Calsequestrin as a risk factor in Graves’ hyperthyroidism and Graves’ ophthalmopathy patients

Background: The pathogenesis of Graves’ ophthalmopathy (GO), Graves’ hyperthyroidism (GH) and the mechanisms for its link to thyroid autoimmunity are poorly understood. Our research focuses on the role of the skeletal muscle calcium binding protein calsequestrin (CASQ1) in thyroid. We measured the concentration of the CASQ1 protein correlating levels with parameters of the eye signs, CASQ1 antibody levels and CASQ1 gene polymorphism rs3838284. Methods: CASQ1 protein was measured by quantitative Western Blotting. The protein concentrations were expressed as pmol/mg total protein by reference to CASQ1 standards. Results: Western blot analysis showed the presence of two forms of CASQ1 in the thyroid. The mean concentration of CASQ1 protein was significantly reduced in patients with Graves’ disease, compared to thyroid from control subjects with multi-nodular goitre or thyroid cancer. Although in patients with GO it was lower than that, compared with patients with GH this difference was not significant. Reduced CASQ1 in Graves’ thyroid correlated with the homozygous genotype of the rs3838284 CASQ1 polymorphism. Conclusions: Decreased CASQ1 in the thyroid of patients with Graves’ disease compared to thyroid from control subjects is not explained but may reflect consumption of the protein during an autoimmune reaction against CASQ1 in the thyroid

Individual Differences in Behavioural Reaction to a Changing Environment in Mice and Rats

Aggressive and non-aggressive male mice differ in their reaction to a changing social environment. In order to investigate if this differentiation holds also for non-social situations male mice are trained in a standard maze task, whereafter a change (extramaze and intramaze, respectively) is introduced. The results indicate that aggressive males fulfil their task fairly routine-like and do not react to a change which is in contrast to the non-aggressive individuals. In a second experiment a more continuously changing situation is created by testing the animals every 3 trials in a different maze configuration. In this situation in which a routine cannot be developed c.q. used, the aggressive males performed worse than the non-aggressive animals. It is suggested that the behaviour of aggressive males is mainly controlled by intrinsic factors whereas the behaviour of non-aggressive males is more dependent on external factors. Similar results are obtained when repeating the experiments with rats. This indicates that the relation between aggression and behavioural reaction to a changing environment has more general validity. The possibly underlying mechanism is discussed as well as the consequences for the functioning of the animals in a social setting.

Aggression and Adaptation to the Light-Dark Cycle:Role of Intrinsic and Extrinsic Control

In wild house mice, the hypothesis that in the organization of behavior the relative contribution of intrinsic factors is more important in aggressive males, while that of extrinsic factors is more important in nonaggressive individuals was confirmed using the circadian rhythmicity of activity. The faster rate of reentrainment and the suppression of activity during a subjective night and during adaptation to the new LD cycle in the nonaggressive males indicate that their circadian rhythmicity of activity is to a large extent determined by the Zeitgeber, an extrinsic factor. The slower reentrainment rate, the lack of response to a subjective night and the normal activity level seen during reentrainment in the aggressive mice suggest strong control by the pacemaker, an intrinsic factor. Tau differences between the aggressive and nonaggressive mice provide some evidence that the pacemaker of nonaggressive males is fairly labile and is easily influenced by external factors, whereas the pacemaker of aggressive animals is rather stable

Behavioural strategies of aggressive and non-aggressive male mice in response to inescapable shock

The effect of exposure to inescapable long-duration shocks of moderate intensity on intershock activity and on subsequent escape or avoidance performance was studied in aggressive and non-aggressive male mice. The activity of the non-aggressive mice was severely suppressed during the inescapable shock session, while that of the aggressive males was hardly influenced. The decremental effect of prior shock exposure on subsequent response latency and activity in an active two-way escape or avoidance task was greater in the non-aggressive than in the aggressive mice. There was no evidence that learned inactivity or learned helplessness (an associative deficit) could explain the results. Instead, individual differences in behavioural strategy in response to threatening situations appeared to account for the effects of inescapable shock. Aggressive male mice predominantly adopted an active behavioural strategy in challenging situations, which resulted in persistent attempts to exercise control over the external situation and hence in a sustained tendency to initiate responses. Non-aggressive mice primarily assumed a passive strategy; their tendency to exercise control was low, which readily resulted in a reduced tendency to initiate responses.

