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.     

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.     

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.     

Modifying effect of the repeated experience of agonistic confrontations on effect of naltrexone in male mice

In mice with different experience of agonistic confrontations: victories or social defeats during 3 and 10 days (T3 and T10 winners and T3 and T10 losers, resp.), T10 winners displayed a lesser aggression and a more hostile behaviour than T3 winners. Naltrexone dose-dependently decreased attacks in the T3 winners and did not affect aggressive grooming, diggings, autogrooming, and exploratory activity. Naltrexone was ineffective in T10 winners. The naltrexone effects were similar in T3 and T10 losers and its high and low doses contrarily affected different parameters of submissive behaviour. The repeated experience of agonistic confrontations seems to modify the naltrexone effects depending on a neurochemical background, differing in winners and losers.     

Neurobiological correlates premeditated (learned) aggression: seeking new experimental approaches]

Theoretical possibility of experimental modeling of learned (premediated) aggression developing in human after experience of aggression is considered. The sensory contact technique increases aggressiveness in male mice and allows aggressive type of behavior to be formed as a result of repeated experience of victories in daily agonistic confrontations. Some behavioral domains confirm the development of learned aggression in males similar to those in humans. The features are: repeated experience of aggression reinforced by victories; elements of learned behavior after period of confrontations; intent, measured by increase of the aggressive motivation prior agonistic confrontation; decreased emotionality estimated by parameters of open field behavior. Relevant stimuli provoke demonstration of aggression. This review summarized data on the influence of positive fighting experience in daily intermale confrontations on the behavior, neurochemistry and physiology of aggressive mice (winners). This sort of experience changes many characteristics in individual and social behaviors, these having been estimated in different tests and in varied situations. Some physiological parameters are also changed in the winners. Neurochemical data confirm the activation of brain dopaminergic systems and functional inhibition of serotonergic system in winners under influence of repeated experience of aggression. The expression of the neurochemical and behavioral changes observed in winners has been found dependent on the mouse strain and on the duration of their agonistic confrontations. Similarities in mechanisms of learned aggression in humans and mice are considered.     

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.     

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 emotionality, exploratory activity and pain sensitivity on manifestation of agonistic behavior in the mouse

Mice of C57BL/6J line with higher exploratory and motor activities and with lower emotionality and pain threshold recorded in standard tests, as compared with the animals of CBA/Lac line, have also been found to manifest a more expressed aggression in their intermale contacts in reaction to a syngeneous partner. It is suggested that the studied physiological and behavioural parameters may determine in considerable degree the character of aggressive and submissive mice behaviour in an agonistic interaction.     

Effect of the D1-receptor antagonist SCH-23390 on the individual and aggressive behavior in male mice with various aggression experience

It has been shown that dopaminergic systems are involved in mechanisms of aggressive behavior. Effects of SCH 23390 (dopamine Di receptors antagonist. 0-1 mg/kg, i/p, 30 min) on aggressive and individual behaviors were studied in male C57BL/6J mice with different experience of aggression. SCH 23390 reduced aggressive attacks in animals without preliminary experience of aggression. However total time of hostile behavior (sum of the total time of attacks, aggressive grooming and diggings) didn't changed. No significant effects on behaviors were found in mice with long (20 days) repeated experience of aggression. It was supposed that long aggressive experience produces pharmacological desensitization of Di receptors as a result of enhanced dopaminergic activity shown earlier in aggressive animals.     

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.     

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 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.     

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.     

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.     

The nature and frequency of agonism in free-ranging and semi-free-ranging brown lemurs,Eulemur fulvus

Agonistic behaviour was studied in three groups each of free-ranging and semi-free-ranging brown lemurs (Eulemur fulvus) at Berenty, Madagascar and the Duke University Primate Center (DUPC) respectively. The purpose of the study was to answer questions arising from the work of other researchers regarding the frequency and intensity of agonism in this species. Authors of field studies generally concluded that agonism was rare and mild, whereas those who had studied semi-free-ranging or captive animals at the DUPC reported intense agonism during the peaks of the mating and birth seasons, with sometimes fatal wounding occurring among captive animals. I recorded 30 agonistic behaviours or “signals” which I grouped into seven general categories — cuffs, other physical contact, threats, chases, third party intervention, unprovoked submissive signals, and reciprocal aggression. The seven categories represent the types of signals which initiated or otherwise defined agonistic interactions, regardless of whether or not there was a submissive response to aggression. The relative percentages of all agonism constituted by the seven categories were not found to be significantly different between study sites. Agonistic signals were also classified as either subtle or obvious, a classification which crosscut the seven categories. At both study sites, the majority of agonistic signals initiating or defining interactions were subtle. Rates of agonism for the Berenty groups, studied during the birth season only, were significantly lower than those for the DUPC groups during the birth season, possibly due to (1) easier observation conditions at the DUPC, and (2) the impossibility of successful emigration at the DUPC, which might have resulted in social stresses translating into higher rates of agonism. In only one DUPC group was there significant variation in rates of agonism between seasons. I found agonistic behaviour to be mild, at both study sites, in the senses of subtlety of both aggressive and submissive signals, unlikelihood of response to aggression, and virtual absence of wounding; and I noted that serious wounding during other studies at the DUPC involved animals captive in caged runs. Comparing rates of the study groups with rates reported in other research for brown lemurs, other lemuriform species, and some New and Old World anthropoid species, I concluded thatE. fulvus agonism was in fact not rare except in comparison to baboons and macaques.     

