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The influence of social disturbance in early life on behavior, response of blood corticosterone level to restraint stress, and endocrine and morphometric indices of the testes was studied in 2-month Norway rat males from three populations: not selected for behavior (unselected), selected for against aggression to humans (tame), and selected for increased aggression to humans (aggressive). The experimental social disturbance included early weaning, daily replacement of cagemates from days 19 to 25, and subsequent housing in twos till the age of 2months. The social disturbance increased the latent period of aggressive behavior in the social interaction test in unselected males and reduced relative testis weights in comparison to the corresponding control groups. In addition, experimental unselected rats had smaller diameters of seminiferous tubules and lower blood testosterone levels. In the experimental group, tame rats had lower basal corticosterone levels, and aggressive animals had lower hormone levels after restraint stress in comparison to the control. The results suggest that the selection in two directions for attitude to humans modifies the response of male rats to social disturbance in early life. In this regard, the selected rat populations may be viewed as a model for investigation of (1) neuroendocrinal mechanisms responsible for the manifestation of aggression and (2) interaction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems in stress., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Two Norway rat (Rattus norvegicus) populations contrasting in behavior have been raised at the Institute of Cytology and Genetics, Novosibirsk, Russia with long-term selection for the absence or enhancement of an aggressive response towards humans. They are designated as tame and aggressive, respectively. In this work we investigated the effects of the selection on behavior, stress responsiveness, and fertility in males of the 78th generation. It is shown that the difference between the strains in their response to humans remains the same as in previous generations. However, the differences in stress response and maturation age contradict earlier data. For the first time, we note a higher glucocorticoid-mediated response to restriction stress and retarded sexual maturation in tame rats compared to aggressive ones, according to morphometric indices of gonads and testosterone levels. It is conceivable that the change in selection effects is determined by the disjunction of the directions of selection for behavior and the modification of the stress response. This study is the first to characterize males recently (six or seven generations of propagation in captivity) caught in the wild with regard to the indices under consideration and used as a control group. Wild rats have the highest stress response and rate of sexual maturation as compared to those selected.

The effects of selection for a type of behavior relative to humans (tame and aggressive) on the intensity of coat color in agouti rats with the AAHH genotype were studied. Animals that were not under selection for behavior (wild animals) were used as the control. Morphometric analysis of the hair parameters that influence the intensity of coat color demonstrated that, on the one hand, polymorphism in the main coat color exists in the population of wild agouti rats, that is, both light and dark agouti animals exist. On the other hand, it was demonstrated that selection for a type of behavior in rats is accompanied by selection of animals that differ in the intensity of the main genetically identical coat color. Dark-colored animals are more prevelent among the aggressive animals, while light-colored animals prevail among tame animals. The association of the effects of selection for behavior with the modification of coat color is probably caused by the presence of common neurohormonal mechanisms for the regulation of these processes.

The involvement of glucocorticoid hormones in the appearance of white spottings during embryogenesis in domesticated gray rats was studied. It was shown that prenatal stress and exposure to dexamethasone on the 12-14 days of pregnancy of fully pigmented gray rats elicited the slowing of melanoblast migration and its development in embryos. It was associated with a 4-fold increase of the offspring percentage with the depigmentation on the ventral side of body in adults. It was also demonstrated that response of H PA axis to emotional stress was lower in adult offsprings from prenatal-stressed and dexamethason-treated mothers than in adult offspring from control mothers. The role of glucocorticoids in the appearance of coat depigmentation under animal domestication is discussed.

In rats selected for aggressive or domesticated (tame) behavior, spleen morpho-functional changes were examined under the conditions of cell-mediated immune response using experimental autoimmune encephalomyelitis (EAE) model. Tame rats were found to present more severe clinical manifestations, characteristic to EAE, than those with an aggressive behavior. Body mass changes in EAE were significantly different in tame and aggressive rats. The relative adrenal gland mass of control animals in both groups was not different, while in EAE it increased in aggressive rats and remained unchanged in tame rats. The relative spleen mass in control tame rats was greater than in aggressive ones. In EAE, it sharply increased in tame rats and slightly decreased in aggressive animals. Spleen lymphoid nodule diameter in control aggressive rats was smaller than in tame rats. In EAE, it decreased in aggressive rats and remained unchanged in tame rats. In aggressive rats with EAE, marginal zone width decreased more abruptly, while germinal center diameter increased more markedly than in tame animals. It is suggested that different responses to EAE of rats with dissimilar behavioral characteristics, are associated with differently directed effect of their hypothalamic-pituitary-adrenal systems on the balance of cell-mediated and humoral components of the immune response in animals with contrasting behavior.

