The study of exploratory behavior in CBA/Lac male mice under influence of positive and negative social interactions

The exploratory activity towards a new object placed in the home cage was studied in CBA/Lac male mice after their repeated daily social victories and defeats. After 10 daily social defeats, submissive mice displayed a significantly declined exploration of a new object, whereas aggressive mice with experience of 10 daily victories expressed only a mild decrease in exploratory activity (as compared to control). Twenty daily social defeats almost completely abolished exploratory behavior in submissive mice, whereas 20 daily victories resulted in the increased exploration of a new object in aggressive mice. It is suggested that repeated social defeats associated with the negative psychoemotional state lead to the development of a pronounced exploratory motivational deficit. On the other hand, the experience of repeated daily aggression forms the enhanced motivational excitement that prevents a relevant response to a neutral stimulus.     

Characteristics of the reaction of submissive mice to distant zoosocial stimuli

In aggressive and submissive mice well-experienced in victories and defeats, the reaction was studied to another male in neighbour section of "home" cage divided by transparent partition with holes. The activity of submissive mice near the partition was significantly lower than that of control animals without experience of agonist contacts or aggressive. Submissive mice did not react to the appearance of unknown smell in the neighbouring section while the animals of other studied groups sharply increased their activity near the partition. It is suggested that long experience of defeat leads to inhibition of perception of specific zoosocial (olfactory) stimuli triggering manifestation of aggressive reaction to another individual.     

Effect on the immobilization-induced stress on the immune response in mice with various behavioral stereotypes

CBA and C57BL/6J mice with aggressive and submissive types of zoo-social behavior fixed during 10-day confrontation testing demonstrated different immune response to immobilization stress. In aggressive mice with confrontation experience stress resulted in a decrease in the immune response in comparison with aggressive inexperienced mice. Therewith, the immune response of CBA mice did not differ from the control level (the immunized mice without experience of victories and defeats), and in C57BL/6 mice the immune response was two times lower than in the control. In contrast to the control and aggressive mice, stress did not suppress the immune response in submissive animals. It is suggested that stress-induced changes in the immune response depend on zoo-social rank of an individual underlain by a particular neurochemical pattern of the brain.     

Extinction and amnesia in aggressive and submissive mice with various terms of agonistic interaction

Dependence of the passive avoidance retrieval on the duration of agonistic interactions was analyzed in C57BL/6J mice in procedures of extinction and amnesia during formation of aggressive and submissive behavioral stereotypes. The resistance to amnestic stimulation was lower in aggressive mice with 10-day experience of victories than in aggressive animals after 20 daily confrontations. Prolongation of extinction in aggressive mice and fast extinction in submissive animals did not depend on the number of agonistic interactions.     

Effect of the activation of GABA A, benzodiazepine, and D2 dopamine receptors on the passive avoidance extinction in submissive and aggressive mice

The effect of activation of GABAA, benzodiazepine, and D2 dopamine receptors on extinction of passive avoidance and their dependence on the initial state of aggressive and submissive C57BL/6J mice were studied. It was found that in mice with the submissive stereotype of behavior produced by experience of defeats in daily agonistic confrontations, extinction of the conditioned reaction occurred faster than in control mice. The activation of D2 receptors by quinpirole and of benzodiazepine receptors by medasepam before training restored the retrieval of the memory trace. A prolongation of extinction was observed in aggressive mice in comparison with control and submissive animals, and activation of GABAA by muscimol and benzodiazepine receptors by medazepam led to acceleration of extinction. Activation of D2 receptors was ineffective. Thus, the difference in initial behavioral strategy determined both the development of extinction of the passive avoidance and variability of participation of D2, GABAA, and benzodiazepine receptors in the maintenance of availability of the memory trace to retrieval.     

Catatonia as an element of submissive behavior in mice during interspecies agonistic interactions

A catatonia-like state was elicited in male mice with different experience of social interactions, by pinch of scruff of the neck in a suspended state. In submissive males with long experience of defeat the total time of catatonia reaction during test is considerably greater than in aggressive individuals with a long experience of victories. The change of the social status of the individuals resulting from agonistic interactions leads to a change of the catatonia reaction: manifestation of submissive behaviour is accompanied by an increase of total time of catatonia reaction in the test, the aggressive behaviour is accompanied by its decrease.     

