Effect of stress and immune stimulus on the pituitary-adrenal axis in gray rats selected for behavior

A comparison of effects of the restrain stress, and lipopolysaccharide and interleukin-2 treatment on pituitary-adrenal system of tame and aggressive rats, was examined. It was found that plasma ACTH and corticosterone levels in response to restrain stress and lipopolysaccharide treatment were significantly decreased in the tame rats compared to aggressive ones. By contrast, the maximum corticosterone level was the same in plasma of both groups after interleukin-2 treatment, although the time patterns of the response were different. Thus the selection of wild grey rats for tame behavior results in change of the response of the pituitary-adrenal axis to the immune stimulus. It is conceivable that the interaction between pituitary-adrenal axis and immune system also changes in tame rats.     

Some features of learning in swimming Morris test in rats selected for behavior towards human

Some features of learning in Morris water test were studied in gray rats after a long-term selection for elimination (tame strain) and enhancement (aggressive strain) of aggressiveness towards human. The content of plasma corticosteroids was estimated at different stages of learning. It was shown that tame rats were better in performance of a special Morris task than aggressive ones. The time of search for invisible platform was increased in aggressive rats owing to the fact that they spent more time near the pool walls. Also, time of rearing at the platform was higher in tame rats compared to aggressive animals. In the retention test, rats of both strains spent significantly more time in the target quadrant than they did in other quadrants. Rats of both strains did not differ in time of search for invisible platform when it was replaced to the opposite quadrant. After the first day of learning, the corticosteroid plasma level was lower in tame rats than aggressive animals. During the following days of training, the content of the hormone increased in tame rats and did not differ from aggressive rats. It is supposed that, in tame rats, low emotionality and stress response facilitated learning in Morris water test.     

Genetical aspects of hormonal modification of the stress reactivity. II. Modification in early ontogenesis of the stress reactivity of adult gray rats selected for behavior toward man

Inherited and modificational changes of the stress reactivity in two outbreed stocks of wild Norway rats trapped in nature and selected for behaviour were studied. During 18 generations the rats of one stock were selected for the lack of defensive behaviour in the glove test (tame), while in another stock the aggressiveness was maintained by the selection (aggressive). Interstock differences in the brain noradrenaline mechanisms were observed. The emotional stress reactivity of the tame animals was decreased, in comparison with the aggressive ones. Definitive stress reactivity of adult rats was modified by injections of hydrocortisone to their mothers on the 16 and 18 days of gestation. Hormonal treatment changed noradrenaline mechanisms and decreased the reaction to emotional stressor in aggressive rats. The modified level of the stress reactivity of aggressive rats was similar to the definitive level of the tame ones. Hormonal treatment did not modify stress reactivity in tame rats. Thus, the phenotype only emerging in aggressive rats, as a result of hormonal modification, is the inherited norm of the tame animals. However, due to rat selection for the lack of defensive behaviour towards the man, high corticosteroid level in the blood of pregnant females, an external developmental factor, in respect to the fetus, loses regulatory function during the development of the neuroendocrine mechanisms of the stress reaction.     

Effect on the immobilization-induced stress on the immune response in mice with various behavioral stereotypes

CBA and C57BL/6J mice with aggressive and submissive types of zoo-social behavior fixed during 10-day confrontation testing demonstrated different immune response to immobilization stress. In aggressive mice with confrontation experience stress resulted in a decrease in the immune response in comparison with aggressive inexperienced mice. Therewith, the immune response of CBA mice did not differ from the control level (the immunized mice without experience of victories and defeats), and in C57BL/6 mice the immune response was two times lower than in the control. In contrast to the control and aggressive mice, stress did not suppress the immune response in submissive animals. It is suggested that stress-induced changes in the immune response depend on zoo-social rank of an individual underlain by a particular neurochemical pattern of the brain.     

Genetics and phenogenetics of the hormonal characteristics of animals. VII. Correlation between brain serotonin and the hypothalamo-pituitary-adrenal system in domesticated and undomesticated silver foxes during emotional stress

Two groups of silver foxes, selected according their behaviour with respect to man and non-selected ones, were exposed to restriction-induced stress. It was found that changes in the level of brain serotonin and its main metabolite, 5-hydroxyindolacetic acid, and elevation of plasma corticosteroids concentration in domesticated (tame) silver foxes were much less pronounced than in non-domesticated (non-tame) animals. Positive relationship between type of behaviour, brain serotonin metabolism and pituitary-adrenal axis response to stress was observed. It is suggested that such correlative pattern as changed pituitary-adrenal axis responses in domesticated animals may be due to changes in metabolism of controlling this axis brain transmitter serotonin.     

