Animal Models of (or for) Aggression Reward, Addiction, and Relapse: Behavior and Circuits

Abstract

Inappropriate and pathological aggression plays a leading role in the suffering and death of millions of people, and further places an untenable strain on the caregivers and families of those afflicted. In some cases, such as addictive drugs, aggression can be highly rewarding (appetitive) and continually pursued despite short- and long-term negative consequences. Similarly, recidivism (relapse) rates for repeat violent offenders are as high as relapse rates for drug addicts. Appetitive aggression and relapse to aggression seeking can be modeled in mice studies using conditioned place preference and self-administration procedures followed by a period of abstinence and subsequent tests for relapse to aggression preference and aggression seeking. These procedures allow for the study of the mechanisms that control the appetitive versus the consummatory (attack) phases of aggressive behavior. In this review, we first discuss the behavioral procedures developed to probe appetitive aggression in mouse models, spanning from Pavlovian to operant tasks, and we also describe the recently proposed phenomenon of "aggression addiction." Next, we discuss the pharmacological and circuit mechanisms of aggression conditioned place preference and aggression self-administration, seeking, and relapse, highlighting mechanistic congruence and divergence between appetitive and consummatory phases of aggression. We conclude by discussing clinical implications of the studies reviewed.

Figure 1.

Trajectory of PubMed citations on aggressive behavior across three model species. Methods were adapted from Blanchard et al. (2003). We found the number of citations in response to the search terms “aggressive behavior AND mouse” (or “… AND rat” or “… AND hamster”). We binned the number of citation counts every 5 years starting from 1970. A, The number of cumulative citations since 1970. B, The number of citations within each 5 year bin.

Figure 2.

Schematics of different behavioral procedures to study motivated aggression seeking behavior. A, In the T-maze test, dominant mice undergo preliminary aggressive experiences with a subordinate in their homecage. On test day, they are placed at the end of the long arm of the T-maze in a start box. At the ends of the short arms are “correct” or “incorrect” goal boxes. A subordinate mouse is placed at each end of the goal boxes and separated by a partition. Upon choosing the “correct” goal box, the partition separating the subordinate mouse is raised and the dominant mouse can engage in attack. Upon choosing the “incorrect” goal box, the subordinate mouse is removed before the partition is raised, eliminating the possibility of attack. B, In the partition test, the behavior of a dominant mouse is assessed when a subordinate mouse is placed at the opposite end of a box separated by a partition. The partition allows for all forms of sensory contact with the subordinate mouse, except for tactile contact. Approach behaviors and time spent in the “interaction zone” are recorded. C, In the CPP test, dominant mice are conditioned to two different contextual chambers, with one chamber paired to the presence of a subordinate mouse and the other chamber serving as an unpaired control. On test day, dominant mice are placed in a middle chamber connecting both contextual chambers. Time spent in the paired chamber compared with the unpaired chamber is measured. D, Operant approach used by Covington et al. (2018). A nose-poke apparatus is inserted into the dominant mouse's homecage. Nose-pokes in the active port are reinforced on a fixed-interval schedule (FI) with presentation of an intruder mouse into the homecage. An aggression-paired houselight illuminates upon insertion of an intruder. The other port serves as an inactive control. Bottom, A schematic of the FI trial design. E, Operant approach used by Falkner et al. (2016). As in D, a noseport panel containing two ports with infrared detectors is inserted into the dominant mouse's homecage. However, nose-pokes in the active port are reinforced on a fixed ratio-1 (FR-1) reinforcement schedule. Bottom, A schematic of the FR-1 trial design. F, Operant approach used by Golden et al. (2017a). Behavior is assessed in an operant chamber with an active and inactive lever. Active lever presses are reinforced on an FR-1 reinforcement schedule. A successful lever press results in sounding of a discriminative tone and opening of an automated guillotine door housing an intruder on the opposite side. An intruder is then guided into the operant chamber. Bottom, A schematic of the trial design. F, Adapted from Golden et al. (2017a).

Figure 3.

Operant assessment of aggression self-administration, aggression suppression, and relapse to aggression seeking. A, Upward trajectory of reward and attack trials over 9 d of self-administration training on an FR-1 reinforcement schedule. B, Voluntary food-choice suppression during 10 d of mutually exclusive choice sessions for food or aggression. C, Decrease of reward and attack trials over 10 d of punishment-imposed suppression of aggression. Mice received response-contingent shocks on 50% of reinforced lever presses. D, Aggression-seeking (relapse) test after forced abstinence in the homecage. During the relapse test, lever presses were recorded after mice were returned to the self-administration chamber and reexposed to the contextual cues associated with aggression self-administration. E, Aggression-seeking test after food choice-imposed suppression of aggression self-administration. F, Aggression seeking test after punishment-imposed suppression of aggression self-administration. Data are from Golden et al. (2017a). *p < 0.05.

Figure 4.

Cluster analysis of operant aggression-related behaviors reveals that a subset of the population are compulsive aggressors. A, Distributions of individual responses for the five operant aggression measures used for cluster analysis: attacks, relapse, choice, progressive ratio (PR), and punishment. B, Unbiased clustering of operant aggression behavior resulted in two phenotypic clusters: compulsive aggressors and typical aggressors. Shown is a 3D representation of clusters using projection data of the first three principal components of the five measures. C, Pie chart showing phenotypic assignments following cluster analysis. Included are nonaggressors that did not acquire operant aggression. D, Comparison of compulsive and typical aggressor clusters of the measures in A. *Different from the typical aggression group, p < 0.05. PC, Principal component. Data are from Golden et al. (2017a).

Figure 5.

NAc Drd1-expressing neurons control aggression self-administration and aggression seeking. A, A schematic of the breeding approach used to generate D1-Cre or D2-Cre F1 hybrid mice. B, Mean latency to first attack bout in resident-intruder screenings of C57, CD-1, C57 × D1-Cre, CD-1 × D1-Cre, C57 × D2-Cre, and CD-1 × D2-Cre mice. F1 hybrids of CD-1 mice show similar latency to attack latencies as CD-1 mice. C, D, D1 hybrid mice were injected with hM4Di or mCherry virus in the NAc. Injection of clozapine, but not vehicle, decreased aggression self-administration and aggression seeking in hM4Di but not mCherry-injected mice. E, F, D2 hybrid mice were injected with hM4Di or mCherry virus in the NAc. There was no effect of clozapine or vehicle on aggression self-administration and aggression seeking in hM4Di or mCherry-injected mice. *p < 0.05. Data are from (Golden et al. 2017b, 2019).

Figure 6.

Neural circuitry of aggression seeking and aggression severity. Top, A circuit schematic of the brain regions implicated in aggressive behavior. Bottom, The main experimental manipulations in these regions pertaining to aggressive behavior and their outcomes, summarized in a table. For the circuit diagram, the legend indicates the effect on aggressive behavior following stimulation of a region or circuit mechanism. In the table, the legend indicates experimental outcome on aggressive behavior. For this review, increased aggression seeking was operationally defined as an increased CPP score or operant responding. Increased aggression severity was operationally defined by higher number of attacks, shorter latency to attack, longer attacks, or increased intensity of an attack bout quantified by measures, such as bite number. HY, Hypothalamus; LH, lateral hypothalamus; VMH, ventromedial hypothalamus.