Effect of genotype on the development of aggressive and submissive behavior in the mouse

Aggressive and submissive behaviour was studied in CBA/Lac and C57BL/6J strains of mice during long-term intermale interaction with syngenic partners. It was shown that the aggressiveness of aggressive C57BL/6J animals was more expressive than that of CBA/Lac' ones. The structure of submissive behaviour of this strains' encounters was also significantly different. Prolonged-defeat experience changed the character of submissive behaviour of C57BL/6J, but not of CBA/Lac' ones. Aggression of dominant animals considerably decreased in both strains. It is suggested that CBA/Lac and C57BL/6J mice had different mechanisms of suppression of intermale aggression.     

Effect of the activation and blockade of D2 dopamine receptors on the immune response in mice with different types of social behavior

Activation of D2 dopamine receptors with a selective agonist quinpirol in C57BL/6J mice was found to induce increase in the immune response regardless of the initial psychoemotional state of animals, e. g. in aggressive mice, submissive mice, and mice without victory or defeat experience (control). However, the immune response level in aggressive and submissive mice was significantly higher than that of control animals. At the same time, the blockade of D2 dopamine receptors with haloperidol suppressed immunogenesis in aggressive and control mice, whereas the immune reactions in submissive mice were unchanged. Thus, the effect of activation and blockade of D2 dopamine receptors on immune function is dependent on the initial psychoemotional status of animals which to a greater extent might be provided by the neuromediator pattern of the brain and activity of DA receptors.     

Learning of submissive behavior in mice: A new model

The experience of winning or loosing fights plays an important role in subsequent aggressive or submissive behaviors. In this study agonistic behavior of male mice was chosen to investigate learning mechanisms in the context of a biologically meaningful situation.An ICR mouse introduced into a group of five C57BL/6 mice was attacked by mice of high social status (Fighter, F), but not by lower ranking animals (Non-Fighter, NF). On this basis the following model was developed to study learning of submissive behavior. Day 1 (baseline trial): An ICR mouse was introduced to a single NF-C57 mouse. Few submissive behaviors (crouch) were observed in naive ICR mice upon contact with NF-C57 mice. Day 2 (learning trial): The same ICR mouse was defeated by an F-C57 mouse until it showed defensive upright posture upon approach. This criterion was reached after a mean latency of 3.5 min and after being exposed to a mean number of 14 bites. Day 3 (retest trial): The same pairs as on day 1 confronted each other. Without being attacked, the ICR mouse showed a significant increase of submissive behavior (crouch, defensive sideways and upright) upon mere contact with the NF-C57 mouse when compared to day 1 and to control mice on day 3. Controls, confronted on all three days with NF-C57 mice, showed no increase in submissive behaviors.The results are discussed in terms of acquisition, memory, retrieval and extinction of learned submissive behavior. It is suggested that the mechanisms underlying learning of submissive behavior include generalization of conditioning and specific extinction processes. The further use of the learning scheme to assess drug effects is illustrated.     

The strategy of submissive behavior in male mice: the effect of the genotype and the experience of preceding agonistic encounters]

The male mice of two strains with experience of 2 or 10 defeats in intermale agonistic confrontations significantly differ in pattern of submissive behavior (balance of upright and sideways defensive postures, withdrawal, freezing, "on the back" posture). In mice with experience of 20 defeats genetic differences have not been found. The acquisition of consequent experience of defeats does not change the pattern of CBA mice submissive behavior, but significantly increases the share of immobile submissive postures in behavior of C57BL mice. Among submissive males of C57BL strain animals with more active strategy of behavior keep capability for aggressive response to weaker partner. The influence of genotype and previous social contact experience on formation of adaptive in experimental situation strategy of submissive behavior is discussed.     

