Research reportEphrin-A5 regulates inter-male aggression in mice
Introduction
Aggressive behavior is defined as behavior that occurs when a conflict between the interest of two individuals exists [1], [2]. Appropriate levels of aggression may be viewed as a universal fitness trait which enables survival, whereas exaggerated levels can inappropriately harm or even cause death of the individual involved [3]. Animal studies classified male aggression into two major categories: offensive and defensive, which differ in their motive, site and intensity of attack, and outcomes [4], [5]. Offensive aggression is also known as inter-male aggression and occurs in response to challenges over resources (i.e., territory). It involves attack toward the back and flank of the opponent [5], [6]. In rodents, offensive aggression is used to gain dominant status and access to sexually active females [1]. In laboratory research, the resident-intruder (RI) model is commonly used to study offensive aggression [7]. Defensive aggression, also known as fear-induced aggression [7], occurs in the presence of a stimulus that is considered dangerous to the animal. Here, the animal will first try to avoid the threat and will attack only if escape is not possible. This type of aggression may elicit submissive posture or, if the threat persists, attacks directed toward the nearest offending body parts, which are usually the head and snout [8]. The target biting test has been used to measure this type of aggressive behavior in rodents [9], [10].
Different brain regions and signaling molecules are linked to aggression including the hypothalamus, medial amygdala (MEA), lateral septum (LAS), periaqueductal gray (PAG) and the bed nucleus of the stria terminalis (BNST) [1], [2], [4]. Studies in rats identified a broadly distributed “hypothalamic attack area” (HAA) from which electrical and pharmacological stimulation elicited attacks, and lesions reduced it [4], [11]. The HAA includes the lateral part of the anterior hypothalamus (AH), the ventromedial nucleus of the hypothalamus (VMN) and the ventral part of the lateral hypothalamus [1]. It has been suggested that under normal conditions, this area controls whether agonist behavior is appropriate or not, but when stimulated the animal will attack even when not suitable [12]. Recently, Lin et al. [13] identified an aggression locus in the mouse ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) that corresponds to the HAA of the rat.
In this study, we found that ephrin-A5, a ligand of the Eph receptor tyrosine kinase family, is important for the development of aggressive behavior in mice. The Eph receptors and their ephrin ligands are the largest family of receptor tyrosine kinases with 14 receptors and 8 ligands in mammals [14]. Members of this family are divided into the EphA/ephrin-A and EphB/ephrin-B subclass based on structural homology and binding affinities [15]. In general A-class receptors bind to all A ligands and B-class receptors bind to all B ligands. However, some exceptions exist, specifically, EphB2 can bind to ephrin-A5 and EphA4 can bind to all the class B ligands [16], [17]. Both receptor and ligand are anchored to the membrane resulting in signal transduction that can propagate into both receptor and ligand-expressing cells. These singling events have been implicated in various biological responses including proper development of the central nervous system and blood vessel formation [17], [18], [19]. In addition, several Eph receptors have been shown to regulate the proper development of motor and social behavior in mice [20], [21], [22]. We have previously shown that EphA5 inactivation caused a decrease in aggressive behavior in mice [23]. In the current study, we report that inter-male, offensive aggression is severely reduced in male mice lacking ephrin-A5 (ephrin-A5−/−). This does not appear to be related to an inability to attack, since during the target biting test, ephrin-A5−/− mice exhibited increased target biting. In addition, testosterone levels and general olfaction were normal in the null mice indicating that their ability to smell and recognize the presence of the intruder is intact. Taken together our data reveal an important role of ephrin-A5 in aggressive behavior.
