Neurogenetics of Social Behavior Sector

THE MAIN MODEL USED FOR RESEARCH

The main technique used is the Sensory Contact Model (Kudryavtseva, 1991), the model of social conflicts, allowing to form the alternative types of social behaviors (aggressive or submissive, social winners or losers) in male mice as a result of consecutive experience of victories or defeats in daily agonistic intermale confrontations.

The male mice are weighed and caged individually for 5 days to abolish group effects. Animals of approximately the same weight are placed in pairs into a steel cage (28x14x10 cm) separated into halves by a perforated transparent partition that permits the animals to see, hear and perceive the smell of the neighbor, but prevents direct physical contact. Testing starts two days after introduction of animals to these new housing conditions (sensory contact). Every afternoon, (14:00-17:00 hrs local time), the steel cover of the cage is replaced with a transparent one, and 5 min later (the period necessary for individuals’ activation and habituation to new lighting conditions) the partition is removed for 10 min to allow agonistic interaction. Undoubted superiority of one of the partners is evident within 2-3 tests in daily social encounters with the same opponent. One partner demonstrates aggression, attacking, biting, and chasing, and the other displays defensive behavior (sideways, upright postures, withdrawal and also lying ‘on the back’ or ‘freezing’) during the tests. As a rule, in our experiments aggressive confrontations between males are discontinued by putting the partition down if the demonstration of severe aggression has lasted more than 3 min. Every day after the test, each defeated member of one pair is paired with the winning member of another pair behind the partition in an unfamiliar cage. Aggressive males are remained in their own compartments. The procedure yielded equal numbers of males with an opposite experience of victories and defeats in social confrontations, i.e. of animals with positive (winners, aggressors), or negative (submissive mice, losers) social experience. The winners and losers can be investigated following different periods of repeated social experiences (agonistic confrontations). Males after 5 days of individual housing are used as the control. They were thought to be the best as intact controls because, in this case, the submissiveness of grouped males would be removed, and the repeated experience of aggression would not yet be acquired.

Perspectives of Application

The sensory contact model (or, in other words, the model of chronic social conflicts) allows aggressive and submissive types of behavior to be formed in male mice as a results of acquisition of repeated experience of social victories or defeats in daily agonistic interactions. Chronic social conflict produces different emotional states in individuals depending on social status (winners or losers) receiving in social interactions. Positive emotions are associated with aggressive behavior resulting in victories in animals. Defeats in intermale confrontations produce negative emotions due to permanent anxiety and fear to be attacked by strong and aggressive partner. Long experience of aggression and submission is accompanied by different changes of brain neurotransmitter activities, behavior, physiological states in male mice with alternative types of social behaviors. It have been demonstrated the possibilities and perspectives of use of the sensory contact model for the basic and medical-biological studies.

Depression and anxiety. Anxiety, phobias and depression are the most wide-spread psychoemotional pathologies in humans produced by stress. Repeated defeat experiences in daily agonistic interactions induce dramatic changes in social and individual behaviors as well as in somatic state of losers, which were similar to human depression with respect to etiology, susceptibility to treatment, symptoms and brain neurochemical changes. A remarkable behavioral deficit, indifference, depressiveness, generalized anxiety, alcohol addiction as well as a loss of weight, decrease of stress reactivity and sexual disfunction were found in the losers. Antidepressants or anxiolytics treatment had positive effects. Chronic unavoidable social stress is considered as a relevant (social defeat, negative emotions, permanent anxiety) pathogenic factor, which provokes the development of mixed anxiety/depression state in animals. The study of brain monoaminergic activity in the losers allowed to hypothesize of dynamic changes in brain serotonergic and dopaminergic activities depending on the duration and depth of depressive disorder. This model is unique since it permits to examine neurochemical, behavioral and physiological changes, spanning between norm and psychopathology and to suggest specific pharmacological correction at every stages of depression development. This model of anxious depression produced by social stress and permanent anxiety is the most adequate and productive one at present time and can be used for many aims of biological psychiatry.

Pharmacological studies. The sensory contact model allows experimentally to form different pathological states produced by chronic social stress (for example, depression, anxiety) and to study the therapeutic and preventative properties of any drug as well as its efficiency under simulated clinical conditions. This approach can be useful in the search of novel antidepressants and anxiolytics, and in a better understanding of the drugs' action. It has been shown also that many drugs have different effects in the winners, losers and controls that suppose different efficacy of drugs in persons with different emotional states. Thus, this model can be used for the search of methods of individual therapy.

Psychogenic immune deficiency. Cell and humoral immune suppression developing in the losers due to repeated social defeats was confirmed by many authors using the sensory contact model in their investigations. It means that pronounced anxiety leads to quick development of psychogenic immune deficiency under chronic social conflicts. It has been shown also that susceptibility to transplanted tumor growth depends on social status of animals. Sensory contact model may be used for the study of neurochemical and physiological mechanisms and pharmacological correction of immune suppression in organism.

Learned aggression. Social conditions requiring the expression of prolonged aggression often appear in communities (war, sports, social security). This type of aggression in humans is known as premeditated (learned) aggression. The sensory contact model allows the aggressive type of behavior to be formed as a result of repeated experience of victories in daily agonistic interactions in male mice. 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. Relevant stimuli (boundary aggression) provoke demonstration of aggression. Positive fighting experience in daily social confrontations changes many characteristics of individual and social behaviors, these having been estimated 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 the winners under influence of repeated aggression, that create the low threshold for aggressive reaction in even weakly provoking environment. Changes in opioidergic systems form aggression abuse in male mice. Similarities in mechanisms of learned aggression in humans and animals are discovered. The understanding the brain neurochemical basis of learned aggression as well as pathological aggressiveness can be useful for pedagogics, science of law and Centers of rehabilitation of war' participants.

From behavior to gene. The role of genetic and environmental factors in regulation of aggressive and submissive behaviors are shown in animals. It has been exhibited, that changes of brain monoaminergic systems activity under daily agonistic confrontations in mice are accompanied by changes in expression of monoaminergic genes. Repeated aggression is accompanied by decrease of mRNA level of catechol-O-methyltransferase gene in the midbrain and increase of mRNA levels of dopamine transporter and tyrosine hydroxylase genes in ventral tegmental area of aggressive male mice. Repeated experience of social defeats produced increase of mRNA levels of serotonin transporter and monoamine oxidase A genes in the midbrain raphe nuclei. Supposed ethological approach discovers theoretical and methodological perspectives for the understanding and study of molecular mechanisms of agonistic behavior in the context of fundamental problem of seeking the ways of regulation from behavior to gene.

Conclusion. The sensory contact model can be used for the study of neurophysiological consequences of chronic social conflicts which are accompanied by development of depression, generalized anxiety, catatonia, affective aggression, disturbances in cognition, immune deficiency, gonad disfunction, gastric mucosa damage etc. Expression and direction of neurophysiological changes depends on genetic predisposition (mouse strains), social status and on duration of social agonistic experience. The sensory contact model is universal relevant model for basic and applied studies in the social biology and biological psychiatry.