Impaired social recognition in male mice with repeated experience of aggression

Social recognition is crucial for many aspects of animal behavior in stabilized population. Preliminary data proposed impairment of social recognition in male mice with long experience of aggression. To check this hypothesis, experiments with male mice with different aggressive experience (during 2 and 20 days) were performed. Two types of losers were used as partners: losers with active defense reactions and losers displaying submissive postures. The enhanced aggressive motivation was found in both groups of aggressors. Mice with short aggressive experience demonstrated intensive attacks toward the active losers and decreased aggression directed to submissive losers. Mice with long aggressive experience did not change their behavior depending on a type of the partner and displayed a high level of aggression as a result of dominant aggressive motivation and impaired social recognition.     

The neurochemical control of aggression and submission]

Neurochemical mechanisms of agonistic behaviour in different models of aggression are discussed. The effects of aggression and submission experience in 10 mice intermale confrontations under conditions of sensory contact on the levels of brain neurotransmitters and their metabolites were investigated in 7 brain areas. The values obtained in aggressive and control, or submissive and control, animals were compared. In this comparison neurochemical alterations specific for aggressive or submissive behaviours, or nonspecific became apparent. The long experience of victories leads to activation of dopaminergic system through DA catabolism which leads to DOPAC formation. The long experience of defeats increases the 5HT metabolism and decreases NA level in some brain areas. The dopaminergic system of Nucleus accumbens and midbrain are nonspecifically activated in both aggressive and submissive animals. The investigation of values obtained in animals with conversion of behavioural type (after defeat of previously aggressive animals and/or display of aggressive reaction by previously submissive mice) allowed to find many significant differences between aggressive, submissive and "converted" males; in particular the amygdala is the site of opposite changes in 5HT system during inversion of aggressive or submissive behaviours. The above data evidence for the specific role of transmitter systems and brain structures in maintaining or inversion of different types of agonistic behaviour.     

Decrease in sucrose solution consumption by CBA/Lac male mice under chronic social stress

The influence of repeated experience of social defeats in daily agonistic interactions on voluntary consumption of 1% sucrose solution supplemented with vanillin (0.2%) was studied in male mice of CBA/Lac strain with genetic predisposition to catalepsy as compared to depression-predisposed C57BL/6J mice. Intact mice of both strains prefered sucrose solution to water under conditions of two-bottle free choice. Sucrose solution intake was shown to decrease in losers of both strains exposed to social confrontations as compared to controls. It was suggested that the high level of anxiety revealed in mice of both strains can be the determining factor of the decrease in sucrose solution consumption under conditions of chronic social stress.     

Significance of initial emotional state for neuroimmunomodulation under conditions of activation or blockade of 5-HT1A receptors

Selective agonist of 5-HT1A receptors--8-OH-DPAT (1 mg/kg) induced a suppression of the immune reaction in aggressive male CBA mice immunized with SRBC (5 x 10(8)). In submissive mice with 10-day defeat experience in confrontation tests, the activation of 5-HT1A receptors with 8-OH-DPAT did not alter the immune response, whereas the application of selective antagonist of 5-HT1A receptors WAY-100635 increased the immune reaction only in submissive mice. It is concluded that activation or blockade of 5-HT1A receptors produced different effects on the immune function of CBA mice depending on the initial emotional state which is known to be provided in aggressive and submissive animals by different activities of the brain neurotransmitter systems including the 5-HTergic system.     

Changes in the Expression of Monoaminergic Genes under the Influence of Repeated Experience of Agonistic Interactions: From Behavior to Gene

The role of genetic and environmental factors as well as brain neurochemistry in regulating aggressive and submissive behaviors in animals are considered. We present a review of data on changes in brain monoaminergic activity (synthesis, catabolism, receptors) and on the expression of monoaminergic genes under repeated daily agonistic confrontations in male mice. A repeated experience of aggression was shown to result in the total activation of the dopaminergic systems and the inhibition of the serotonergic one. This was accompanied by a decrease in the mRNA level of the cathecol-O-methyltransferase gene in the midbrain and an increase of the mRNA level of the dopamine transporter and tyrosine hydroxylase genes in the ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced dynamic changes in the serotonergic system of some brain areas and an increase of the mRNA level of the serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Theoretical and methodological possibilities of the proposed ethological approach for studying molecular mechanisms of agonistic behavior are discussed in the context of the fundamental problem of investigating the ways of regulation from behavior to gene.     