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.     

Roles of brain monoamine neurotransmitters in agonistic behaviour and stress reactions,with particular reference to fish

1. Experimental results on the involvement of brain monoamines in agonistic behaviour and stress in fish are reviewed and discussed in relation to available data from other vertebrates.2. In fish as well as mammals, stress induces increased brain serotonergic activity, and a similar increase in serotonergic activity is seen in subordinate individuals in a dominance hierarchy.3. The brain serotonergic system appears to inhibit aggression and spontaneous locomotor activity in both fish and mammals.4. Subordinate fish show several behavioural characteristics, notably inhibition of aggressive behaviour, low spontaneous locomotor activity and decreased food intake, that are likely to be related to their increased brain serotonergic activity.5. By contrast, the brain dopaminergic system appears to stimulate aggressive behaviour in both fish and mammals, and dominant fish show signs of elevated dopaminergic activity in telencephalon.6. The similarities between fish and mammalian monoaminergic functions suggest that these are phylogenetically very old mechanisms that have been conserved during the last 400 million years of vertebrate evolution.     

Effects of repeated exposure to electric footshock on subsequent agonistic behaviour and adrenocortical secretion in male mice of different androgen status

Two experiments were conducted to examine effects of repeated exposure to electric footshock on subsequent agonistic behaviour and adrenocortical secretion in male mice of different androgen status. Aggressive and submissive behavioural components were independently studied in the two experiments. It was found that repetition reduced aggressive, and stimulated submissive and adrenocortical responses to shock, particularly in castrates. The direction of the shock effects on aggressive behaviour was reversed by repetition in castrates, whereas only the magnitude of the behavioural responses was changed at normal androgen levels. It is suggested that the changes in agonistic responses to shock induced by repetition are mediated by changes in pituitary-adrenocortical secretion, and that androgen inhibits the shock effects on agonistic behaviour through inhibition of the pituitary-adrenocortical responses to shock.     

Inter-male aggression with regard to polygynous mating system in Pampean grassland mouse, Akodon azarae (Cricetidae: Sigmodontinae)

Based on the hypothesis that, in Akodon azarae, polygyny operates through female defence, we studied inter-male aggression in order to test the following predictions: during the breeding period (1) resident males are more aggressive than intruder males in the presence of females (FP), and (2) aggressive behaviour is independent of male condition (resident or intruder) in the absence of females (FA). To test our predictions, we used the resident male behavioural response towards an intruder male in relation to FP or FA. We conducted 30 encounters in FP and 27 in FA in 0.79-m² round enclosures placed in the Espinal Reservation. Our results support the prediction that, in FP, the intensity of aggressive behaviour exhibited by males varied in relation to resident or intruder condition. Resident males showed high levels of aggression towards intruders, and intruders exhibited the greatest values of submissive behaviours with residents. In FA, the intensity of aggressive behaviour did not vary in relation to resident or intruder condition. Both resident and intruder males exhibited low aggressive behaviour and inter-male encounters resulted mainly in non interactive behaviours. Our results support the hypothesis that, in A. azarae, the polygynous mating system operates through female defence.     

Interference with ritualized threat behaviour in Cichlasoma nigrofasciatum

According to ethological theory, ritualized threat behaviour functions to prevent overt aggression. This prediction was tested in twenty-three pairs of male Cichalasoma nigrofasciatum. Pairs prevented from giving frontal displays by surgically restrained gill covers showed significantly less mouth fighting than sham operates. Pairs prevented from giving frontals and impaired in delivering tail beats because of separated caudal-fin rays showed intermediate aggressive behaviour. Experimental animals in both groups fought and frequently became dominant when paired with sham operates. It was concluded that threat behaviour in C. nigrofasciatum increases subsequent aggressive behaviours both quantitatively and qualitatively. It is suggested that ethological theory has identified the effects of ritualized aggression as a complex behavioural sequence ending in submissive behaviour with that of its first phase alone.