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.     

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.     

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.     

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 prolonged interaction of mice with aggressive and submissive types of behavior on the concentration of serotonin, 5-hydroxyindoleacetic acid and noradrenalin in the brain

As a result of repeated experience of victories and defeats in mice of C57BL/6 line, submissive and aggressive types of behaviour were elaborated, the stabilization of which was accompanied by a change in serotonin and noradrenaline content in various parts of the brain, at least of two kinds. Nonspecific unindirected changes in transmitter' levels found in both groups of animals in comparison with the control, are apparently due to the experience of zoosocial contracts. Changes were also noted connected with specificity of the observed behaviour.     

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.     

The development of pathological forms of behavior in submissive male C57BL/6J mice during agonistic zoosocial interactions. A possible model of depression?

It is shown that a long experience of defeats in daily zoosocial collisions (ZC) elicits changes in the structure of submissive behaviour. Male mice of C57BL/6J line after 20 defeats demonstrated poses of passive subordination instead of active defence and run away which they manifested in the first ZC. Moreover, new immobile poses appeared which were rare in the first ZC. Submissive animals (CA) demonstrated a decrease of travels in the open field test and an increase of immobility time in the Porsolt test. Chronic administration of imipramine (10 mg/kg, i.p., twice a day during two weeks against the background of repeated ZC) prevented an increase of depressivity, estimated in Porsolt test. Changes were noted in the content of serotonin and 5-HIAA in some brain structures of subordinated mice in comparison to control animals (five days of isolation). The data are discussed from a position of the development of depression in SA of C57BL/6J line as a result of a long nonavoided zoosocial stress.     

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 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 effect of the animals' emotional state on ethanol consumption under free-choice conditions

Voluntary ethanol consumption (20% solution) in mice of C57BL/6J strain with different experience in social agonistic confrontations was studied. It has been shown, that aggressive males daily winning other individuals did not change the level of ethanol consumption, while the submissive mice with daily experience of defeat in intermale encounters dramatically increased that level. Ethanol enhanced the behavioural reactivity of submissive animals to other individuals. It was supposed that emotionally positive or negative states differentiate the ethanol motivations in mice.     

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.     

Immune responses in C57BL/6J mice with the inverted pattern of behavior during social conflict

Inversion of aggressive behaviour into a submissive one led to immunosuppression in C57BL/6J mice as well as in those mice which did not change their behaviour, whereas inversion of submissive behaviour into aggressive one resulted in immunostimulation. A possibility to influence immune response changing the brain neurochemical pattern by reversing behaviour under conditions of a social conflict, is discussed.     

Distribution of serotonin and its metabolites in the brain structures and immunosuppression in submissive mice

The development of submissive behaviour in C57BL/6J mice in the sensory contact model was associated with an increase in the content of serotonin (5-HT) in the amygdala, hippocampus, dopaminergic nuclei A11, A10, A9, as well as in the caudate nucleus and hypothalamus after 10 and 20 days of confrontations compared to the controls. The level of 5-HT metabolite 5-hydroxyindolacetic acid (5-HIAA) was significantly higher in the most structures examined after 20 daily encounters as compared to animals with experience of 10 confrontations. The time course of submission over 10 or 20 days resulted in an increase of 5-HIAA/5-HT ratio in the midbrain nucleus raphe, nucleus accumbens, A9 and hypothalamus. In mice immunised on the 10th or 20th day of confrontations, the immune response inhibition was observed while its level remained unchanged after more prolonged confrontations (40 days). Thus, the experience of defeats during 10 days shown to be accompanied with an activation of 5-HT system in a number of the brain structures, produced immunosuppression. With increasing number of confrontations the ratio 5-HIAA/5-HT was decreased in the same structures and a tendency to the immune response elevation appeared.     

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.     

The development of catatonic reactions in male mice of CBA/Lac strain: the effect of repeated experience of aggression and submission

The development of catatonic reactions with rigid muscle tension due to stimulation of the skin at the scruff (catatonia-"pinch" test) and wax muscle plasticity (repeated pinch-induced catalepsy displayed on the parallel bars--BAR-test) was investigated in aggressive and submissive CBA/Lac male mice with repeated experiences of social victories (winners) or defeats (losers), accordingly. The expression of catatonic-like state in "pinch" test was significantly more in the losers after 20 daily agonistic confrontations in comparison with the winners. The catalepsy in the BAR-test was increased in animals with experience of agonistic confrontation in comparison with the controls, however expression of catalepsy reaction depended on kind and duration of agonistic interactions. The pronounced freezing predominated in the free behavior of the losers and, on the contrary, the winners demonstrated the abnormal undirected jumping. It was suggested that two contrast forms of catatonic syndrome accompanying by development of akinesia- or hiperkinesia-like states, are developed in the defeated and victorious (accordingly) mice of cataleptic CBA/Lac strain.     

Interaction of stereotypic behavior in mice and effects of activation of presynaptic dopaminergic receptors in extinction and amnesia

Using the methods of agonistic confrontations of C57BL/6J mice for formation of aggressive and submissive types of behavior and passive avoidance training we investigated the influence of activation of dopamine presynaptic receptors on retention of a memory trace during extinction and amnesia. Autoreceptor agonist (+)3PPP (2 mg/kg, intraperitoneal injection) impaired learning and retention of a memory trace during extinction and strengthened the amnestic influence of animal detention in a dangerous compartment on the training day only in aggressive mice. In submissive mice, (+) 3PPP improved the retrieval of passive avoidance during extinction but did not change the development of amnesia. This work was the first to demonstrate that the effects of dopamine autoreceptor activation on the passive avoidance retrieval depend on behavioral stereotype (aggressive or submissive). It is suggested that different basic states of the dopaminergic system in aggressive and submissive mice are responsible for different (+) 3PPP effects.     

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.     

Effect of novelty and behavioral stereotype on development of amnesia in mice

The research was aimed at analysis of interaction of basic behavioural strategy, extinction of information novelty and efficiency of amnesic influence. It is shown that preliminary habituation to the task apparatus prevented development of amnesia, induced detention of the animal in a dangerous compartment in submissive rather than aggressive mice C57BL/6J. The findings suggest that revealed distinctions in effects of pre-exposure on development of amnesia are essentially predetermined by selectivity of extinction of the information novelty specific to a stereotype of 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.