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Mice selected for high score in the extrapolation test (EX line) and kept under conditions of "enriched environment" for 3 months demonstrated changes in locomotor and exploratory activity and enhanced reaction to novelty. The relative brain weight was higher and neurogenesis in the hippocampal fascia dentate was more intensive in this group. In non-selected mice, the changes were similar, but insignificant in many cases.

Experimental data were reviewed which demonstrated that the neonatal injection effects of certain biologically active drugs (ACTH(4-10) fragment and its analogue Semax, piracetam, caffeine, levetiracetam, busperone, etc.) could be detected in adult animals as changes in physiological and behavioral reactions and in several morphological traits as well. Audiogenic seizures proneness, anxiety-fear and exploration behavior as well as pain sensitivity were analyzed. The remote effects discovered were either similar in direction to those applied to an adult organism, or opposite to it. Pharmacological treatments of such type presumably interfere the CNS development during early postnatal ontogeny and change the normal pattern ofbrain development. These modulatory influences could be due to changes in neurotransmitter system development and are presumably capable to induce CNS morphological deviations (numbers of neurons, adult neurogenesis).

The behavior scores were assessed in mice selected simultaneously for high percentage of correct extrapolation task solutions and for low anxiety during test performance. Extrapolation test requires that the hungry animal searches for the food bait which disappeared from the view moving in the direction of food bait movement. In the 4th selection generation no significant changes occurred in the percentage of correct task solutions neither in comparison to control unselected population, nor against 50% chance level. Although the proportion of mice in selected strain which performed with 80-100% of correct solutions increased and in F4 was higher in comparison to controls (approaching significance). The proportion of "0" solution (when mouse made no choice) and of "refusals" of performance (anxiety indices in this test) were lower in selected line and the proportion of refusals in F4 was significantly lower than in controls. Elevated plus maze, closed plus maze and inescapable slippery funnel tests demonstrated significantly lower anxiety in mice of selected strain. These data demonstrate much more complex genetic basis for the capacity for extrapolation (lack of response to selection) in comparison with that of anxiety traits in mice (changes in the response to selection).

Mice from the earlier developed recombinant inbred strains (RIS), which were derived by crossing 101/HY mice (carrying the mut-1 allele determining increased susceptibility to the mutagenic action of alkylating compounds) with C3H/Sn mice (lacking this trait), were tested for the presence of two neurological pathologies, audiogenic epilepsy and splitting of pyramidal cell layer of the CA3 hippocampal field (specific only to 101/HY mice). It was demonstrated that segregation of RIS relative to these traits was independent from the presence or absence of the mut-1 allele. These findings suggested the appearance of mut-1-independent mutations in the 101/HY mice, which resulted in the development of neurological pathologies. The appearance of such mutations can be the consequence of the genetic repair defects, earlier observed in the mice with the same genotype, or they can be caused by other reasons.

We studied cytoarchitectonics of the hippocampus in 101/HY and CBA mice on brain sections stained after Nissl and Timm. In CBA mice, the structure of hippocampus was normal. In 10/HY mice, stratum pyramidale in field CA3 was "splitted" and the density of pyramidal neurons was decreased. Abnormalities were also found in the zone of suprapyramidal projections of mossy fibers (sp-ME), i.e., terminals of axons of the fascia dentata granular cells on the apical dendrites of pyramids. If in CBA mice the sp-MF zone was normal, i.e., looked like a vast compact formation or dense ordered bundle, in 101/HY mice, the sp-MF zone represented a group of scattered, diffuse, and interrupted bundles of varying length, some of which were incorporated in stratum pyramidale. Possible causes of the described morphological abnormalities are discussed, as well as their relation to specific features of biology, behavior, and neurological status of 101/HY mice.

