Effects of Social Isolation on the Development of Anxiety and Depression-Like Behavior in Model Experiments in Animals.

This review describes the role of social isolation in the development of anxiety and depression-like behavior in rodents. The duration of social isolation, age from onset of social isolation, sex, species, and strain of animals, the nature of the model used, and other factors have been shown to have influences. The molecular-cellular mechanisms of development of anxiety and depression-like behavior under the influence of social isolation and the roles of the HHAS, oxidative and nitrosative stress, neuroinflammation, BDNF, neurogenesis, synaptic plasticity, as well as monoamines in these mechanisms are discussed. This review presents data on sex differences in the effects of social isolation, along with the effects of interactions with other types of stress, and the roles of an enriched environment and other factors in ameliorating the negative sequelae of social isolation.

[Propranolol Impairs Memory Reconsolidation at Single and Multiple Paired with Tone Painful Electrocutaneous Stimulations].

In the current paper there were used two methods for assessment of the propranolol effect on reactivated memory at reconsolidation phase--a classical pavlovian conditioning and the two-ways escape reflex. The difference between these two models was that in the first case a tone was paired with electrocutaneous painful stimulation only once, while in the second case it was applied multiply. Reminding was produced in the first case by placing the animals into the same context, whereas in the second case by application of the same amount of pairings of conditional and unconditional stimuli as it was used at the first day of learning. Propranolol reduced intensity of freezing reaction on 25% from the baseline at the classical conditioning approach and practically led to disappearance of memory and complete regress of the two-ways escape reflex. There was suggested on existence of the possible different mechanisms of noradrenergic blockade on memory loss at the stage of its reconsolidation in the used models of learning.

[Does Impulsivity Affect a Long-term and Working Memory in rats?].

In the present paper usingthe method of delay discounting three groups of animals were discovered: a) those that at choice between immediate weak and delayed strong rewards have chosen an immediate reinforcement (high impulsive rats); b) those that were able to inhibit its own behavior and get the delayed reinforcement (low impulsive rats); and c) the rats with both types of reactions. In the water maze the different groups of rats did find a hidden platform for different time, swum various distance and with different speed. The differences however were significant only at overall comparison (for all days and trials) of the above mentioned parameters of the water maze learning. ANOVAs Group x Days, Group x Trials, and Groups x Days x Trials interactions were insignificant. The data obtained indicate that the difference between groups was appeared evidently due to the difference in general motor activity, rather than difference in their cognitive abilities assessed by reference and working memory tasks.

[Impulsive Choice Improves the Cue Memory at an 8-arms Radial Maze Learning in Rats].

At the process of learning in an 8-arm radial maze the impulsive animals found the reinforced arms and ate the pellets faster, than self-control and ambivalent rats. They committed less working memory errors at the cue memory task, though there was no difference in the rate of learning and a number of errors of reference memory in animals of different groups. During reversion learning at the change of reinforced arms on unre- inforced, and vice versa, the impulsive animals spent less time to enter into the reinforced arms compared to other groups. They had fewer errors of cue working and reference memory, but the rate of learning was the same as in other groups. The date obtained indicate that in the impulsive rats in comparison with the other groups of animals are stronger the general motor activity and better the working memory.

[Effect of Agonists and Antagonists of α2 Adrenergic Receptors on Choice of Reinforcement Value in Rats with Different Levels of Impulsivity].

The influence of drugs, agonist (clonidine) and antagonist (yohimbine) of α2-adrenergic receptors 5-HT2 on the behavior of rats tested by the method of choice to the value of reinforcement was investigated. Based on the selection of a rat the pedal for immediate poor and delayed valuable reinforcement rats were divided into 3 groups. Rats, in most cases, choosing valuable delayed reinforcements were classified as low-impulsive, those who mainly chosen poor immediate reinforcement to the high-impulsive group. Rats who were not able to determine, was ambivalent group. Administration (i.p.) of the α2-adrenergic receptors agonist clonidine resulted in a reduction of the select valuable delayed reinforcement by low-impulsive animals and increasing the number of missing responses of pressing the pedal in high-impulsive animals. Clonidine also reduced the latency of nose-poking in all groups of animals. The antagonist of these receptors yohimbine did not cause changes in the choice of the reinforcement in all groups of animals. At the same time yohimbine caused a significant reduction in the number of missing responses. The results suggest that the effect of drugs used in this work on α2-adrenergic receptors depends on the individual feature of rats, in particular from high and low degree of impulsivity.

[Synchronization and propagation of electrical potentials in neural networks of the brain cortex].

