Excessive aggression as model of violence: a critical evaluation of current preclinical methods

Abstract

Rationale: Preclinical experimental models of pathological aggressive behavior are a sorely understudied and difficult research area.

Objectives: How valid, reliable, productive, and informative are the most frequently used animal models of excessive aggressive behavior?

Methods: The rationale, key methodological features, supporting data, and arguments as well as their disadvantages and limitations of the most frequently used animal models for excessive aggressive behavior are summarized and their validity and reliability are evaluated.

Results: Excessive aggressive behavior is validly and reliably seen in (1) a proportion of feral-derived rats and selectively bred mice; (2) rats with compromised adrenal function resulting in a hypoglucocorticoid state; (3) a significant minority of mice, rats, and monkeys after consumption of a moderate dose of alcohol; and (4) resident animals of various species after social instigation. Limitations of these procedures include restrictive animal research regulations, the requirement of expertise in surgical, pharmacological, and behavioral techniques, and the behaviorally impoverished mouse strains that are used in molecular genetics research. Promising recent initiatives for novel experimental models include aggressive behaviors that are evoked by optogenetic stimulation and induced by the manipulation of early social experiences such as isolation rearing or social stress.

Conclusions: One of the most significant challenges for animal models of excessive, potentially abnormal aggressive behavior is the characterization of distinctive neurobiological mechanisms that differ from those governing species-typical aggressive behavior. Identifying novel targets for effective intervention requires increased understanding of the distinctive molecular, cellular, and circuit mechanisms for each type of abnormal aggressive behavior.

Figure 1

Frequency distribution of offensive resident-intruder aggression in a population of unselected feral Wild-Type Groningen rats (A) and in standard Wistar laboratory rats (B) as well as in a population of unselected feral house mice (C). The two rat strains differ considerably in the number of animals that will show aggressive behavior at all; note that the highly aggressive phenotype is absent in the domesticated rat strain. Note also that in the feral rodent populations, animals with an extreme high or low aggressive behavioral phenotype do not only coexist but are also encountered at a much higher rate than expected by chance, i.e., a bi-or tri-modally distributed pattern. This is in sharp contrast with the usually-encountered normal distribution patterns for most behavioral phenotypes in laboratory animals. (Adapted from van Oortmerssen and Bakker 1981)

Figure 2

A. Normal and violent aggressive behavioral characteristics in low-aggressive and medium-high aggressive WTG rats after multiple (>10) victorious experiences. B. Generally similar violent aggressive characteristics are observed in artificially-selected high-aggressive SAL mice after only 4 repetitive winning experiences. * indicates significant differences from the other two groups.

Figure 3

The impact of glucocorticoid deficiency on autonomic arousal, behavior, and the neural background of aggression. Upper panels: aggression-induced autonomic activation (left) and locomotion (right) during a 20 min-long aggressive encounter. B, baseline; the grey horizontal bar indicates the standard error of the baseline. Middle panels: intention signaling as expressed by the threat/offense ratio (left) and the share of vulnerable targets (right) in rats exposed to three aggressive encounters at three day intervals. Values represent the average of the three encounters. ADXr+CORT, acute corticosterone treatment before each encounter. Lower panels: the behavior of ADXr rats in the social interaction test (left) and the putative mechanism of glucocorticoid deficiency-associated aggression (right). ADXr did not change anxiety levels as shown by the elevated plus-maze test but reduced social interaction-induced heart rates (data not shown). PFC, prefrontal cortex; CeA, central amygdala; DLPAG, dorsolateral column of the periaqueductal gray; LH, lateral hypothalamus. For more details see Haller et al. 2001; Haller et al. 2004; Haller et al. 2007; Tulogdi et al. 2010.

Figure 4

Histogram representing the proportion and individual magnitude of alcohol-heightened aggression after gavage (A) or operant self-administration (B) of 1.0 g/kg alcohol. Dark vertical bars represent outbred CFW mice whose average frequency of attack bites after 1 g/kg alcohol exceeds their baseline levels of aggression by >2 SD (Alcohol-Heightened Aggression, or AHA). Gray vertical bars represent mice whose aggressive behavior is not significantly altered by 1 g /kg alcohol (Alcohol Non-heightened Aggression, or ANA), and white vertical bars represent mice whose aggressive behavior after 1 g/kg alcohol is reduced by >2 SD (Alcohol-Suppressed Aggression, or ASA). Dotted horizontal lines represent a 95% confidence interval, ±2 SD from average baseline.

Figure 5

Aggression heightened by social instigation. For five minutes, a resident male mouse is exposed to an intruder male that is protected by a screen through which olfactory and visual cues are still available. After an interval, the resident attacks an unprotected intruder with greater frequency. Bars represent the median attack bites and vertical lines represent the inter-quartile range after control (light gray) and instigated (dark gray) conditions. (From Miczek et al. 2007b).