The participation of the glutamatergic neurotransmitter system in the pathogenesis of audiogenic seizures (AS) and post-ictal catalepsy (PIC) in Krushinsky–Molodkina (KM) strain rats was analyzed. Effects of D-serine and disocilpine administration were investigated. In intact KM rats, the intensity of AS correlates with the duration of PIC. The administration of D-serine (acute administration, doses of 200, 400 and 600 mg/kg, as well as after chronic administration—5 days of 300 mg/kg, n = 34) had no significant effect on AS and PIC. Disocilpine (MK-801, a non-competitive NMDA antagonist) was administered in an acute experiment at doses of 0.1, 0.2 and 0.4 mg/kg (n = 41). MK-801 dose-dependently reduced the intensity of AS and caused a “two-wave pattern” of seizures in the most of animals, and removed PIC at a lower dose than AS seizures. PIC was completely eliminated already at a dose of 0.2 mg/kg, while the clonic component of AS still persisted. Thus, it was possible to show the “dissociation” between AS and PIC. It is assumed that although dopaminergic control is involved in the mechanisms of PIC development, glutamatergic neurotransmission is also taking part in the PIC manifestation.

Mice of two strains selected for successful solution of "object permanence" test and for lack of such solution demonstrated the differential reaction to injections of two drugs. The effects of injections of atomoxetine. which blocks the noradrenaline reuptake, and of 'non-benzodiazepine" anxiolytic afobazol was different. The success of solutions increased in mice selected for this test "non-solution": and decreased or was inefficient in mice, selected for successful solution of object permanence cognitive test.

The description of the developed experimental set, permitting to evaluate rats solution of the "object permanence" test (be J. Piaget), which reflects animal capacity to operate one of the most simple empirical rules (by Krushinsky), i.e. capacity to solve elementary logic task. An animal, being placed in the brightly lit part of the box, is eager to run into the dark one via underpass, although after the first attempts the underpass was hidden by several means, and now an animal can solve the task overcoming the obstacle in case it operates the object permanence rule. The test solution does not require the previous learning, and it is similar to the test used in mice experiments. The test was applied in experiments with rats of five genetic groups - outbred Wistar and Long-Evans rats, rats of inbred audiogenic-prone Krushinsky - Molodkina (KM) strain, the strain derived from KM rats, selected for audiogenic non proneness and inbred SHR strain with spontaneous arterial hypertension. The preliminary experiments (performed with an animal during one experimental day) revealed interstrain differences with the test solution prevalence in SHR strain. This test could be used in pharmacological and neurophysiological experiments with rats.

Mice of two strains, selected, respectively, for successful solution of puzzle-box test (addressed to “object permanence” rule operation) and for non-solution of this test, were tested for short term memory, attention to moving object and neophagia. The data obtained demonstrated, that mice, selected for successful “object permanence” test solution demonstrated higher scores in recent memory and attention indices. It was suggested, that interstrain differences discovered should be addressed to differences in the “executive functions” expression.

Learning difficulties are a fairly common comorbid complication in patients diagnosed with epilepsy. The relationship between the predisposition to epilepsy and the ability to learn is an important problem. The aim of the study was to analyze how the learning capacity differs in rats with different predispositions to reflex audiogenic epilepsy (AE). The success of active avoidance (AAC) conditioning in the shuttle box in rats of 3 strains was evaluated. These were rats predisposed to audiogenic epilepsy—the Krushinsky–Molodkina strain (KM), strain “4” (selected from a population of F2 hybrids of the KM strain and AE non-prone Wistars) and rats of “0” strain, selected for the absence of AE from the same population (i.e. these strains differ radically in AE-proneness, but have a similar genetic background). The training was conducted continuously for 5 days (20 presentations per day). Experiments have shown significantly more successful acquisition of this skill in rats of the “0” strain: in total, 75 of AAC training (70 intermediate—41.7 (8.3 possible to identify more successful learning in rats, selected for the absence of AE seizures (strain “0”) compared to rats of the KM and “4” strains (expressing tonic seizures of maximum intensity in response to sound exposure). The weakest acquisition was revealed in the KM strain, in which the selection process duration for AE proneness was significantly longer than in the rats of the “4” strain.

This investigation included an analysis of the nootropic effects of a dimeric dipeptide, substance GK-2, a nerve growth factor mimetic, in a cognitive test (object permanence, by J. Piaget) in mice of two strains selected for their large and small relative brain weights (strains LB and SB). The influences of the dipeptide (0.5 mg/kg, injected i.p., subchronically, 5 days) on cognitive test solution in mice of different genotypes were opposite, mice of both strains escaped more quickly in the comfortable dark part of the box, but in cases of the obstacles (the underpass being masked by wood shavings) this effect was significant for 8-month-old LB strain mice, while in SB mice no effect was found. The proportions of mice that solved the task successfully when the underpass was blocked by a plug were lower in LB and higher in SB (the small sizes of groups permitted us to obtain only the tendency in differences from controls). Neophagophobia test performance show that the dipeptide infusion induced more active reaction to the novel food with LB reactions being clearer. The age interstrain differences in solution of this test were also found, both in dipeptide and in the control groups. The data on genotype–dependent changes in behavior after GK-2 infusion are important for more extensive characteristic of GK-2 pharmacological properties as a possible therapeutic drug.