Heritable variation for aggression as a reflection of individual coping strategies

Evidence is presented in rodents, that individual differences in aggression reflect heritable, fundamentally different, but equally valuable alternative strategies to cope with environmental demands. Generally, aggressive individuals show an active response to aversive situations. In a social setting, they react with flight or escape when defeated; in non-social situations, they react with active avoidance of controllable shocks and with sustained activity during an uncontrollable task. In contrast, non-aggressive individuals generally adopt a passive strategy. In social and non-social aversive situations, they react with immobility and withdrawal. A main aspect of these two alternative strategies is that individuals with an active strategy easily develop routines (intrinsically determined behaviour), and consequently do not react (properly) to 'minor' changes in their environment, whereas in passively reacting animals it is just the other way around (extrinsically determined behaviour). It has become clear that active and passive behavioural strategies represent two different, but equivalent, coping styles. The coping style of the aggressive males is aimed at the removal of themselves from the source of stress or at removal of the stress source itself (i.e. active manipulation). Non-aggressive individuals seem to aim at the reduction of the emotional impact of the stress (i.e. passive confrontation). The success of both coping styles depends upon the variability or stability of the environment. The fact that aggressive males develop routines may contribute to a fast execution of their anticipatory responses, which is necessary for an effective manipulation of events, However, this is only of advantage in predictable (stable) situations, but is maladaptive (e.g. expressed by the development of stress pathologies) when the animal is confronted with the unexpected (variable situations). The flexible behaviour of non-aggressive individuals, depending strongly upon external stimuli, will be of advantage under changing conditions. Studies on wild house mice living under natural conditions show how active and passive coping functions in nature, and how the two types have been brought about by natural selection.

Behavioural strategies of aggressive and non-aggressive male mice in active shock avoidance

The hypothesis, partly based on findings in social interactions, that aggressive mice generally adopt an active behavioural strategy (cf. fight-flight) in threatening situations, while non-aggressive ones generally assume a passive strategy (cf. conservation-withdrawal) was tested using a two-way active shock avoidance paradigm. Overall, aggressive mice were found to be better active shock avoiders than non-aggressive animals, a finding that is consistent with our hypothesis. However, within the non-aggressive mice a clear dichotomy in high and low avoidance individuals was found. The high intertrial activity in the superior avoidance groups and the low activity in the poor avoidance group was interpreted as another indication of an active versus passive strategy respectively. Accordingly, it was concluded that not all non-aggressive mice assume a passive strategy, but that some mice adopt an active strategy, like all aggressive males.

Genetic and environmental (inter)actions in male mouse lines selected for aggressive and nonaggressive behavior

The purpose of this study was to investigate the effects of genetic and environmental factors, as well as their interaction, in the etiology of aggressive behavior in two mouse lines bidirectionally selected for offensive aggression. To this end, we raised the Finnish TA (aggressive) and TNA (nonagressive) selection lines either in isolation or in cohabitation with a female after weaning. At the age of 3 months we determined their aggressive behavior in three paradigms (intruder resident, neutral cage, resident intruder) against a male standard opponent. We also determined the animals' aggressive behavior against a female mouse. The results show genetic and environmental effects, as well as gene-environment interaction. We see prominent genotype effects under all conditions but each test is sensitive to a specific combination of environmental effects. A particularly noteworthy result is that variation in the unusual behavior of aggression towards a female is largely explained by the interaction of genotype with isolation. We also examined whether test experience influenced the outcome of an encounter between an experimental animal and an opponent, and found that this factor should not be underestimated, its effect size and direction depending on the type of paradigm and way of housing. These data suggest that the identification of genes underlying aggressive behavior in mice is by no means straightforward and that the result of this search will depend on the environmental design of the study (type of paradigm, housing conditions). These data also suggest that the use of 'test battery' mice might produce different results than the use of test-naïve animals