On the basis of the published data the scheme is proposed which explains the spread and synhronization of oscillatory activity in cortex. The main property of the neocortex is the existence of vertically oriented functional columns. Within and between the neuronal columns exist a feedforward and feedback morphological and functional connections. At the certain conditions inside the single module temporal windows are created using inhibitory process, and a synchronized activity can be generated of variable frequency (oscillations). The activity in the columns is enhanced by the synchronous involvement of great amount of neurons which is expressed in the form of local field potentials of high amplitude. Further the information about arisen in a single generator activity is transmitted through direct links to the nearby generator or to the group of such generators. In the nearby generator the activity increases and is transferred to the next generator. At the same time the signal is transmitted through feedback to the primary generator, and the activity is terminated until the next cycle will be initiated and so on along the cortex. The most important notion is that in the transfer of activity from one generator to another is involved a small number of elements. The major part of recorded oscillations of different frequency or epileptiform discharges, is not transmitted via the brain, but is generated in each module according to the characteristics transferred to it. The generation of epileptiform spikes occurs in cases when balance of inhibition determined by GABA A and GABA B receptors is disturbed.

[Effect of agonists and antagonists of 5-HT2 receptors on rats with different choice of reinforcement value].

The influence of drugs, agonist (DOI) and antagonist (ketanserin) ofserotonin receptors 5-HT2 on the behavior of rats tested by the method of choice to the value of reinforcement was investigated. Depending on their preferences in food reinforcement rats were divided into self-control (choosing more valuable, delayed reinforcement) and impulsive (low value, immediate reinforcement) groops. An hour before the test animals were administrated i.p. DOI and ketanserin at a dose of 0.2 mg/kg. Evaluated parameters of rat behavior: number of clicks on a particular pedal, the latencies and the number of omitted responses. The administration of ketanserin resulted in a statistically significant decrease in the choice of low-value immediate reinforcement of impulsive rats, and did not statistically significant alter the behavior of self-control animals. After the administration of DOI no statistically significant changes in the choice of reinforcement were observed in the groups of impulsive and self-control rats. But the study of the effect this drug in tote without division into typological groups the decreasing in impulsivity was revealed. In some cases DOI reduced the number of missing responses, and ketanserin--reduced the latency of response.

[Evaluation of exploratory activity and anxiety in rats with different levels of impulsive behavior].

Rats were divided into 3 groups according to their preference for reinforcements of different values. Animals that preferred valuable but delayed reinforcement in more than 70% of cases formed as self-controlled group, less than 30% of cases formed an impulsive group, the rest formed an ambivalent group. Behavior of animals of different groups was scored for exploratory activity and anxiety in x-maze, fear-conditioning and novelty suppressed feeding. The least active and the most anxious in all procedures used were self-controlled rats. Ambivalent animals as compared to self-controlled and impulsive rats were the least anxious in x-maze and had more successful trials in novelty suppressed feeding test. Impulsive animals demonstrated greater percent of freezing response during acquisition of conditioned fear and they were quicker in finding food in novel environment.

[Effect of the selective ligands 5-HT(1A) receptors administration on the impulsive and self-control behavior in rats].

The influence of drugs, agonist and antagonist of serotonin receptors 5-HT(1A) on the behavior of rats tested by the method of choice to the value of reinforcement was investigated. Depending on their preferences in food reinforcement rats were divided into self-monitoring (choosing more valuable, delayed reinforcement) and impulsive (low value, immediate reinforcement). An hour before the test animals were administrated i.p. agonist 5-HT(1A) receptors 8-OH-DPAT, [(+)-8-Hydroxy-2-(dipropylamino)tetralin] in a dose of 0.1 mg/kg or antagonist WAY-100635, [N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleat salt] at a dose of 0.2 mg/kg. Evaluated parameters, such as number of clicks on a particular pedal, the latencies and number of omitted responses. The results showed that the administration of drugs to modify individual behavior parameters both groups of animals. The introduction of 5-HT(1A) agonist receptors in impulsive animals caused an increase in the number of clicks on the pedal for more valuable reinforcement, and administration of an antagonist did not have any significant effect to behavior.

[Effect of D1/D2 dopamine receptors agonists and antagonists on rats with different choice of reinforcement value].

The effects of D1/D2 dopamine receptors agonist (SKF, TNPA) and antagonist (SCH 23390, raclopride) on rat behavior, associated with the choice of the reinforcement value were investigated. Animals were divided into two typological groups--group of impulsive, choosing low-value immediate reinforcement, and self-control group, preferring valuable delayed reinforcement (paradigm delay-discount). The results showed that i.p. administration of D1/D2 receptors antagonists (SCH 23390 and raclopride) resulted in a statistically increase in the choice of pedals with immediate reinforcement of low value in animals of self-control group, without causing a change in the behavior of impulsive rats. Also, the increase in number of missed responses was obtained. When D1/D2 receptors agonists (SKF, TNPA) were administered no significant changes were observed in rats' behavior. However, we noted a trend to change the preferences in choosing pedals for reinforcements, which was different in the rats of two groups--the self-control rats showed a decrease of pressing the pedal to get valuable delayed reinforcements, while in impulsive animals, on the contrary, the number of elections pedal receive valuable reinforcements increased. Thus our results suggest the difference between the effects of dopamine in animals differing in their individual and typological characteristics.