The effects of prolonged selection for behavior on the stress response and activity of the reproductive system of male grey mice (Rattus norvegicus)

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 function of testes 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 rate of maturation 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.     

Chronic stress influences the immune system through the thyroid axis

The aim of the present work was to analyze the effect of chronic stress on thyroid axis and its influence on the immune response. For this purpose a murine model of chronic stress was developed to evaluate and to correlate thyroid hormone levels with humoral alloimmune response. Results show a reduction in serum levels of thyroid hormones, specially a significant decrease in serum levels of triiodotyronine (T3) in stressed animals. On the other hand, alloimmunization was not able to induce an early increment in T3 and thyroxine (T4) levels as it was previously reported in normal animals. In addition, lower titers of alloantibodies were obtained in animals under stress conditions as compared to normal mice. The sustitutive T4 treatment in stressed animals increased significantly alloantibody production as well as the early increment in thyroid hormones after antigenic challenge. These findings suggest that chronic stress induces an alteration of the function of thyroid axis that alters the immune response.     

Genetics and phenogenetics of the hormonal characteristics of animals. II. Changes in the reactivity of the pituitary-adrenal system and influence of the sex glands in selection of silver-black foxes by behavior]

Seasonal changes in the reactivity of adrenal cortex to ACTH and of the pituitary-adrenal system to psychic stress in intact and castrated domesticated (tame) and non-domesticated (non-tame) silver foxes of both sexes were studied. It is demonstrated that in tame foxes there are differences among the intact and castrated animal in their reaction to ACTH and psychic stress. These differences are maifested especially in autumn (September, October) which is the period of extra-seasonal sexual activity for domesticated animals. This points to the fact that the sex glands exert a great influence on the condition of central regulating mechanisms of the pituitary-adrenal complex and that the selection of silver foxes for tame behaviour changes the functional state of these mechanisms through the change of the functional state of the sex glands.     

The pleiotropic effect of selection for behavior on coat color in grey rats (Rattus norvegicus)

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.     

Behavioral effects of bidirectional selection for behavior towards human in virgin and lactate Norway rats

Although numerous studies have demonstrated strong differences in behavioral, hormonal and neurobiological characteristics between male rats selected for elimination (tame) and enhancement (aggressive) of aggressiveness towards humans, few studies have examined changes in female behavior under this selection. The objective of the current work was to evaluate the effects of bidirectional selection for aggressiveness towards humans on behavioral profiles of virgin and lactating rats compared with the behavior in tame, aggressive and unselected (wild-type) females. The behavior of virgin females was studied using the light-dark box, the startle response test and the modified glove test. Tame females were less anxious and more tolerant towards humans than unselected and aggressive rats. Principal component analysis of all behavioral parameters produced three independent factors, explaining 66.37% of the total variability. The measures of behavior towards humans and the measures of anxiety mainly loaded on PC1 (first principal component) which separated the tame females from the unselected and aggressive ones. These data suggest the genetic correlation between the selected behavior towards humans and anxiety-related behavior in virgin rats. No significant effect of line was found for PC2 scores, associated with risk assessment behavior. Measurements of freezing behavior mainly loaded on PC3, and this component separated rats of different genetic groups from each other. The behavior of lactating rats was studied in maternal defense and pup retrieval tests. Females of selected lines did not significantly differ in behavioral measurements of these tests and were characterized by higher maternal motivation than unselected rats. It is suggested that long-term breeding of tame and aggressive rats in captivity has reduced the threshold for maternal behavior.     

The relationship between different types of genetically defined aggressive behavior

Aggressive behavior is not a unitary trait, and different stimuli/situations elicit different kinds of aggressive behavior. According to numerous data the genotype plays a significant role in the expression of aggressive behavior. However, it remains unclear how genetic predisposition to one kind of aggression is linked with other kinds of aggressive behavior, especially pathological aggression (infanticide). Here, we report on our investigation of the expression of defensive, offensive, predatory and asocial aggression in wild rats selectively bred for 85 generations for either a high level or a lack of aggression towards humans. We found that those rats genetically predisposed to a high level of defensive aggression showed decreased social behavior and increased pathological aggressive behavior towards juvenile males. The highly aggressive rates showed a reduced latency time of attack and an increased latency time of the first social contact. Rats genetically predisposed to defensive aggression demonstrated increased predatory aggression—latency time of muricide was shorter in highly aggressive than in tame animals. At the same time, both lines of rats did not differ significantly in intermale aggression. We conclude that the data indicate a close relation between defensive, predatory and pathological aggressive behavior that allows us to suggest that similar genetic mechanisms underlie these types of aggressive behavior.     

