Irina L. Kovalenko

A Model of Anxious Depression: Persistence of Behavioral Pathology

Chronic psychoemotional stress induced by negative experience of social defeats in intermale confrontations over a period of 30 days was found to lead to the development of anxious-depressive symptomatology in male mice. Cessation of the psychopathogenic conditions and placing of depressed animals in comfortable conditions for 1–2 weeks with females did not lift the pathological state. Individuals continued to show marked anxiety, a behavioral deficit, decreased communicativeness, and a high level of depressivity, as revealed by a variety of behavioral tests. Persistence of the resulting psychoemotional disturbance in these animals is evidence for the development and persistence of the behavioral pathology requiring drug treatment.

Molecular Implications of Repeated Aggression: Th, Dat1, Snca and Bdnf Gene Expression in the VTA of Victorious Male Mice

Background It is generally recognized that recurrent aggression can be the result of various psychiatric disorders. The aim of our study was to analyze the mRNA levels, in the ventral tegmental area (VTA) of the midbrain, of the genes that may possibly be associated with aggression consistently shown by male mice in special experimental settings. Methodology/Principal Findings The genes were Th, Dat1, Snca and Bdnf; the male mice were a group of animals that had each won 20 daily encounters in succession and a group of animals that had the same winning track record followed by a no-fight period for 14 days. Increased Th, Dat1 and Snca mRNA levels were in the fresh-from-the-fight group as compared to the controls. Increased Th and Dat1 mRNA levels were in the no-fight winners as compared to the controls. Significant positive correlations were found between the level of aggression and Th and Snca mRNA levels. Conclusions Repeated positive fighting experience enhances the expression of the Th, Dat1 and Snca genes, which are associated with brain dopaminergic systems. The expression of the Th and Dat1 genes stays enhanced for a long time.

Extended effect of chronic social defeat stress in childhood on behaviors in adulthood

Individuals exposed to social stress in childhood are more predisposed to developing psychoemotional disorders in adulthood. Here we use an animal model to determine the influence of hostile social environment in adolescence on behavior during adult life. One-month-old adolescent male mice were placed for 2 weeks in a common cage with an adult aggressive male. Animals were separated by a transparent perforated partition, but the adolescent male was exposed daily to short attacks from the adult male. After exposure to social stress, some of the adolescent mice were placed for 3 weeks in comfortable conditions. Following this rest period, stressed young males and adult males were studied in a range of behavioral tests to evaluate the levels of anxiety, depressiveness, and communicativeness with an unfamiliar partner. In addition, adult mice exposed to social stress in adolescence were engaged in agonistic interactions. We found that 2 weeks of social stress result in a decrease of communicativeness in the home cage and diminished social interactions on the novel territory. Stressed adolescents demonstrated a high level of anxiety in the elevated plus-maze test and helplessness in the Porsolt test. Furthermore, the number of dividing (BrdU-positive) cells in the subgranular zone of the dentate gyrus was significantly lower in stressed adolescents. After 3 weeks of rest, most behavioral characteristics in different tests, as well as the number of BrdU-positive cells in the hippocampus, did not differ from those of the respective control mice. However, the level of anxiety remained high in adult males exposed to chronic social stress in childhood. Furthermore, these males were more aggressive in the agonistic interactions. Thus, hostile social environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life.

Behavioral effect of terahertz waves in male mice

We studied the effect of terahertz waves (3.6 THz, 81.5 µ, 15 mW) on the behavior of mice. The mice perceived terahertz waves even after short-term exposure (15 min). The effect of terahertz waves was maximum in direct contact of the mice with the laser. Increased anxiety of experimental animals was observed on the next day after 30-min irradiation.

Repeated positive fighting experience in male inbred mice

Repeated aggression is a frequent symptom of many psychiatric and neurological disorders, including obsessive-compulsive and attention deficit hyperactivity disorders, bipolar and post-traumatic stress disorders, epilepsy, autism, schizophrenia and drug abuse. However, repeated aggression is insufficiently studied because there is a lack of adequate models in animals. The sensory contact model (SCM), widely used to study the effects of chronic social defeat stress, can also be used to investigate the effects of repeated aggression. Mice with repeated positive fighting experience in daily agonistic interactions in this model develop pronounced aggressiveness, anxiety and impulsivity, disturbances in motivated and cognitive behaviors, and impairments of sociability; they also demonstrate hyperactivity, attention-deficit behavior, motor dysfunctions and repetitive stereotyped behaviors, such as jerks, rotations and head twitches. In this protocol, we describe how to apply the SCM to study repeated aggression in mice. Severe neuropathology develops in male mice after 20–21 d of agonistic interactions.