The results demonstrate and confirm the significant role of monoamine imbalance in the ictogenesis of Krushinsky–Molodkina rats with genetically determined audiogenic epilepsy and in the development of audiogenic kindling (AuK) in them. The experiments were carried out on rats of the Krushinsky–Molodkina (KM) line without sound stimulation (KM-background) and after the development of AuK (KM-AuK). The control group was rats of line “0”, in which convulsions in response to sound were completely absent. AuK was generated using 20-fold sound stimulation (120 dB). Neurochemical analysis was performed by HPLC/ED in the frontal cortex, hippocampus, hypothalamus, nucleus accumbens, and brainstem. It has been established that AuK in KM rats leads to the appearance of myoclonic and attenuation of stem convulsions, which is accompanied by a change in the functional activity of the noradrenergic and serotonergic systems of the brain. KM rats exhibiting tonic convulsions in the “background” have a low content of norepinephrine in the hippocampus and hypothalamus, and when audiogenic myoclonic convulsions develop, norepinephrine deficiency is observed in the frontal cortex. After the formation of AuK, the excessively intense serotonin metabolism revealed in KM slows down in the hippocampus, nucleus accumbens, and, especially, in the brainstem, and the serotonin deficiency in the striatum also disappears. The peculiarities of norepinephrine metabolism in KM rats before and after AuK emphasize the important role of the cortex in the development of myoclonic convulsions, and of the hippocampus and hypothalamus in the implementation of stem convulsions. Excessive functional activity of the serotonergic system, revealed in KM “background” rats, slows down in a number of brain structures during the production of AuK.

This study provides a review of experimental research on selection in mice, which yielded positive results. The selection of mice was high (the task required mice to understand that an object that has become invisible still exists and can be found) and poor performance occurred in a cognitive test. The results we obtained revealed better short term memory in mice selected for high performance scores and that these mice also had higher performance in tests for novelty and attention. This suggests that differences between the mice used in the experiment are associated not only with cognitive abilities in tests, but also with more pronounced “executive functions.”

Dexamethasone is a synthetic glucocorticosteroid with anti–inflammatoryand immunosuppressive effects. In order to identify new targetsfor pharmacotherapy, as well as to study immune mechanisms in thepathogenesis of epilepsy, the influence of dexamethasone on audiogenicepilepsy and catalepsy in Krushinsky–Molodkina (KM) rats has beenstudied. The chronic (but not acute) infusion of dexamethasone decreasedthe audiogenic seizure fits intensity in male rats of Krushinsky–Molodkina(KM) strain which is highly susceptible to audiogenic epilepsy,but was accompanied by part of animal deaths. In a month after dexamethasoneinjections the audiogenic sensitivity of the rescued animals restoredto the control levels. The “0” strain rats, bred from F2 KM x Wistarhybrids, no dexamethasone induced mortality was found. The acuteand chronic dexamethasone action in rats of “0” strain induced theemergence of catalepsy after the sound exposure, although the audiogenicseizure was found only in one animal. The chronic and acute dexamethasonedecreased the postictal catalepsy in KM rats. Thus, pro-inflammatory mechanismsare involved in the pathogenesis of audiogenic epilepsy. Dexamethasonehad a distinct anticonvulsant effect in the chronic experiment.

Mice of two strains bred for large and small relative brain weight (BB and SB) were tested for hyponeophagy, responses in the unavoidable slippery funnel test and the test for understanding object permanence (as per J. Piaget), in which they had to find an underpass to a comfortable shelter when hidden (a cognitive test). Between-strain differences were evaluated in control mice and in groups after 2 h of restraint, which provokes the development of a stress reaction. In the hyponeophagy test, reactions to a novel foodstuff in a novel environment were significantly greater in SB mice (but not BB mice) after restraint than in controls. In the unavoidable slippery funnel test, BB mice showed significantly longer adaptive escape reactions after restraint, while this change was insignificant in SB mice. BB mice transferred from one type of response to another more frequently than SB mice. In SB mice the pattern of the ratio of the amounts of time spent in the three types of reaction in the funnel test in controls and after restraint were different from those in BB, which is evidence of between-strain differences. BB mice (total control and experimental) solved the cognitive test better than SB mice. Stress had no significant influence on measures of solving this test. These data show that differences in behavior exist between the BB and SB strains (including in the state of stress), despite cessation of selection for relative brain weight.