Thie expression of an intraspecific aggressive reaction in the face of a stressor agent alters the immune response in rats.

The repercussion on the immune response of the expression of intraspecific aggressiveness in the face of a stressor agent was investigated in rats. Ninety-day-old animals were divided into three groups: the control group (only immunological measurements were performed), the foot-shock (FS) (animals individually receiving FS), and the intraspecific aggressive response (IAR) group (animals receiving FS and presenting IAR). For immunological measurements, blood samples were collected promptly at 7 and 15 days after FS or IAR. The FS reduced the total leukocyte amount presented. However, aggressiveness triggered not only reduction of the leukocytes, but also lymphocyte decrease and neutrophil increase. Moreover, an elevation in total leukocytes associated with an increase in the humoral immune response was also observed one week after IAR. In this study, the expression of intraspecific aggressiveness in the face of a stressor seemed to activate the immune system and to potentiate the antigen specific humoral response.     

Time course of vasopressin and oxytocin secretion after stress in adrenalectomized rats.

To characterize the participation of vasopressin (AVP) and oxytocin (OT) in hypothalamus-pituitary-adrenal regulation after adrenalectomy (ADX), we evaluated corticosterone, ACTH, AVP and OT plasma concentrations and AVP and OT content of the paraventricular nucleus (PVN) at different periods (3 h, 1, 3, 7 and 14 days) in sham or ADX rats under basal conditions and after immobilization stress. ADX animals showed undetectable corticosterone levels, while sham animals showed a marked increase in corticosterone and ACTH 3 h after surgery, then lowering to basal control levels. ADX rats showed high basal ACTH levels with a triphasic response without changes after immobilization. After three hours, the ADX group showed higher OT levels than the sham group. OT was increased after immobilization stress in sham and ADX groups. AVP plasma levels did not change throughout the basal or stress studies in either group. There was a decrease in hypothalamic AVP content 1 and 3 days after ADX under basal and stress conditions. Plasma osmolality showed a significant decrease in the ADX group at 3, 7, and 14 days. In conclusion, there are different pituitary-adrenal axis set points after removal of the glucocorticoid negative feedback. The role of vasopressinergic and oxytocinergic neurons in the ACTH secretion after ADX or immobilization stress appears to differ. Magnocellular AVP is unlikely to contribute to ACTH secretion in response to ADX or immobilization stress. On the other hand, OT is elicited by immobilization stress and might contribute to the ACTH secretion during short-term ADX.     

Genotypic differences in the reactivity of the hypophyseo-adrenal system and the resistance of mice to cooling

The response of pituitary-adrenal axis (non-specific stress reaction) and body temperature change (specific reaction to cold) to mild and extreme cold was studied in ten mice strains. Genotypic systems controlling the activity of pituitary-adrenal axis under the cold of various intensity seem to be different. It is possible that the extent of decrease in body temperature under the cold of various intensity is determined by the same hereditary mechanisms. It was shown that the considerable phenotypic variability in response of pituitary-adrenal axis and body temperature depends on environmental conditions as well, i.e. on the intensity and duration of cold stress. Significant variability in the survival under cold conditions in different mice strains and the important role of specific reaction to forecast of resistance to cold were discussed.     

Hypophysectomy and neurointermediate pituitary lobectomy decrease humoral immune responses to T-independent and T-dependent antigens

In rats, hypophysectomy (HYPOX) or neurointermediate pituitary lobectomy (NIL) reduce humoral and cell-mediated immune responses. However, to our knowledge, the differences in the effects of anterior versus posterior pituitary hormones on the immune responses have not been studied to date. We compared in rats, the effects of sham surgery (SHAM), HYPOX, and NIL on humoral immune responses to T cell-independent (TI) type 1 antigen DNP-LPS and to TI type 2 antigen DNP-FICOLL, as well as to T cell-dependent (TD) antigens ovalbumin (OVA) and bovine serum albumin (BSA). The results showed that: (1) both HYPOX and NIL induced a similar and significant decrease in IgM responses towards TI-1 antigens, (2) NIL but not HYPOX induced a decreased IgM response to TI-2 antigens, and (3) both HYPOX and NIL induced similar and significant decrease in IgG responses to TI-2 antigens. Compared with the SHAM group, IgM responses to both TD antigens did not change in HYPOX and NIL animals, whereas the IgG responses to OVA and BSA significantly decreased in HYPOX and NIL animals. These results indicate that hormones of the anterior and posterior pituitary play their own role in the regulation of humoral immune responses.     