The effects of fluoxetine and its complexes with glycerrhizic acid on behavior in rats and brain monoamine levels

The effects of the serotonin reuptake inhibitor fluoxetine (FL) and its complexes with glycyrrhizic acid (GA) in molar ratios of 1:1 (FLG-1) and 4:1 (FLG-4) on the behavior of adult rats were studied in an elevated cross maze, with measurement of brain monoamine and monamine metabolite levels. Agents were given via the intragastric route using a cannula at a dose of 25 mg/kg 1 h before testing. FL increased anxiety in the rats and decreased their movement activity; FLG-1 and FLG-4 had no effect on behavior. None of the agents affected brain serotonin content, though all decreased the levels of its metabolite 5-hydroxyindoleacetic acid in the hypothalamus, FLG-4 also decreasing this in the cortex. Noradrenaline levels in the hypothalamus were increased after FLG-1 and FLG-4. In the striatum, FL increased the levels of dopamine and its metabolite dihydroxyphenylacetic acid but had no effect on the level of transmitter catabolism. Unlike FL, FLG-1 activated dopamine metabolism in the striatum. Overall, use of FL complexed with GA significantly modified its behavioral effects, which appears to be associated with the effects of FL and its complexes on the function of the monoaminergic systems involved in controlling behavior.

Effects of single episodes of severe stress on the behavior of male and female CBA/Lac and C57BL/6J mice.

Experiments were performed to compare the behavior of male and female mice of the inbred strains CBA/Lac and C57BL/6J in the open field test after single episodes of severe stress imposed by forced swimming. Testing was performed 2 h (first test) and one day (second test) after stress. Control animals were intact males and females of these strains, and were also tested in the open field on two sequential days. Both male and female CBA/Lac mice showed increases in the latent period of excursions from the center of the field 2 h after stress. This change persisted to the second test in female CBA/Lac mice. In female C57BL/6J mice, there were changes in four of seven behavioral measures 2 h after stress, though at one day their behavior was as in control individuals. Stress had virtually no effect in males of this strain, only increasing the number of grooming acts in the first test. In addition, detailed analysis of the effects of repeat testing in control and stressed individuals of these mouse strains also revealed interstrain and gender-related differences in the effects of stress. The possible existence of increased basal (trait) and situational (state) anxiety in female C57BL/6J and CBA/Lac mice respectively is discussed.

Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq

Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs, and Mprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach may be used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with “ribosomopathies.”

Gender-Related Characteristics of Responding to Prolonged Psychoemotional Stress in Mice

The behavior of male and female C57BL/6J mice was studied after prolonged psychoemotional stress imposed by enforced cohabitation with an aggressive male on the other side of a partition in the cage and daily witnessing of 10-minute confrontations between the aggressor and another male placed with it. The elevated plus maze test demonstrated marked anxiety in mice of both genders after one month of psychoemotional stress. However, only females, but not males, showed an increase in the duration of passive swimming in the Porsolt test, along with some reduction in communicativeness in the partition test. Thus, these studies showed a more marked reaction to prolonged pscyhoemotional stress in females than in males.

Heterogeneity of Brain Ribosomal Genes Expression Following Positive Fighting Experience in Male Mice as Revealed by RNA-Seq

Repeated positive fighting experience in daily agonistic interactions is accompanied by changes of brain neurotransmitter activity and genes’ expression in male mice. This paper is focused on the analysis of ribosomal genes expression data as revealed by whole-transcriptome analysis (RNA-Seq) in five brain regions of male mice with long repeated experience of aggression accompanied by wins (winners). Downregulation of most Rps, Rpl, Mrps, and Mrpl genes was found in the midbrain raphe nuclei and striatum and upregulation—in the hippocampus and hypothalamus of the winners. There were no changes in ribosomal gene expression in the ventral tegmental area. The data allow considering the alteration in ribosomal gene expression as an animal model of ribosomal dysfunction developed under positive fighting experience in male mice.