The effects of selection of agouti rats (with genotype AAHH) on the tame and aggressive behavior and dietary methyl given to females from the eighth day of pregnancy to the fifth day after the birth of the offspring on the intensity of the agouti coat color in the offspring have been studied. The morphometric parameters of hair determining the darkness of the agouti color (the total length of guard hairs, the lengths of their eumelanin end and pheomelanin band, the ratio between the lengths of the eumelanin and pheomelanin portions of the hair, the total length of the awn hairs, and the relative length of their widened "lanceolate" upper end) have been compared. It has been found that selection of agouti rats for aggressive behavior is accompanied by darkening of the coat color compared to tame rats due to an increase in the ratio of the length of the black eumelanin end of the guard hairs to the length of the yellow pheomelanin band. Methyl-containing additives to the diet of females affect the intensity of the agouti coat color in the offsprings with both types of behavior, but to different extents. Aggressive offspring is more sensitive to the mother's methyl-containing diet: the percentage of animals that are darker than control rats is higher among aggressive animals than among tame ones due to a greater increase in the ratio between dark and light portions of hairs. The possible mechanisms of differences in the phenotypic modifications of coat color in control and experimental agouti rats with different types of behavior are discussed.

The morphological patterns of hair pigmentation (the size and shape of pigment granules and their distribution among layers) have been studied in four compound coat color forms of the American mink: moil-sapphire also known as violet (genotype m/m a/a p/p); moil-silver or sage (genotype m/m p/p); the color form determined by genotype m/+ a/a; and platinum leopard (S(k)/+ a/+ p/p). The hair pigmentation pattern specific for each coat color form and its difference from the standard coat color of the American mink (genotype +/+) has been determined. The possible mechanisms of the phenotypic expression of the nonallelic genes contributing to the described compound color forms are discussed.

Maternal choline diet is known to affect the processes of spatial learning. We report here our studies of learning ability in the Morris swimming test in the adult offspring of maternal rats given a methyl-containing supplement enriched with choline and betaine during pregnancy and lactation. Increases in the time taken to find the invisible platform and the duration of swimming close to the vessel walls were seen, these demonstrating worsening of learning ability in response to the maternal diet. Changes in the platform search strategy were not associated with increases in anxiety in male rats. The possible role of a maternal methyl-containing diet in altering the expression of genes controlling the development of the nervous system is discussed.

Maternal choline diet influences the spatial learning processes. In this work, the learning ability of adult progeny of mothers who had received methyl diet enriched with choline and betain during pregnancy and lactation was studied in Morris test. The introduction of the diet to pregnant rats resulted in an increase in the time of search for invisible platform and time of swimming near the pool walls in offsprings, which meant a worsening of their learning ability. It was also found that change in platform searching strategy was not associated with an increase in anxiety of male rats. Possible involvement of maternal methyl diet in the change of expression of genes which control development of the nervous system is discussed.

The effect of methyl supplements to the diet of pregnant homozygous (AAHH) female rats with agouti coat color mated with homozygous (aahh) males on the phenotypic modification of the coat color of their heterozygous offspring (AaHh) has been studied. Comparative morphological analysis of the main parameters of hair that determine coat color, including the total length of hairs of different types and the length of the upper black (eumelanin) and light (pheomelanin) parts of awn hairs has been performed. The pattern of pigment granule distribution among hair layers has been analyzed. The melanin content of the hair has been determined using electron spin resonance (ESR). Although all offspring have a typical agouti coat color (alternating black and light portions of hair), 39% of them have a darker coat color than control and other experimental rats have. The main differences between the offspring with darkened and standard coat colors are accounted for by the ratio between the eumelanin and pheomelanin portions of awn hairs. In darkened offspring, this ratio is significantly higher than in control rats. The possible mechanisms of the phenotypic modification of agouti coat color in experimental animals are discussed.