Effect of selection for behavior on the pituitary-adrenal function of norway ratsRattus norvegicus in postnatal ontogeny

The activity of the pituitary-adrenal system was studied in the Norway rats selected for both maintenance and elimination of the aggressive behavior towards man in the postnatal ontogeny. The selection of the wild rats for domesticated behavior was shown to result in changes of the pituitary-adrenal system formation in the postnatal ontogeny, which is indicated by differences in the dynamics of the adrenals weight as well as of corticosterone content in the blood plasma and in the adrenals both at rest and under stress conditions between the domesticated and aggressive rats.     

Effect of acute and chronic psychogenic stress on corticoadrenal and pituitary-thyroid hormones in male rats

The effects of acute and chronic stress on serum corticosterone and pituitary-thyroid hormones were studied in male Wistar rats. Acute noise activated both the pituitary-adrenal and pituitary-thyroid axes. Chronic noise did not modify the basal serum levels of either corticosterone or pituitary-thyroid hormones. A decreased corticosterone response to noise was observed in chronically stressed rats, but the pituitary-thyroid response was the same in control and chronically stressed rats, suggesting that the mechanisms which control the responsiveness of both axes to a repeated stimulus are dissociated.     

Effects of maternal methyl-supplement diet on hippocampal glucocorticoid receptor mRNA expression in rats selected for behavior

In the present work, we study glucocorticoid receptor (GR) gene expression in gray rats selected for aggressive and domestic behavior, as well as in offspring of mothers with methyl-supplemented diet during pregnancy. Tame selection is associated with increased GR mRNA expression as compared with aggressive rats, whereas maternal methyl-supplemented diet inhibits GR activity in tame rats. GR gene promoter methylation is an important way of altering GR expression.     

Increased Biodiversity in the Environment Improves the Humoral Response of Rats

Previous studies have compared the immune systems of wild and of laboratory rodents in an effort to determine how laboratory rodents differ from their naturally occurring relatives. This comparison serves as an indicator of what sorts of changes might exist between modern humans living in Western culture compared to our hunter-gatherer ancestors. However, immunological experiments on wild-caught animals are difficult and potentially confounded by increased levels of stress in the captive animals. In this study, the humoral immune responses of laboratory rats in a traditional laboratory environment and in an environment with enriched biodiversity were examined following immunization with a panel of antigens. Biodiversity enrichment included colonization of the laboratory animals with helminths and co-housing the laboratory animals with wild-caught rats. Increased biodiversity did not apparently affect the IgE response to peanut antigens following immunization with those antigens. However, animals housed in the enriched biodiversity setting demonstrated an increased mean humoral response to T-independent and T-dependent antigens and increased levels of “natural” antibodies directed at a xenogeneic protein and at an autologous tissue extract that were not used as immunogens.     

Lipopolysaccharide injection induces rapid decrease of hypothalamic GnRH mRNA and peptide, but does not affect GnIH in zebra finches

Lipopolysaccharide (LPS) is frequently used experimentally to mimic acute infection. Through activation of the host's immune response, an LPS injection has profound effects on the adrenocortical response to stress and on behaviors including reduction in activity, water and food intake, and libido. These behavioral changes occurring during infection are collectively called "sickness behavior." It is thought that adoption of sickness behavior reallocates energy from other fitness-enhancing activities, such as reproduction, for use in the immune response. Although the behavioral effects of LPS treatment are well-known, less information is available regarding the effects of LPS on the brain in terms of controlling reproductive behavior, specifically concerning a newly discovered neuropeptide, gonadotropin-inhibitory hormone (GnIH). This study investigated the effects of an LPS injection on the behavior and the hypothalamic neuropeptides controlling reproduction [GnIH and gonadotropin-releasing hormone (GnRH)] of zebra finches (Taeniopygia guttata). Overall, there was a decrease in activity in birds injected with LPS. The number of GnRH-immunoreactive neurons was significantly reduced in birds injected with LPS when compared to controls, while the number of GnIH-releasing neurons remained unchanged. At the level of gene expression, a similar pattern was found: there was reduced expression of GnRH mRNA in LPS-injected animals, whereas GnIH expression remained unchanged. Plasma testosterone did not change significantly in LPS-injected animals, nor did plasma corticosterone. Taken together, these results indicate a rapid (within 3h) inhibition of the reproductive axis during an immune challenge mimicking an infection, specifically acting on the GnRH system. The present study expands our knowledge on the interaction between the immune system and the reproductive system.