Studies of behavior, neurophysiological reactions, neuromediator synthesis and brain structure of mice of the 101/HY strain (including those of the authors) are reviewed. This mouse strain is characterized by a chromosomal instability because of a recessive mutation mutator-1 (mut-1) and the defective DNA excision repair. Experimental studies revealed a number of behavioral and neurological deviations in the 101/HY as compared to the CBA and the C3H strains. These are abnormalities in spatial orientation, altered fear and anxiety reactions, anomalous locomotion, seizure developing in response to agents of various nature, and disturbances of the central nervous system, both structural and biochemical. Genome instability results in a number of neurological mutations, that may lead to the phenotypical effects observed in the 101/HY mice. Since the 101/HY mice partially display signs of severe human hereditary diseases caused by chromosomal instability and defective DNA repair, they can serve as a promising genetic model for these and other diseases related to impairment of the central nervous system.

Neonatal injection of the ACTH4-10 fragment (5 micrograms daily for five days) caused genotype-dependent changes in concentrations of some monoaminergic neuromediators and their metabolites in hippocampus and brain stem of adult CBA and 101/HY mice. The catecholaminergic neurons increased in number in hypothalamic zona incerta of adult 101/HY mice. Neonatal injection of the peptide caused also genotype-dependent changes in the exploratory behavior of adult animals. Sound sensitivity was reduced in the 101/HY mice, whereas no sensitivity was revealed in both control and experimental groups of the CBA mice. The effects discovered were suggested to be caused by changes in neuronal differentiation.

Rationale: AZT is commonly administered to seropositive women and their neonates to prevent mother-to-child transmission of HIV. Recently, animal studies performed in monkeys and rodents have revealed that pre- and/or perinatal exposure to AZT induces age- and sex-dependent behavioural alterations in the offspring, possibly resulting from an action of this drug on CNS targets. Long-term effects of prenatal AZT treatment on social/aggressive behaviour of adult male mice have been previously described. Specifically, AZT has been shown to induce selective changes in the offensive components of agonistic interactions., Objective: The aim of the present study was to extend previous findings, analysing the long-term effects of a more prolonged AZT exposure on intraspecific male mice agonistic behaviour., Methods: AZT was given orally twice daily to pregnant CD- mice. The dosage selected for AZT was 160 mg/kg. Saline solution (0.9% NaCl) was used as vehicle. Starting on postnatal day (PND) 60 isolated males underwent five 15-min repeated encounters with an opponent of the same age and strain isolated for the same amount of time. Furthermore, a locomotor activity test (PND 67) and a hot-plate test (52 +/- 0.1 degrees C) (PND 74) were performed to assess AZT effects on, respectively, general activity and pain sensitivity., Results: AZT perinatal exposure reduced attack behaviour of adult mice, while increasing the likelihood of them behaving as subordinates. Furthermore, long-term effects of AZT treatment on pain sensitivity were found in the hot-plate test, with AZT mice showing higher pain thresholds than controls., Conclusions: Overall, these data indicate that perinatal exposure to drugs such as AZT exerts selective effects on the developing CNS, resulting in long-term behavioural disturbances. Future studies will need to address the issue of the specific mechanisms underlying these effects.

We have identified interstrain differences in the rate of formation of certain reflexes and parameters of physical development in CBA/LacSto and 101/HY mice. We have shown that in young 101/HY mice, the maturation of reflexes reflecting the development of the vestibular, neurosensory, and neuromuscular systems, such as surface righting, bar holding, negative geotaxis, and auditory startle response, takes place later during postnatal life. Opening of eyes and auditory canals in mice of all studied groups takes place at the same time. In CBA females, maturation of cliff avoidance reflex occurs later than in 101/HY females; hair also appeared later. Body weight of young 101/HY mice of both sexes is significantly higher during the period of postnatal development from day 2 to day 20 than in the CBA strain. However, the relative brain weight was lower in the 101/HY strain. CBA males had a higher brain weight and also showed a faster rate of formation of inborn reflexes. We discuss possible factors underlying the observed difficulties in the rate of formation of reflexes in 101/HY and CBA young mice in relation to general background information about their genetic and neurobehavioral features. The results provide evidence that these differences are genetically determined; the rate of reflex formation does not depend on the overall physical development of mice and is rather due to a delay and/or abnormalities in nervous system development.