Using the selected mouse strain EX as the founding population (selection for extrapolation ability) three selection generations of mice were obtained, which were selected for successful solution of object permanence test (plus-sub-strain) and for lack of such solution (minus-sub-strain). The successful solution required not only the ability to operate the object permanence rule (by J. Piajet), but the performance of complicated action (executive function) which was significantly higher in plus-substrain, and this is the unique example of successful selection for cognitive trait.

Audiogenic epilepsy (AE), inherent to several rodent strains is widely studied as a model of generalized convulsive epilepsy. The molecular mechanisms that determine the manifestation of AE are not well understood. In the present work, we compared transcriptomes from the corpora quadrigemina in the midbrain zone, which are crucial for AE development, to identify genes associated with the AE phenotype. Three rat strains without sound exposure were compared: Krushinsky-Molodkina (KM) strain (100% AE-prone); Wistar outbred rat strain (non-AE prone) and “0” strain (partially AE-prone), selected from F2 KM × Wistar hybrids for their lack of AE. The findings showed that the KM strain gene expression profile exhibited a number of characteristics that differed from those of the Wistar and “0” strain profiles. In particular, the KM rats showed increased expression of a number of genes involved in the positive regulation of the MAPK signaling cascade and genes involved in the positive regulation of apoptotic processes. Another characteristic of the KM strain which differed from that of the Wistar and “0” rats was a multi-fold increase in the expression level of the Ttr gene and a significant decrease in the expression of the Msh3 gene. Decreased expression of a number of oxidative phosphorylation-related genes and a few other genes was also identified in the KM strain. Our data confirm the complex multigenic nature of AE inheritance in rodents. A comparison with data obtained from other independently selected AE-prone rodent strains suggests some common causes for the formation of the audiogenic phenotype.

Behavior in the open field test was compared in rats of two strains differing in terms of the manifestation of convulsions in response to sound (audiogenic epilepsy (AE)). These strains (“4” and “0”) were bred on the basis of a single hybrid population. Testing was performed before a series of exposures to sound (21 days) and after exposure. During sequential presentations of sounds, rats of strain “4” formed myoclonic convulsions, while “0” rats had no AE and, thus, no myoclonic convulsions. In the initial test, the level of locomotion and exploratory activity were greater in “4” rats than in “0” rats. In the second test, “4” rats showed significant changes in many behavioral parameters reflecting general suppression of exploratory activity and locomotion. Rats of strain “0” exposed to sound (but not displaying signs of AE) showed more active behavior in the second test than the first, reflecting acclimation of the animals to the experimental context, though changes in a number of indicators in the second test provided evidence of the complex nature of changes in anxiety levels in these animals (as a result of serial exposure to loud sounds). The similar genetic backgrounds of the two rat strains contrasting in terms of AE leads to the conclusion that changes in the behavior of “4” rats resulted from induction of a series of the epileptiform phenomena of AE. This pair of strains may provide a clear genetic model of convulsive states providing for reliable assessment of the effects of both external actions and pharmacological agents.

Mice from two lines selected for large and small relative brain weight (LB and SB) were tested for hyponeophagia, for the behavior in the "unescapable slippery funnel" and for understanding the rule of "object permanence" (by J. Piajet) they had to find the underpass to the comfortable cover when it was masked (the cognitive test). The interline differences were evaluated in the control groups and groups after 2 hour immobilization, which provoked the stress reaction. Neophagia test (new food in the new environment) revealed the significantly higher reaction to new food in SB (but not in LB) mice after immobilization in comparison to their controls. In the unescapable slippery funnel LB mice after the immobilization demonstrated the significantly longer time of the most adaptive "escape" reaction, while in SB mice this effect was not significant. LB mice shifted from one type of reaction to another one more frequently. The "pattern" of time intervals spent in reactions of three types in funnel test by SB mice (controls and after immobilization) had been different from that of LB. LB mice (control and experimental groups in sum) solved the cognitive test more successfully, than SB. Although no significant influence of the stress on the indices of this test was found. The data obtained permit to state that the behavioral differences between LB and SB mice still could be found (including those in the state of stress), in spite of the lack of active selection for relative brain weight differences.

Браконьеры, а порой и люди, не соблюдающие правила охоты «на берлоге», убивая медведицу, обрекают на гибель и ее потомство; в лучшем случае медвежата могут оказаться в цирке или в зоопарке. Как помочь осиротевшим медвежатам Как воспитать дикого медведя, чтобы можно было вернуть его в лес Эти вопросы давно волновали зоологов, в том числе и В.С.Пажетнова, который посвятил жизнь изучению поведения и биологии медведей. Этот опыт позволил ему разработать уникальную методику выращивания и воспитания медвежат и создать Центр спасения медвежат-сирот, где занимаются реабилитацией и реинтродукцией бурого медведя для восстановления его группировок в пределах ареала. Недавно Валентин Сергеевич скончался, но остались его многочисленные последователи, и в их числе его замечательная семья.