Spleen morphological characteristics were studied in rats with contrasting behavior towards man (aggressive and tame). It was shown that intact tame rats surpassed the aggressive ones in body mass, absolute and relative splenic mass and in diameter of lymphoid nodules. Humoral immune response to sheep erythrocytes in tame rats was significantly lower than in aggressive ones. Exposure to restriction stress for 4 hours stimulated formation of antibody-forming cells in the spleen and increased the differences in humoral immune response between the rats with contrasting behavior. In aggressive rats the exposure to stress caused significant increase in diameter of lymphoid nodules and their germinal centers, while in tame rats it resulted in augmentation of marginal zone thickness. The data obtained demonstrate for the first time the differences in morpho-functional characteristics of the spleen activity in response to restriction stress in animals with contrasting behavior.

Several reproductive parameters were studied in males homozygous (hh) or heterozygous (Hh) for the hooded mutation as compared with completely pigmented wild-type males (HH). Histological analysis of the testes was carried out in males of the three genotypes. The proportion of sterile males in homogeneous matings of homozygotes hh was twice as high as in matings of heterozygotes. The proportion of sterile males in matings yielding no progeny was also twice higher in homozygotes hh as compared with heterozygotes. No sterile males were detected in matings of completely pigmented wild-type animals. Unilateral cryptorchidism, a hypoplastic testis combined with a hyperplastic one, or hypoplasia of both testes were observed in some males homozygous for the hooded mutation. Morphologically, these defects were associated with underdevelopment or the complete absence of spermatogenic epithelium or with the presence of gaps and cells with large nondivided nuclei in the epithelium. The results showed that the hooded coat-color mutation exerts a pleiotropic effect on male fertility in rat.

Directional left-sided asymmetry of the adrenals was typical of black and silver foxes, American minks, and gray rats selected by their behavior. In domesticated, but to a greater extent, in aggressive animals, the weight of the left adrenal and the width of its medulla and cortex markedly surpassed the corresponding parameters of the right adrenal. In aggressive animals enlargement of the left adrenal cortex was associated with widening of the zona reticularis, while in domesticated animals with enlargement of the zona fasciculata.

The effects of dominant allele Ar of locus Agouti on the morphology of hair pigmentation were described in foxes. The Ar allele was shown to determine the type of melanin and its content in hair with no effect on the morphology of pigment granules and their distribution throughout a hair. Using the method of electron spin resonance (ESR), the types of melanin (eumelanin and pheomelanin) and their content in the hair of red (ArArEE) and silver (aaEE) foxes and their hybrids (AraEE) were determined. In silver foxes, only one type of melanin (eumelanin) was found. In red foxes and their hybrids (which are phenotypically similar but darker than red foxes), both types of melanin (eu- and pheomelanin) were found. The highest melanin content was detected in the coat of silver foxes. In the hybrids, the total melanin content was lower than in silver foxes, but significantly higher than in red foxes. In red foxes, the contribution of pheomelanin to the total hair melanin content was twice as large as in the hybrids.

A comparative morphological and functional study of adrenal cortex was conducted in adult male Norway rats selected for domestic and aggressive behavior. Morphological changes were shown to occur in the structure of zona fasciculata of adrenal cortex during selection for domestic behavior.

Selection of wild Norway rats for behavior conducted in different directions was shown to affect the rate of appearance of coat-color mutants. In the population selected for domestication (reduced aggressive-fearful behavior toward humans), almost all animals acquired the semirecessive mutation hooded (h). Selection for aggressiveness (enhanced aggressive-fearful response) was accompanied by an increase in the frequency of homozygotes for a recessive mutation nonagouti (a). In the population selected for aggressive behavior, seasonal variation in the rate of appearance of mutant animals was observed. Experiments on the maintenance of nonselected rats under artificial short-day conditions showed possible interaction between alleles Agouti (A) and nonagouti but exclusively in heterozygotes for hooded. This interaction may lead to the inactivation of the normal A allele in some AaHh heterozygotes and their transformation into aa homozygotes, which would resemble paramutation. Discussion of the results is focused on several issues: recent evidence on coat-color genes and their function, directional (as opposed to random) nature of appearing mutations, and the possibility of meiotic inheritance of genetic changes occurring in early development.

