Table 1.

A selected list of published papers on aggression motivation in mice using Pavlovian conditioning and operant-based self-administration/relapse models and their major findings. The data are based on PubMed research.

YearCitationBehaviorMajor findings
Historical Papers
1964(Lagerspetz, 1964)Conflict (electric barrier)Male mice bred for aggressiveness crossed an electric grid to a submissive mouse more readily if permitted to fight immediately before the trial.
1969(Tellegen et al., 1969)T-mazeMale BALB/cJ mice acquired, extinguished, and reversed a position preference in a T-maze when the opportunity to attack a submissive mouse was a reinforcer.
1970(Legrand, 1970)RunwayMale BALB/cJ mice ran aross a runway to defeat a submissive mouse as a reinforcer. High aggressiveness ratings and a brief fight immediately prior facilitated running behavior.
1972(Tellegen and Horn, 1972)T-mazeMale mice from three inbred strains (BALB/cJ, RF/J, and SJL/J) acquired a position preference in a T-maze when the opportunity to attack a nonaggressive mouse was a reinforcer.
Aggression Conditioned Place Preference (CPP)
1995(Martinez et al., 1995)Biased CPPMale OF-1 outbred mice form CPP to an intruder-paired context. However, the analysis for this preference was carried out in a context biased manner.
2016(Golden et al., 2016)Unbiased CPPMale CD-1 outbred mice form CPP to an intruder-paired context. GABAergic forebrain projections to the lateral habenula (LHb) bidirectionally control aggression CPP but do not control unconditioned aggression. Direct LHb manipulation does the same.
2017(Golden et al., 2017b)Unbiased CPPMale CD-1 mice show persistent aggression CPP across time, and non-aggressive mice switch phenotypes. Hybrid F1 generation transgenic mice show strong unconditioned aggression.
2018(Aleyasin et al. (2018b)Unbiased CPPMale CD-1 mice exhibit increased ΔFosB in NAc Drd1-MSNs after repeated aggressive encounters. In hybrid F1 transgenic mice induction of ΔFosB in Drd1-MSNs of the NAc increases aggression severity without effecting CPP. In contrast, ΔFosB induction in Drd2-MSNs reduces aggression CPP without affecting the severity of aggression.
2018(Stagkourakis et al. 2018)Unbiased CPPActivation of dopamine transporter-expressing neurons in the hypothalamic ventral premammillary nucleus (PMvDAT neurons) triggers attack behavior; silencing these neurons interrupts attacks. PMvDAT projections to the ventrolateral part of the ventromedial hypothalamic and the supramammillary nuclei control attack execution and aggression reward, respectively.
2018(Flanigan et al. 2018)Unbiased CPPIn CD-1 mice, orexin neurons from the lateral hypothalamus activate a small population of GABAergic interneurons in the LHb via orexin receptor 2. Stimulation of this projection enhances aggression severity and aggression CPP.
Aggression Self-administration (SA) and Relapse
2002(Fish et al., 2002)SA (FR and FI)First published study of operant aggression SA in mice. Male CFW outbred mice were maintained on a FR10 or FI10 reinforcement schedule; GABA(A) positive modulator heightened aggression severity and operant responding in a dose-dependent manner.
2005(Fish et al. 2005)SA (FI)In male CFW mice, corticosterone elevations are required for operant responding motivated by aggressive behavior and for escalated aggression that follows this responding. Corticosterone elevations appear to inhibit the aggression heightening effect of GABA(A) receptor positive modulators.
2007(Bannai et al., 2007)SA (FI)In male CFW mice, 5-HT(1B) agonists CP-94,253 and CP-93,129 reduced escalated aggression towards the intruder at doses lower than those required to affect operant responding.
2008(Fish et al., 2008)SA (FI)In male CFW mice, 5-HT(1B) agonist CP-94,253 reduced operant responding for aggression, alcohol-induced aggression, drinking, and wheel running. Of these behaviors, alcohol-heightened aggression is the most sensitive to the 5-HT(1B) receptor agonist.
2008(Couppis and Kennedy, 2008)SA (VR)Male CFW mice were trained on a VR5 reinforcement schedule of aggression SA. NAc injections of Drd1 and Drd2 antagonists microinjected inhibited operant responding, but also caused sedative effects at higher doses.
2009(May and Kennedy, 2009)SA (FR, FI, PR, DRL)Male CFW mice were trained on FR, FI, PR and DRL reinforcement schedules for aggression SA.
2016(Falkner et al. 2016)SA (FR, PR)In male CFW mice, VMHvl neurons are active during aggression-seeking and their activity tracks changes in task learning and extinction. Inactivation of the VMHvl reduced aggression seeking, whereas optogenetic stimulation of the VMHvl accelerated immediate aggression seeking and intensified future attacks.
2017(Golden et al., 2017a)SA (FR, PR); forced, punished, voluntary abstinenceMale CD-1 mice trained on aggression SA show relapse vulnerability following forced abstinence, punishment-induced suppression, and choice-based suppression of aggression seeking. Cluster analysis of the operant aggression measures identified a subset of compulsive aggressors (∼19%) that scored higher on aggression taking and seeking across all operant measures. Using procedures established to model drug addiction, we showed that a subpopulation of CD-1 mice demonstrate “addiction-like” aggressive behavior, suggesting an evolutionary origin for compulsive aggression.
2018(Covington et al. 2018)SA (FI)Male C57BL/6J inbred mice trained on an FI reinforcement schedule for aggression SA while receiving daily non-contingent alcohol injections. Alcohol augmented FI response rates for aggression SA but suppressed fighting performance. Systemic injections of NMDA or AMPA receptor antagonists (ketamine, dizocilpine, or NBQX) during later challenges with alcohol had minimal effect on alcohol-escalated rates of FI responding.
2019(Golden et al., 2019)SA (FR), forced relapseIn male CD-1 mice, aggression SA and relapse testing induced higher Fos expression in NAc shell than in core, while Fos colocalized with Drd1 and Drd2 in both subregions, Chemogenetic inhibition of Drd1-, but not Drd2-, expressing neurons decreased aggression self-administration and relapse. Results indicate a cell-type specific role of Drd1-expressing neurons that is critical for both aggression self-administration and relapse to aggression seeking.
  • Abbreviations: CPP, conditioned place preference; CFW, Swiss Webster; SA, self-administration; FR, fixed ratio; FI, fixed interval; VR, variable ratio; PR, progressive ratio; DRL, differential reinforcement of low rate behavior reinforcement; LHb, lateral habenula; Drd1, dopamine D1 receptor; Drd2, dopamine D2 receptor; MSN, medium spiny neuron; NAc, nucleus accumbens; PMvDAT, Dopamine transporter-expressing neurons in the hypothalamic ventral premammillary nucleus; VMHvl, ventrolateral part of the ventromedial hypothalamus.