seen in experimentally naive DBA mice. Antagonism of place avoidance conditioning was observed regardless of whether testing was carried out in the drugged or undrugged state, excluding possible state-dependent effects as an explanation for the naltrexone-induced impairment. Individual correlational analysis in saline-injected, attacked DBA mice revealed a negative relationship between the analgesic state immediately after training and the avoidance of attack place during testing. In summary, the results suggest strain-dependent analgesic and learning mechanisms and indicate that endogenous opioids released in attacked DBA mice support pain inhibition and modulate the memorization of attack place by their analgesic effects, as well as by mechanisms independent of pain inhibitory systems.     

Postaggression footshock inhibits aggressive behavior in dominant but not in isolated mice

Aggressive behavior of dominant and isolated mice was assessed in intermale encounters with nonaggressive intruder mice. After an attack period of 90 s, the aggressor was exposed to a footshock punishment and retested the next day. The shock treatment, independent of the intensity and duration, failed to inhibit spontaneous aggression in isolated DBA/2 mice, while it significantly suppressed spontaneous aggression in dominant C57BL/6 mice. The different effects of post-trial shock punishment were not due to a different shock sensitivity and did not depend on the type of opponent used. Strain differences have been ruled out by the use of dominant and isolated ICR mice. Again, shock punishment was ineffective in isolates, while it reduced aggression in dominant animals. The findings were discussed with reference to the impaired learning performance reported for isolated animals, and suggest a difference between the aggression of isolated and that of dominant mice.