Section snippets
Animals
Both wild-type and ephrin-A5−/− animals used for this study were generated from litter mates on a mixed background (C57BL/6 and 129/SV) as described previously [24], [25], since backcrossing into pure C57BL/6 background leads to embryonic lethality (data not shown). Mice were maintained on a 12 h light/dark reverse cycle (lights off from 07:00 to 19:00 h), and had free access to food and water. The temperature was maintained at 25 °C. All behavioral experiments were performed during the first
Reduced inter-male (offensive) aggression in ephrin-A5−/− mice
In order to evaluate roles of ephrin-A5 in animal behavior regulations, we examined effects of its inactivation on mouse motor activity, spatial learning, and aggression. We found no defects in motor activity except a mild hyperactivity [25] and no significant differences in spatial learning between ephrin-A5−/− and wild type control mice (data not shown). In contrast, our analysis revealed a striking absence of fighting in ephrin-A5−/− male mice (Fig. 1). Wild-type male mice took an average of
Discussion
In this study we observed that inactivation of ephrin-A5 in male mice results in a major reduction in offensive aggressive behavior toward an intruder male. When tested with age and genotype matched intruders, none of the ephrin-A5−/− animals engaged in attack behavior. It has been reported that the level of aggressive behavior is influenced by the intruder; changes in social investigation, movement and pheromones led to different responses from the resident [7], [32]. For example, castrated
Acknowledgements
Research partially supported by 2PO1HD023315 (RZ), RO1EY019012 to RZ, P30ES005022, T32007148, and R01ES015991 to JRR; and Charles and Johanna Busch Memorial Fund to GCW.
References (69)
- et al.
Neuropharmacology of brain-stimulation-evoked aggression
Neurosci Biobehav Rev
(1999) - et al.
Problems in the study of rodent aggression
Horm Behav
(2003) - et al.
Differential effect of Fyn tyrosine kinase deletion on offensive and defensive aggression
Behav Brain Res
(2001) - et al.
Effects of nicotine on target biting and resident-intruder attack
Life Sci
(2003) Ethology and pharmacology of hypothalamic aggression in the rat
Neurosci Biobehav Rev
(1991)- et al.
Ephrin regulation of synapse formation, function and plasticity
Mol Cell Neurosci
(2012) - et al.
Bidirectional Eph-ephrin signaling during axon guidance
Trends Cell Biol
(2007) - et al.
Learning and memory impairment in Eph receptor A6 knockout mice
Neurosci Lett
(2008) - et al.
Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity
Neuron
(2001) - et al.
Changes in attack behavior and activity in EphA5 knockout mice
Brain Res
(2008)
Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system
Neuron
Ephrin-A5 deficiency alters sensorimotor and monoaminergic development
Behav Brain Res
In vivo visualization of olfactory pathophysiology induced by intranasal cadmium instillation in mice
Neurotoxicology
Lack of aggression and anxiolytic-like behavior in TNF receptor (TNF-R1 and TNF-R2) deficient mice
Brain Behav Immun
Testosterone facilitates aggression by modulating vasopressin receptors in the hypothalamus
Physiol Behav
Testosterone enhances aggression of wild-type mice but not those deficient in type I 5alpha-reductase
Brain Res
Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression
Neurosci Biobehav Rev
Dominance, plasma testosterone levels, and testis size in house mice artificially selected for high activity levels
Physiol Behav
The impact of hemolysis on ortho-clinical diagnostic's ECi and Roche's elecsys immunoassay systems
Clin Chim Acta: Int J Clin Chem
The relation between olfactory stimulation and aggressive behaviour in mice
Anim Behav
Ominous odors: olfactory control of instinctive fear and aggression in mice
Curr Opin Neurobiol
Axonal ephrin-As and odorant receptors: coordinate determination of the olfactory sensory map
Cell
EphA receptors and ephrin-A ligands exhibit highly regulated spatial and temporal expression patterns in the developing olfactory system
Brain Res Dev Brain Res
The role of ephrin-A2 and ephrin-A5 in sensorimotor control and gating
Behav Brain Res
Gonadal influence on agonistic behavior in the male domestic rat
Horm Behav
The effects of castration and silastic implants of testosterone on intermale aggression in the mouse
Horm Behav
Activation and inhibition of isolation induced inter-male fighting behavior in castrate male CD-1 mice treated with steroidal hormones
Horm Behav
The role of the androgen receptor in anabolic androgenic steroid-induced aggressive behavior in C57BL/6J and Tfm mice
Horm Behav
Physical provocation potentiates aggression in male rats receiving anabolic androgenic steroids
Horm Behav
Aggression in male rats receiving anabolic androgenic steroids: effects of social and environmental provocation
Horm Behav
Neurobiology of social behavior: toward understanding of the prosocial and antisocial brain
Neural mechanisms of aggression
Nat Rev Neurosci
Genetics of aggression
Annu Rev Genet
Biology of aggression
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