Aggression in BALB/cJ mice is differentially predicted by the volumes of anterior and midcingulate cortex

Abstract

Anterior cingulate cortex (ACC) and midcingulate cortex (MCC) have been implicated in the regulation of aggressive behaviour. For instance, patients with conduct disorder (CD) show increased levels of aggression accompanied by changes in ACC and MCC volume. However, accounts of ACC/MCC changes in CD patients have been conflicting, likely due to the heterogeneity of the studied populations. Here, we address these discrepancies by studying volumetric changes of ACC/MCC in the BALB/cJ mouse, a model of aggression, compared to an age- and gender-matched control group of BALB/cByJ mice. We quantified aggression in BALB/cJ and BALB/cByJ mice using the resident–intruder test, and related this to volumetric measures of ACC/MCC based on Nissl-stained coronal brain slices of the same animals. We demonstrate that BALB/cJ behave consistently more aggressively (shorter attack latencies, more frequent attacks, anti-social biting) than the control group, while at the same time showing an increased volume of ACC and a decreased volume of MCC. Differences in ACC and MCC volume jointly predicted a high amount of variance in aggressive behaviour, while regression with only one predictor had a poor fit. This suggests that, beyond their individual contributions, the relationship between ACC and MCC plays an important role in regulating aggressive behaviour. Finally, we show the importance of switching from the classical rodent anatomical definition of ACC as cingulate area 2 and 1 to a definition that includes the MCC and is directly homologous to higher mammalian species: clear behaviour-related differences in ACC/MCC anatomy were only observed using the homologous definition. Electronic supplementary material The online version of this article (10.1007/s00429-018-1816-9) contains supplementary material, which is available to authorized users.

Anterior cingulate cortex hypofunction causes anti-social aggression in mice

“…In line with previous reports [18][19][20], BALB/cJ mice consistently behaved more aggressively than control BALB/cByJ mice in the resident-intruder (RI) test -a paradigm in which an unfamiliar 'intruder' mouse is introduced into the home cage of another mouse (the resident) for 5-10 minutes per day, with a new encounter taking place daily for five days in a row (see Supp. Mat.…”

“…2e-f, repeated measures ANOVA: ACC: (F(1, 27) = 136.83, p < .001, η2 = .84). In some layers, up to a ten-fold difference was observed, suggesting reactive astrogliosis may be responsible for the increased volume of ACC observed here and previously [18]. To decipher whether these reactive astroglia were toxic A1 astroglia, we performed a co-staining Serping1 (marker upregulated in A1 astroglia) with S100B (general marker for astroglia).…”

“…3), the mice in the DREADD group started to show increased socially expected biting and threat behaviour -again very similar to control mice. These increases can be interpreted as an adaptive aggressive response to repeated territorial challenge [18,19]. This suggests that boosting ACC activity removed the anti-social aspects of aggression, but left adaptive aggression largely intact.…”

“…1). In this scenario, BALB/cJ mice not only attacked faster and more frequently than control mice, they also targeted vulnerable body parts like the face, abdomen and necka behaviour that is not expected during territorial conflicts in mice and can therefore be considered as anti-social in this context [18,19]. To exclude possible litter effects, we tested several independent cohorts.…”

“…For instance, studies in patients with pathological aggression demonstrate alterations in ACC volume [15,16] as well as ACC activity [16,17]. Similarly, studies of ACC structure in a mouse model of maladaptive aggression, the BALB/cJ strain, show a volumetric increase of ACC compared to the nonaggressive BALB/cByJ control strain [18], as well as a decrease of Parvalbumin-and Somatostatin-expressing interneurons across cingulate cortex [19].…”