The structure of guard hairs was analyzed in the mottling mutants of silver foxes. The mottling mutation occurred in the population of silver foxes which has been subjected to domestication. Hairs from the mottling areas were shown to have the following distinctions from silvery-black hairs: the lack of clear grana-shaft separation, a lesser thickness and length, another shape and pattern of guard-hair scales, another thickness ratio between cortical and medullar layers, a lesser number of melanocytes in hair bulbs, and a lesser number of dendritic processes in melanocytes. Putative mechanisms underlying the phenotypic effect of the mutant gene that controls mottling are suggested.

Selection of wild gray rats for domestication (tame behavior) resulted in a sharp increase in the frequency of heterozygotes at the h allele of hooded, the main locus of rat depigmentation. The observed effect of the selection on the manifestation of the h allele is compared with similar effects giving rise to piebaldness in other animals subjected to experimental domestication. The results are discussed in terms of genetic specificity of piebaldness and of the selection vector.

A new dominant coat color mutation "talitsa" was revealed in the mink population of "Znamenskii" state fur farm (Tverskaya region', Russia). Qualitative analysis and quantitative assessment of the hair pigment of minks with the standard coat color, Talitsa, Royal-Pastel and American pearl mutations, as well as Talitsa x Royal-Pastel and Talitsa x American Pearl hybrids were conducted. It was shown that hair of all genotypes studied contained only one pigment type, namely, eumelanin. Hair of the standard-colored minks showed the greatest eumelanin content, whereas hair of Talitsa x Royal-Pastel and Talitsa x American Pearl hybrids showed the least content. The morphologic patterns of pigmentation of the mutant minks studied was described, including the shapes, dimensions and color of the pigment granules, as well as their distributions throughout the length and layers of the hair. Talitsa mutation was demonstrated to behave as a strong coloration attenuator in combinations with the Royal-Pastel and American Pearl mutations. It was proposed that the main mechanism determining the phenotypic expression of the Talitsa mutation is the reduction of number of melanocytes in the hair bulbs.

Examination of 255 patients with different pyo-inflammatory and septic diseases revealed high effectiveness of the detection of staphylococcal infection by the determination of antigen-binding lymphocytes (ABL) in the indirect rosette-formation test with the use of specially designed staphylococcal erythrocytes immune reagents. ABL were detected in 63% of the examined patients, their content varied between 0.57% and 6.41% (which was, on the average, equal to 1.92 +/- 0.10%). The effectiveness of the method depended on the specificity of the staphylococcal reagent used in the test and on the time of examination of the patients. In patients with acute processes the determination of ABL permitted the diagnosis of staphylococcal infection before the activity of the corresponding serum antibodies could be measured. ABL were classified with T, B and "zero" populations of lymphocytes.

Qualitative and quantitative analysis of fur pigmentation in brown and black water voles (Arvicola terrestris L.) was performed. Morphology of pigment granules, their distribution along the hair layers and histology of hair bulbs were studied. Morphological data and the results of the analysis of segregation in the progeny, when brown voles were self-crossed and crossed with black ones, led to conclusion that fur colour of water voles is mediated by genes from the agouti series, precisely, black colour is determined by the extreme non-agouti allele (aeae genotype), and in brown voles which are homo- or heterozygous the colour is determined by the agouti allele (AA or Aae genotypes).

Fixation of native chicken red cells with a solution containing 14.4 percent of acetate aldehyde and 0.85 percent of NaCl (pH 7.0-7.2) permitted preparation on the basis of these red cells of stable immunoreagents for the detection of antigen-fixing lymphocytes using any (optimal for the antigen used) procedure. Experiments have demonstrated a high efficacy of detecting staphylococcal, proteus, or Ps. aeruginosa etiology of pyoinflammatory and septic conditions in indirect rosette formation test with the developed immunoreagents. The levels of the detected antigen-fixing lymphocytes varied in the patients from 0.7 to 8.0 percent, the mean value being 2.1 +/- 0.1 percent.

Quantitative and qualitative analysis of pigmentation in "singne"-type fur color mutation arising in silver foxes during domestication, was made. It was shown that the decrease in quantity of eumelanine in hair and uneven distribution of pigment granules lengthwise the hair were the reason for formation of "singnes".