Experience of defeat increases the susceptibility to catatonic - like state in mice

The ability to develop the catatonic-like state (reflex immobility reaction - RIR) due to stimulation of the skin at the scruff was investigated in mice of two strains — C57BL/6J and CBA/Lac. The total time of immobility and number of paroxysms during test were measured. It has been shown that the number of paroxysms was significantly fewer and the total time of immobility was significantly longer in CBA/Lac strain than in C57BL/6J. In each strain group housed animals as well as submissive ones with successive experience of defeats demonstrated a more expressed immobility than individually housed or aggressive males with successive experience of victories, respectively. Changing the social status in aggressive animals as a consequence of confrontation with aggressive males resulted in the increased immobility in CBA/Lac but not in C57BL/6J mice. The results suggest that the experience of defeat in submissive males is connected with increased ability to develop RIR.     

饮酒小鼠动物模型建立及其对雌性激素的影响

目的建立模拟人类饮酒的小鼠动物模型,并以此动物模型进一步研究酒精对小鼠雌激素水平及乳腺癌的影响。方法 SPF级C57BL/6雌性小鼠,随机分对照组和酒精组两组,酒精组20:00到次日8:00给予含有一定浓度酒精的饮用水,其他时间给予常规饮用水,对照组全天给予常规饮用水。观察两组小鼠的饮水量及体重变化;用ANALOX AM1酒精分析仪检测小鼠凌晨2∶00和8∶00血液的酒精浓度(BEC);酶联免疫法(ELASA)检测两组小鼠血清中雌激素水平的差异。结果饮酒组小鼠血液BEC明显增高,类似人类饮酒水平,饮酒组小鼠的饮水量及体重无明显变化;饮酒组小鼠体内雌激素的水平明显高于对照组。结论成功的建立模拟人类饮酒的动物模型,并通过此动物模型初步证实酒精刺激可以增加小鼠体内血清雌激素的水平。     

Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: from behavior to gene

The role of genetic and environmental factors as well as brain neurochemistry in regulating aggressive and submissive behaviors in animals are considered. We present a review of data on changes in brain monoaminergic activity (synthesis, catabolism, receptors) and on the expression of monoaminergetic genes under repeated daily agonistic confrontations in male mice. A repeated experience of aggression was shown to result in the total activation of the dopaminergic system and the inhibition of the serotonergic one. This was accompanied by a decrease in the mRNA level of the catechol-O-methyltransferase gene in the midbrain and an increase of the mRNA level of the dopamine transporter and tyrosine hydroxylase genes in the ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced dynamic changes in the serotonergic system of some brain areas and an increase of the mRNA level of the serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Theoretical and methodological possibilities of the proposed ethological approach for studying molecular mechanisms of agonistic behavior are discussed in the context of the fundamental problem of investigating the ways of regulation from behavior to gene.     

Involvement of kappa-opioid receptors in mechanisms of aggressive and submissive types of behavior in male mice

Effects of the kappa-opioid receptor agonist U-50.488H (0.0, 0.6, 1.25, 2.5 mg/kg. s.c., 30 min) on behavior of the winner with repeated experience of victories and the losers with repeated experience of social defeat in 20 daily agonistic confrontations as well as the control mice were investigated in the tests estimating exploratory activity (open-field) and communication (partition test). Different effects of drug on behaviors of animals with different social story were shown in both tests. In the losers, all doses of U-50.488H had anxiolytic effect, increasing the communication in the partition test. In the winners, the drug induced an increase of aggressive motivation. The control mice were less sensitive to the treatment. In the open-field test, U-50.488H increased the locomotor and exploratory activity in high anxious losers. Winners significantly differed in their reaction to drug treatment in most behavioral forms in comparison with the controls and losers. It was concluded that kappa-opioid receptors are specifically involved into mechanisms of formation of aggressive or submissive types of behaviors under positive or negative social experience.     

Features of the aggressive behavior of victorious mice in inter-male interactions

Latency of the first attack, number of attacks and total attacking time in aggressive male C57BL/6J strain mice were studied during agonistic interactions with submissive mice which had a great defeat experience. Then, aggressive mice were placed together in order to find out which will be the winner in each pair. It has been shown that males with a shorter latency of the first attack and greater total attacking time gained the victory.