It has been established that mice of strain 101/HY suffer from audiogenic epilepsy seizures, the frequency and severity of which depend on animal sex and age. Mice were subjected to high intensity sound (about 100 dB) at the age of 14-16, 30, 60, and 190-270 days (Groups I, II, III, and IV, respectively). The testing was done three times. Mice of Group I were tested twice. The duration of sound stimulus was 20 s. Mice of both sexes from Group I were most sensitive. During the first test, the so-called "wild-run" behavior developed in 90% of animals and 60% showed tonoclonic seizure. Lethal outcomes in animals of this group (26.7% of the males and 23.5% of the females) were observed mainly during the second test, conducted one day after the first one. Only 6.7% of the males died during the first test in Group I. Severity of audiogenic seizure in males decreased with age, whereas among females there was a decrease in the number of animals with sensitivity to the sound stimulus. Among females of Groups III and IV, we did not detect any animals responding to the audiogenic stimulus by seizure and there were no deaths. Mechanisms underlying the audiogenic sensitivity of 101/HY mice are reviewed in the light of other information about the development of this genetic trait in rodents and in connection with other biological characteristics of these animals.

Females of strains 101/HY and CBA were treated with a single dose of thio-TEPA (0, 0.625, or 1.25 mg/kg body weight) on day 12 of gestation (deposition of a vaginal plug was considered as the first day of gestation). Special experiments were performed on their offspring at 3 months of age to study exploratory-research activity (burrow reactions, upright postures), locomotor activity in a "open field" cage, emotional reactivity, and level of feeding motivation. Changes in behavior after exposure to thio-TEPA were observed in mice of both sexes and genotypes; however, in 101/HY mice, which are characterized by genetically determined genome instability and a defect in DNA repair system, such changes were more pronounced. In general, they may be defined as a decrease in intensity of exploratory-research activity with some modulation of the level of motor activity. Sex differences in behavior of animals of both strains after prenatal exposure to thio-TEPA were also found. The data provide evidence about the specific role of genetic factors in variation of mouse behavior after prenatal exposure to thiophosphamide and allow consideration of thio-TEPA as a behavioral teratogen.

An unusual type of locomotion--backward movements--was revealed in the 101/HY mouse strain characterized by a chromosomal instability and the defect in DNA repair. The backward movements were found in 60% of mice belonging to the population under study. The manifestation of the character was found to vary: it was high in 16% of the animals. No age and sex differences were found. The backward movements in the 101/HY mouse strain were somewhat similar to the peculiarity in locomotion of the neurological hot-foot mouse mutants. The latter had mild anatomical alterations in the cerebellum. No obvious brain pathology was revealed in the 101/HY mice.

On pregnancy day 12 101/H and CBA mice were injected intraperitoneally 2.5 mg/kg bw thiophosphamide. 3.5-month-old male offspring were sacrificed. The drug effect on the testes was evaluated by karyologic analysis of the germ cell generations on stage 7 of the seminiferous epithelium cycle. A reliable reduction in the number of spermatogonia A, preleptotene and pachytene spermatocytes and spermatids at development stage 7 was found in 101/H mice. There were interspecific differences in spermatogenesis intensity in intact animals and recovery of germ cell pool after thiophosphamide action inducing toxicity.

Spontaneous and mitomycin-C-induced chromosomal aberration level was studied in bone marrow cells of mice F1 (NZBXNZW), an experimental model of systemic lupus erythematosus and in C57BL/6J mice. The chromosome instability level is found to correspond to the degree of the autoimmune process: F1 (NZBXNZW) mice with the highest titer of autoantibodies to DNA has higher chromosomal mutability.

Chromosomal aberrations were studied in cells of embryonic liver and bone marrow of A/He and C57BL/6 mice following mutagenic treatment by the alkylating agent thiophosphamide in g1-S periods of the cell cycle. Higher sensitivity of chromosomes to aberration induction was found in A/He mice.

