Translational models of adaptive and excessive fighting: an emerging role for neural circuits in pathological aggression

Abstract

Aggression is a phylogenetically stable behavior, and attacks on conspecifics are observed in most animal species. In this review, we discuss translational models as they relate to pathological forms of offensive aggression and the brain mechanisms that underlie these behaviors. Quantifiable escalations in attack or the development of an atypical sequence of attacks and threats is useful for characterizing abnormal variations in aggression across species. Aggression that serves as a reinforcer can be excessive, and certain schedules of reinforcement that allow aggression rewards also allow for examining brain and behavior during the anticipation of a fight. Ethological attempts to capture and measure offensive aggression point to two prominent hypotheses for the neural basis of violence. First, pathological aggression may be due to an exaggeration of activity in subcortical circuits that mediate adaptive aggressive behaviors as they are triggered by environmental or endogenous cues at vulnerable time points. Indeed, repeated fighting experiences occur with plasticity in brain areas once considered hardwired. Alternatively, a separate "violence network" may converge on aggression circuitry that disinhibits pathological aggression (for example, via disrupted cortical inhibition). Advancing animal models that capture the motivation to commit pathological aggression remains important to fully distinguish the neural architecture of violence as it differs from adaptive competition among conspecifics.

Keywords: Aggression; animal models; circuitry; phylogeny; plasticity; reward; violence.

Figure 1.. The sequence of experimental events for establishing individual levels of motivated responding for aggression and fighting performance during a daily fixed interval (FI) trial for aggression reward.

Prior to their confirmation of territorial aggression, resident male mice are initially housed with females for at least 1 month. In subsequent daily resident–intruder confrontations, each resident male encounters a novel male intruder for less than 5 minutes in the resident’s home cage. After establishing an aggressive phenotype, each resident is trained during a daily FI schedule that is reinforced by the presentation of an intruder (delivered into the resident’s home cage). The duration of the FI is progressively increased from 1 second to 10 minutes over the course of about a month. Resident mice then are allowed to establish a consistent pattern of FI responding. The upper left panel displays typical FI10 scalloped patterns of responding by mice for an aggression reward. Individual responses (tick marks) that are typically generated during a 10-min FI are indicated at the bottom left for varying levels of anticipatory arousal. The first response initiated after the completion of the FI allows the introduction of an intruder into the resident’s home cage. The upper right panel displays one element of fighting behavior (attack bites) that can be examined and potentially altered by experimental manipulations. Other aggressive elements that can be quantitatively and qualitatively examined include the latency to a first attack, number of attack bouts (bottom right), and biting topography (not shown). Changes in appetitive motivational responding can occur with or without alterations in fighting performance.

Figure 2.. Aggression that serves as a reward is more intense than species-typical fighting.

Aggressive behaviors, including tail rattle, sideways threat, and attack bites, are substantially increased when outbred male mice work during a fixed interval schedule for the opportunity to fight a conspecific (dark bars) as compared with species-typical levels of agonistic behavior that occurs during spontaneous aggression (open bars). Adapted from Fish et al. with permission from Springer-Verlag.

Figure 3.. Aggressive motivation escalates with repeated administrations of alcohol and remains persistently sensitized to lower concentrations of alcohol.

Fixed interval (FI) response rates (upper middle) are depicted over repeated oral administrations (via gavage) of water or alcohol (2.2 g/kg; top) and 10 days later in response to a dose of water or a low challenge dose of alcohol (1.0 g/kg; bottom middle). Here, the motivation to fight is initially disrupted by alcohol before levels of FI responding recover to baseline. After just seven daily alcohol administrations, the motivation to fight in response to a low dose of alcohol becomes sensitized (bottom middle). Fighting behavior is persistently disrupted over the course of seven consecutive daily administrations of alcohol (2.2 g/kg; upper right) but not significantly affected 10 days later by a challenge dose of alcohol (1.0 g/kg; bottom right). Adapted from Covington et al. with permission from Frontiers Media SA.