Neurogenetics of aggressive behavior: studies in rodents

Abstract

Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals' survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression) and maladaptive violence (escalated aggression) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques, e.g., immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here, we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), excitatory and inhibitory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie individual differences in aggression, using the so-called forward genetics approach.

Figure 1

Schemas of brain areas that are activated during and after an aggressive encounter. Observed by c-Fos immunohistochemistry. Open circles indicate intermale aggression; shaded circles, maternal aggression; and black circles, escalated aggression. An arrow in a circle indicates the area where the c-Fos activation was inhibited compared with intermale aggression (downwards arrow) or mixed reports, depending on the study (bidirectional arrow). Prefrontal cortex (PFC), claustrum (Cl), lateral septal nucleus (LS), bed nucleus of the stria terminals (BNST), nucleus accumbens (NAc), piriform cortex (Pir), medial preoptic area (MPOA), paraventricular nucleus (PVN), parafacicular nucleus of thalamus (PF), hypothalamus attack areas (HAA), amygdala (Amy), hippocampus (Hipp), periaqueductal gray (PAG), 5-HT neurons in the dorsal raphe nucleus (DRN), and locus coeruleus (LC). In this figure, HAA includes the anterior, ventromedial and lateral hypothalamic nuclei. (Kollack-Walker and Newman, 1995; Joppa et al., 1995; Potegal et al., 1996; Wang et al., 1997, 2011; Delville et al., 2000; Gammie and Nelson, 2001; Halász et al., 2002, 2006; van der Vegt et al., 2003; Davis and Marler, 2004; Haller et al., 2005b, 2006; Veening et al., 2005; Gobrogge et al., 2007; Pan et al., 2010; Nehrenberg et al., 2012; Wall et al., 2012; Konoshenko et al., 2013)

Figure 2

Changes of dopamine and serotonin in the PFC and NAc during species-typical aggressive behavior in the rat. Measurements of extracellular dopamine and serotonin via in vivo microdialysis in resident male rats before, during, and after a confrontation with an intruder. (a) In the nucleus accumbens (top panel), dopamine levels increased after the confrontation, while serotonin levels did not change significantly. (b) In the prefrontal cortex (bottom panel), dopamine levels increased after the confrontation, whereas serotonin decreased after the confrontation. The vertical light gray bar indicates the occurrence of the 10-minute fight. * p<0.05 and ** p<0.01 compared with baseline. Reprinted with permission from Van Erp and Miczek (2000).

Figure 3

Modulation of the dorsal raphe nucleus (DRN) by GABA receptors and escalated aggression in the mouse. (A) Microinjection of the GABA_B receptor agonist baclofen into the DRN increased intermale aggressive behavior, whereas microinjection of the GABA_A receptor agonist muscimol into the DRN did not have any effect. (B) Temporal change in the effect of 0.06 nmol baclofen on attack bites. Escalated attack bites were observed both 10 and 40 minutes after the intra-DRN baclofen injection, and return to basal level after 100 minutes. (C) Extracellular serotonin (5-HT) concentration in the medial prefrontal cortex (mPFC) of mice after intra-DRN baclofen injection. Baclofen increased 5-HT release in the mPFC whereas saline injection did not change the level of 5-HT. Data are expressed as percentage of baseline (n=7). * p<0.05 compared with the vehicle control (A and B) or baseline (C). Adopted from Takahashi et al. (2010).

Figure 4

Systemic administrations of non-competitive NMDA receptor antagonists enhance aggressive behavior specifically when associated with the administration of alcohol. Frequencies of attack bites following self-administration of either water or ethanol (1g/kg) combined with either memantine (left panel) or neramexane (right panel) treatment. *p < 0.05, **p < 0.001 compared with vehicle; #p < 0.05, ##p < 0.001 ethanol compared with water. Reprinted with permission from Newman et al. (2012).

Figure 5

GABA_A-positive allosteric modulators and aggression. Biphasic effects of GABA_A receptor-positive modulators on aggression in rats (top panel) and mice (bottom panel). Low doses of alcohol, the benzodiazepines diazepam (rats only) and midazolam and the neurosteroid allopregnanolone (mice only) increase the frequencies of attack bites, expressed as a percentage of vehicle control, whereas higher doses decrease this measure of aggression. Triazolam increases attack bites in rats but not mice. No increase in aggression was seen after treatment with zolpidem, a alpha1 receptor selective agonist (tested for mice only). The dotted line represents the baseline at 100%. Reprinted with permission from Miczek et al. (2007).