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Institute Cytology and Genetics
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Laboratory of Phenogenetics of Behavior


Head N.K.Popova, Dr.Med.Sci., Prof.
npopova@bionet.nsc.ru





Restraint-induced immobility in a CBA/Icg mouse

CBA mice are able to maintain the awkward position for several minutes and serve as a new genetic model for studying molecular-genetic risk factors of behavioral pathology. The black segments on chromosome diagram represent the regions including the putative QTLs of catalepsy, letters represent the alleles of the genes



Effect of MAO A deficiency on behavior and alcohol tolerance in mice


Genetic control of behavior and the role of brain neurotransmitters in its expression have been the focus of research. The key problems of modern genetics, molecular biology and medicine are the genetic risk factors determining predisposition to major psychopathology. At this laboratory, it has been previously shown that CBA mice are highly predisposed to catalepsy displayed as a natural freezing response to a threatening situation in vertebrates and catalepsy, the schizophrenia syndrome in its exaggerated form in human. Using Mendelian analysis, catalepsy was shown to be a recessive trait determined by a small gene number. In collaboration with the Institute of Neurobiology (Bordeaux, France), predisposition to catalepsy was investigated in CBA mice using QTL and microsatellite markers for this purpose. It was found that the high predisposition is determined by two QTLs located on chromosomes 8 and 13. The necessary condition for catalepsy is homozygosity for the recessive alleles at one or both loci. The third QTL with dominant alleles drastically increasing the penetrance of the main QTL was located on chromosome 17. It is well known that regulation of behavior is effected through the genetic control of brain neurotransmitters, the principal regulators of behavior and emotions. It has been previously shown that the brain neurotransmitter serotonin is involved in the mechanism of genetic predisposition to the main types of defensive behavior: passive defensive freezing and active defensive fighting. Selection for the two defensive behaviors is associated with different changes in the brain serotonin system. Genetically determined high aggressiveness in wild rats toward human is associated with a decreased metabolism and level of serotonin in the brain; in contrast, genetically determined predisposition to the freezing response is associated with a local increase in the activity of serotonin metabolism in the striatum, the brain region involved in the control of muscular tone and activity. In rats highly predisposed to any type of defensive behavior, the density of serotonin 5-HT1A receptors in a number of brain structures is reduced. Because fear is the main inducer of both types of defensive responses, it was suggested that genetic predisposition to strong expression of defensive behavior, irrespective of the strategy, is determined by reduced density of the 5-HT1A receptors involved in the regulation of anxiety and fear. This suggestion was supported by studies on the expression of the fear-elicited startle response: rats with genetically determined high agressiveness and highly expressed defensive freezing showed an increased amplitude of the auditory startle response. A recent achievement of molecular biology is technology for the development of mouse strains lacking the specific gene that controls the metabolism of brain neurotransmitters. A transgenic mouse strain (Tg8) was produced at the Curie Institute (France) with the monoamine oxidase A (MAOA) gene irreversibly destroyed. MAO A is known to be the principal enzyme involved in the metabolism of brain serotonin and catecholamines. It was demonstrated in collaboration with French researchers that MAO-A deficient mice showed increased serotonin and decreased levels of its metabolite 5-HIAA and behavioral changes. Tg8 mice showed increased tolerance to ethanol, a decreased auditory startle response, attenuated exploratory behavior and high aggressiveness. This is in agreement with Brunner's (1993) observation of the syndrome of borderline mental retardation and increased agressiveness in a human of Dutch origin with a mutation in the MAO-A gene.