Fighting in the home cage: Agonistic encounters and effects on neurobiological markers within the social decision-making network of house mice (Mus musculus)

Highlights

• We determined competitive abilities within the homecages of group-housed C57Bl/6 mice.

• Dominance status influenced neurobiological markers associated with aggression.

• We present a “tube test” as a tool for assessing dominance status.

Abstract

Inbred strains of mice, such as C57Bl/6, have become preferred animal models for neurobehavioral studies. A main goal in creating inbred lines is to reduce the effects of individual genetic variation on observed phenotypes. Most studies use only males, and there is increasing evidence that agonistic interactions within the home cage may produce systematic variability in behavior and brain function. Previous studies have demonstrated that the outcomes of aggressive interactions have powerful effects on the brain and behavior, but less is known about whether aggressive interactions within the home cage have similar effects. We assessed group-housed laboratory mice C57Bl/6 for competitive ability and then tested the extent high competitive ability (CA) or low CA was related to gene and protein expression within related pathways. We focused on a broad social behavior network, including the nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST). High CA mice had significantly more corticotropin releasing hormone receptor 2 (CRHR2) and estrogen receptor alpha (ESR1) mRNA in the BNST. Our data suggest a simple test of CA could yield valuable information that could be used to reduce error variance and increase power in neurobiological studies using mice.

Introduction

The laboratory mouse (Mus musculus) is used as a genetic model for a wide range of human diseases, particularly within clinical neuroscience [1], [7]. Interestingly, even though most studies use identical strains of inbred mice, variability in experimental outcomes is often a problem [7], [38]. It is well known, although perhaps underappreciated, that many mundane aspects of the lab environment such as diet [9], cage bedding [37], or noise levels [28] can have a major impact on study outcomes. The sex of the animal is also critical, and most neuroscience studies focus exclusively on male rodents [2]. Although typically not acknowledged, a common rationale for focusing on males is to avoid potential confounds related to hormone fluctuations of the female ovarian cycle. However, in some contexts males can be more variable than females [24]. Dominance hierarchies are an important part of Mus life history [23], [25], [27], and the outcomes of aggressive encounters have important effects on the brain and behavior [4]. Aggressive interactions between males in the home cage are common in many strains of Mus [10], [17]. Indeed, anxiety-like behavior in male C57Bl/6 mice is reduced in single-housed males compared to group-housed males [34], suggesting that ongoing aggressive interactions have important implications for behavioral testing [35].

Previous studies have demonstrated differences between dominant and subordinate M. musculus in behavior and brain function [35], [36], but these studies typically used outbred strains, such as CD-1, and observed dominance relationships in dyadic pairs. In contrast, little is known of the potential impact of competitive ability in group-housed C57Bl/6, the predominant background for genetic studies. Here, we investigated the impact of competitive ability on signaling pathways in nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST). The nuclei are components of a social decision-making network known to regulate both social behavior and behavioral responses to stress [26]. We show that dominance hierarchies within the home cage have very strong effects on brain function that could systematically affect the outcomes of neuroscience experiments.