Fibroblasts from 101/H mouse fetuses manifest a higher rate of spontaneous chromosome aberrations as compared to fibroblasts from CBA fetuses. The molecular weight of single-strand DNA fragments from 101/H mice was found to be lower than that in CBA mice. No differences were disclosed in the strength of the DNA-protein bond in the cell chromatin of both mouse strains. It is assumed that the alkaline-labile-sites in DNA may be the cause of chromosome aberrations. The possibility of using 101/H mice as a model of human chromosomal instability syndromes is discussed.

The temporal, parameters of the cell cycle in the Atlantic salmon embryos were studied at the temperature 4.8 +/- 0.1 degrees from 10.5 hrs after fertilization (end of interphase of the 1st cleavage division) till 93 hrs (beginning of blastulation). The period of cleavage comprises 11 cell cycles. The II--V cell cycles equal each other by their duration, then the divisions accelerate and the VII--X cell cycles are shorter than the former by 10%, on the average. The duration of some phases (pro-, ana- and telophase) in different cycles proved to be variable and all mitotic phases varied by their relative duration from cycle to cycle; however, in all cell cycles of the cleavage period the mitosis occupied 2/3 of each cycle. The synchroneous character of the passage of cell cycle phases by all the cells is preserved only up to 8-blastomere stage. Beginning from the 16-blastomere stage when two cell layers appear along the animal--vegetative axis, the gradient is initiated: the animal layer cells in the cycle phases leave behind the vegetative layer cells which border the yolk.

The same damages were found to occur in hepatocyte DNA from old mice of different strains by means of sedimentation in alkaline sucrose concentration gradient. At the same time, the number of hepatocytes with aberrant chromosomes is strongly different in these strains. From these data an assumption is made that some other damages being accumulated with aging are responsible for chromosome aberrations except for single-strand DNA breaks. The number of single-strand breaks registered in hepatocyte DNA of the old animals under gamma-irradiation is two-three times more than that of the young animals, though the rates of repair of the induced single-strand breaks in DNA are the same for mice of different age and strains.

Frequencies of chromosomal aberrations have been shown to increase with the age in the liver cells of 101/H mice. The rate of accumulation is much higher in 101/H than in C54BL/6 mice. The frequencies of mitomycin C-induced chromosomal aberrations in bone marrow cells increased with the age in 101/H mice, but not in C57BL/6. Possible relationships between repair defects and instability of chromosomes in the aged 101/H mice are discussed.

No differences were found in both the baseline and mitomycin C induced levels of sister chromatid exchanges (SCE) between 101/H and C57BL/6J mice differing in chromosome mutability. An increase with the age of the spontaneous and mutagen induced SCE rates was similar in the strains compared, though instability of chromosomes was much higher in old 101/H than in C57BL/6J mice. Thus, no correlation was observed between chromosomal aberration and SCE levels in these strains. As 101/H mice were recently found to be DNA repair-deficient, possible connection of SCE and repair is discussed.

Sensitivity of bone marrow cell chromosomes to alkylating agent thiophosphamide and to gamma-irradiation has been studied in the course of ageing in 101/H, A/He, CBA, BALB/c and C57BL/6 mice. The effects of both the kinds of mutagenic treatment and of the genotype of the animals on the age-dependent changes in sensitivity of bone marrow cell chromosomes were found. Following gamma-irradiation under our experimental conditions, no variation in the output of chromosomal aberrations was observed between the strains studied. Following thiophosphamide treatment, aged mice of strains 101/H, A/He and CBA showed an increased chromosome instability as compared to young ones. In C57BL/6 mice the level of induced chromosome aberrations was found to be age-independent. Following thiophosphamide treatment, cells with multiple chromosome lesions were found in the bone marrow. The higher instability of aged animals in some strains was mainly due to a sharp increase in the number of such cells. In the intact mice of all the strains studied no age-dependent increase in the number of cells showing structural chromosome aberrations was observed, while accumulation of aneuploid cells varied with genotype.