[Effects of blockade of dopaminergic D1/D2 receptors on behavior of impulsive and self-controlled rats].

Selective antagonists of D1 and D2 receptors (SCH 23 390 and raclopride respectively) were injected to rats divided on the basis of preliminary experiments into groups of"self-controlled" (preference of valuable but delayed reinforcement) and "impulsive" (choice of less valuable but immediate reinforcement) animals. Number of omissions of reactions and their latencies were recorded. In "self-controlled" rats, both drugs increased the number of reactions for less valuable immediate reinforcement, i.e., increased impulsiveness, whereas practically did not change the behavior of "impulsive" animals. Introduction of SCH 23 390 to animals ofboth groups increased the number of reaction omissions the effect being stronger in "self-controlled" animals. Raclopride also increased the number of reaction omissions in "self-controlled" rats but only on the next day after the injection. In "impulsive" animals, both drugs increased the latencies of reactions.

[Differences in behavior of impulsive and self-controlled rats in the open-field and light-dark tests].

The aim of the study was to reveal the relationship between impulsive behavior in rats, on the one hand, and locomotor activity and emotionality on the other hand. Rats were divided into groups according to their preference for reinforcements of different values. Animals that preferred valuable but delayed reinforcement in more than 60% of cases formed a self-controlled group, whereas rats that selected poor but immediate reinforcements in more than 60% of the cases were considered as impulsive. The two groups of animals were subjected to the "open field" and "light-dark" tests. The impulsive animals more quickly adapted to new surroundings and displayed more pronounced research activity as compared to the self-controlled animals. The level of anxiety was higher in the self-controlled group.

[Investigation of behavior of "impulsive" and "self-controlled" animals by the method of "emotional resonance"].

Rats divided into groups of "impulsive" and "self-controlled" animals by their preference of either high valuable but delayed or a low valuable but immediate food reward were studied by the method of "emotional resonance". It was shown that all rats of the "self-controlled" group choosing a high valuable although delayed reinforcement did not escape the defensive signals of another animal of the same species and for the most part of the trial time preferred to stay in the dark "house". The majority of animals belonging to the "impulsive" group (80%) spent more than a half of the time of the experiment in the bright compartment and thus saved a partner from electrical stimulation. The existence of some general mechanisms that underlie these two types of behavior is discussed.

[Remote control of the goal-directed behavior of freely moving rats by telestimulation of the rewarding brain structures].

The procedures are described that make it possible to train laboratory rats for remote control of their goal-directed behavior in open environments by telestimulation of rewarding brain structures. Rats were implanted electrodes in the lateral hypothalamus and lateral preoptic area. A week after surgery, rats were placed in an operant chamber and given electrical stimulation of increasing/decreasing intensity to each location to determine the most suitable site/hemisphere for reward delivery as well as the optimal stimulation parameters and the thresholds of behavioral reactions elicited. Then in T-maze, the animals were trained to obtain rewarding brain stimulation by running forward and turning correctly to the left or right arm of the maze in response to corresponding left- or right-turning light signal. At the last stage, rats were worn a backpack containing receiver-based remote-controlled microstimulator, connected to the implanted brain electrodes, and the animals were placed in open environments. The rewarding brain stimulation was delivered remotely using a transmitter connected to a laptop PC. Rats moved forward performing 'scanning' left-right head movements. Head movement in a desirable for the experimenter direction was reinforced. Animals remotely controlled by electrical stimulation of rewarding brain structures moved from one place of the environment to another according to any route given by an experimenter, overcame obstacles of different difficulties, not reacting to bright illumination, sounds and other external stimuli, and not exhibiting fear or curiosity, which are the typical reactions to novel surroundings. The more difficult was an obstacle the more stimulation was required to force an animal to overcome it.

[Study of impulsivity in rats under conditions of choice between food reinforcements of different values].

Rat behavior was studied under conditions "with the right to choose the values of reinforcements depending on the time delay of its receipt". Rats were placed in a chamber equipped with two retractable pedals, pressing one of which provided a small portion of food (1 pellet), and pressing the second pedal was followed by the delivery of more valuable food (4 pellets), but delayed reinforcement. Rats preferring small reinforcement without the delay were considered as "impulsive" and rats choosing more valuable delayed reinforcement were considered as "self-controlling". Influence of the delay duration and change in the level of motivation on the pedal pressing was studied in both groups of rats. Preference in the selection of the pedal, latency of pressing the pedal and the number of omitted reactions were estimated. It was found that "impulsive" animals more rapidly pressed the pedal and less frequently omitted trials than "self-controlling" rats. After the increase in the delay duration up to 7 seconds, rats stopped choosing the pedal with the delayed reinforcement. Increased food motivation shifted the behavior of rats to "self-control", whereas rats after feeding preferred less valuable immediate reinforcement.

