Abstract
Aggression constitutes a central problem in several psychopathologies, including anxiety and depression disorders and antisocial behaviours. In particular, the activity of the HPA axis has been associated with aggression-related disorders. The present study assessed whether genetically-determined levels of anxiety-related behaviour influence the level of intermale aggression and whether this is associated with differences in neuroendocrine responsiveness and neuronal activation in the brain. Adult male Wistar rats bred for high or low anxiety-related behaviour were used, as well as non-selected rats with an intermediate anxiety level.
LAB residents displayed more aggressive behaviour than HAB and NAB residents during the RI test. Moreover, an inverse correlation was found between the level of anxiety and the level of aggression. The plasma ACTH response to RI test exposure was significantly higher in LAB than in HAB and NAB rats, indicating that a higher level of aggression was linked to an elevated hormonal stress response. Furthermore, LAB residents showed more neuronal activation in the parvocellular part of the PVN than HAB residents one hour after the RI test.
In addition, a tendency towards a higher number of c-Fos-positive cells in LAB compared with HAB rats was observed in the medial amygdala, hypothalamic attack area and central amygdala, areas relevant for the regulation of aggression. These data demonstrate that low trait anxiety is correlated with high intermale aggression. Furthermore, the increased neuronal activation of the PVN along with the higher ACTH responsiveness might underlie the display of high aggression.
Introduction
Aggressive behaviour has been associated with numerous neurological and psychiatric conditions, including anxiety and depression disorders (Apter et al., 1990; van Praag, 1998;
Fehon et al., 2001). In preclinical research, aggressive behaviour has been predominantly
studied by utilizing the natural drive of animals to defend their territory (Blanchard et al., 2003). Furthermore, to mimic abnormal forms of male aggression, and to reveal the underlying brain mechanisms, animal models, such as glucocorticoid hypofunction (Haller et al., 2001; Haller et al., 2004), olfactory bulbectomy (Leonard & Tuite, 1981; Mucignat-Caretta et al., 2004), alcohol administration (Miczek et al., 1997), social instigation and frustrative non-reward (de Almeida et al., 2005), have been developed. Additionally, the etiology of psychiatric disorders, and the appearance of behavioural abnormalities, are influenced by the genetic background (Caspi et al., 2002; Caspi et al., 2003). Therefore, selective breeding of animals for extremes in behaviour constitutes a powerful research tool to analyse genetic and neurobiological correlates of specific psychopathologies (Steimer et al., 1997; Landgraf & Wigger, 2002; Sluyter et al., 2003; Veenema et al., 2004; Overstreet et al., 2005).
In our laboratories, Wistar rats have been selectively bred for high or low anxiety-related behaviour (Liebsch et al., 1998a; Landgraf & Wigger, 2002; Neumann et al., 2005a). HAB and LAB rats also differ in other parameters of stress coping strategies in addition to their difference in anxiety. HAB rats show a more passive strategy, as indicated by, e.g., increased freezing during social defeat, more floating in the forced swim test, increased risk assessment and decreased exploration in the modified hole board and open field (Liebsch et al., 1998b;
Ohl et al., 2001; Bosch et al., 2005; Frank et al., 2006). These behavioural characteristics of HAB rats are genetically determined (Murgatroyd et al., 2004), and represent some symptoms prevalent in human anxiety and depression disorders (Keck et al., 2003). In contrast to HAB rats, LAB rats are less anxious and show a more active coping style when exposed to non-social and non-social stimuli, also compared with Wistar rats not selected for anxiety-related behaviour (Liebsch et al., 1998b; Ohl et al., 2001; Bosch et al., 2005). Moreover, LAB rats show a lower reactivity of the HPA axis to non-social stressors (Landgraf et al., 1999; Salome et al., 2004) and a lower level of social interaction compared with HAB rats (Henniger et al.,
2000; Ohl et al., 2001). In humans, low resting salivary cortisol levels have been associated with antisocial behaviour, conduct problems and persistent aggressive behaviour (McBurnett
& Lahey, 1994; McBurnett et al., 2000; Shoal et al., 2003). Cortisol reactivity was also found to relate to antisocial and aggressive behaviours. Some studies reported an attenuated (Moss et al., 1995; van Goozen et al., 1998), while others reported an elevated (Susman et al., 1997;
McBurnett et al., 2005; van Bokhoven et al., 2005a) cortisol reaction to experimental stressors. Information about HPA axis responses during the display of aggression in animal models is very limited. Therefore, the LAB rats are an interesting candidate for studying intermale aggression and their underlying neuroendocrine mechanisms.
In the present study HAB, LAB and NAB rats were used in order (i) to investigate the influence of genetic variation in anxiety-related behaviour on the display of intermale aggression, (ii) to reveal whether differences in aggressive behaviour are accompanied by differences in neuroendocrine responsiveness (by measuring plasma ACTH, corticosterone, and testosterone concentrations), and (iii) to study whether different levels of aggressive behaviour are accompanied by a different neuronal activation within brain regions implicated in aggressive behaviour.
Materials and Methods
Animals
Experiments were carried out with male rats (400-450 g body weight) selectively bred for either high or low anxiety-related behaviour on the EPM over the last decade (Landgraf &
Wigger, 2002). In addition, male NAB rats (400-450 g body weight, Charles River, Sulzfeld, Germany) were included to confirm selective breeding for both high and low anxiety-related behaviour. The rats were kept under standard laboratory conditions (12:12 light/dark cycle with lights on at 6:00 a.m., 22°C, 60 % humidity, and food and water ad libitum). All rats
were housed in groups of 3-5 unless mentioned otherwise. All experimental procedures were approved by the local government of Bavaria, Germany.