Comparative analysis of spike activity of neurons in hippocampal field CA1 and CA3 in rats of different typological groups on exposure to emotional stimuli.

Spike activity from neurons in hippocampal field CA1 and CA3 was compared in rats avoiding ("altruists," group A) and not avoiding ("egoists," group E) the cries of a "victim" partner on testing using the emotional resonance method. Neuron discharge frequencies were compared in animals in the state of starvation, after satiation, and on exposure to emotionally positive and negative intracerebral electrical stimuli. These studies showed that hippocampal field CA1 was dominated by cells increasing their spike frequencies after satisfaction of the food motivation, while in field CA3, conversely, most cells decreased activity after eating. Exposure to emotionally significant stimuli identified interhemisphere differences in the activities of hippocampal neurons which were associated with the typological characteristics of the animals. In rats of group A, neurons in field CA1 were activated only in the left hippocampus, while the activity of cells in the right hippocampus was no different from that in baseline conditions. Field CA3 of rats of this group showed no asymmetry. In rats of group E, conversely, lateralization of activity was seen only in field CA3: discharge frequencies were significantly greater in the left hippocampus.

[Comparative analysis of neuronal impulse activity in the CA1 and CA3 hippocampal fields in various typological groups of rats under exposure to emotional stimuli].

Hippocampal unit activity in the right and left CA1 and CA3 fields was studied in rats divided in two groups by the method of "emotional resonance": the animals which did ("A") and did not stop ("E") crying of a partner rat. The rate of neuronal firing was studied in the state of hunger, satiation, and under exposure to intracranial electrical stimulation of the emotional positive and negative structures of the brain. It was shown that units increasing their activity after satiation prevailed in the CA1 field, whereas, in the CA3 field, the majority of neurons decreased the firing rate under these conditions. Intracranial stimulation, especially positive, increased the rate of firing in both hippocampal fields. Under exposure to emotional stimuli, "A" rats displayed asymmetric unit activity only in the CA1 field, whereas in "E" rats, activity was asymmetric only in the CA3 field. Under these conditions in both groups of animals, the left-side activity was more intense than the right-side activity independently of the emotion sign.

Hippocampal field Ca3 neurons in animals of different typological groups exposed to emotiogenic stimuli.

The spike activity of hippocampal field CA3 neurons was studied in rats avoiding (group A) and not avoiding (group E) the cries of a victim partner in the emotional resonance test. The frequencies of neuron discharges were compared in animals in the state of hunger, after satiation, and on exposure to emotionally positive and negative intracerebral electrical stimulation. The results showed that intracortical electrical stimulation produced increases in the discharge activity of neurons and that this activation was more marked for emotionally positive stimulation. Rats of group E showed asymmetry in their neuron responses to emotional stimulation on the right and left sides of the hippocampus. Left-sided cell activation was significantly greater than right-sided and was independent of the emotional sign of the stimulus. This asymmetry was not seen in rats of group A.

[Impulse activity in the CA1 field in animals of various typological groups exposed to emotional stimuli].

Hippocampal unit activity in the right and left CA1 fields was studied in rats divided in two groups by the method of "emotional resonance": the animals that did (A) and did not stop (E) crying of rat-partner. The rate of neuron firing was studied in the state of hunger, satiation, and under exposure to intracranial electrical stimulation of the emotional positive and negative structures of the brain. It was shown that the intracranial stimulation, especially positive, increased the rate of firing. Under exposure to emotional stimuli, the neural activity was asymmetric only in the A rats. The activity at the left was more intensive than the right-sided activity and did not depend on the sigh of emotion.

[Hippocampal neurons of the CA3 field in animals of different typological groups exposed to emotional stimuli].

Hippocampal unit activity in of the right and left CA3 fields was studied in rats which were divided in two groups by the method of "emotional resonance": the animals that did ("A") and did not stop ("E") crying of rat-partner. The rate of neuron firing was studied in the state of hunger, satiation, and under exposure to intracranial electrical stimulation of the emotional positive and negative structures of the brain. It was shown that the intracranial stimulation, especially positive, increased the rate of firing. Under exposure to emotional stimuli, the neural activity was asymmetric only in E rats. The activity at the left was more intensive then the right-side activity and did not depend on the sigh of emotion.