Successfully navigating social interactions requires the precise and balanced integration of social and environmental cues. When such flexible information integration fails, maladaptive behavioral patterns arise, including excessive aggression, empathy deficits, and social withdrawal, as seen in disorders such as conduct disorder and autism spectrum disorder. One of the main hubs for the context-dependent regulation of behavior is cingulate cortex, specifically anterior cingulate cortex (ACC) and midcingulate cortex (MCC). While volumetric abnormalities of ACC and MCC have been demonstrated in patients, little is known about the exact structural changes responsible for the dysregulation of behaviors such as aggression and social withdrawal. Here, we demonstrate that the distribution of parvalbumin (PV) and somatostatin (SOM) interneurons across ACC and MCC differentially predicts aggression and social withdrawal in BALB/cJ mice. BALB/cJ mice were phenotyped for their social behavior (three-chamber task) and aggression (resident-intruder task) compared to control (BALB/cByJ) mice. In line with previous studies, BALB/cJ mice behaved more aggressively than controls. The three-chamber task revealed two sub-groups of highly-sociable versus less-sociable BALB/cJ mice. Highly-sociable BALB/cJ mice were as aggressive as the less-sociable group—in fact, they committed more acts of socially acceptable aggression (threats and harmless bites). PV and SOM immunostaining revealed that a lack of specificity in the distribution of SOM and PV interneurons across cingulate cortex coincided with social withdrawal: both control mice and highly-sociable BALB/cJ mice showed a differential distribution of PV and SOM interneurons across the sub-areas of cingulate cortex, while for less-sociable BALB/cJ mice, the distributions were near-flat. In contrast, both highly-sociable and less-sociable BALB/cJ mice had a decreased concentration of PV interneurons in MCC compared to controls, which was therefore linked to aggressive behavior. Together, these results suggest that the dynamic balance of excitatory and inhibitory activity across ACC and MCC shapes both social and aggressive behavior.

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Overt aggression, increased anxiety, and dysfunctional fear processing are often observed in individuals with conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD). Methylphenidate (MPH), a psychostimulant increasing dopamine and noradrenaline tone, is effective in reducing aggression in both CD and ADHD individuals. However, it is unclear to which extent these effects of MPH are dose dependent. Here, the effects of acute intraperitoneal MPH (3 and 10 mg/kg) on aggression, anxiety, social behavior, and fear extinction were investigated in BALB/cJ mice. Previous studies in BALB/cJ mice have revealed high levels of aggression and anxiety that are associated with reduced top-down cortical control. Administration of 3 mg/kg MPH prolonged the attack latency and prevented escalation of aggression over time compared to vehicle-treated mice, while 10 mg/kg MPH increased number of bites and attacks. In addition, 3 mg/kg MPH decreased social interaction slightly. A strong anxiolytic effect was found after administration of both the 3 and 10 mg/kg doses in the elevated plus maze and the open-field test. In addition, while vehicle-treated BALB/cJ animals showed intact freezing, both doses of MPH decreased freezing to the unconditioned stimulus in a fear-conditioning paradigm. A long-lasting effect on fear extinction was visible after treatment with the 10 mg/kg dose. The data support a role for MPH in the regulation of anxiety, fear processing, and aggression in BALB/cJ mice, with the latter effect in a dose-dependent manner. The findings provide a further context for examining the effects of MPH in clinical disorders such as ADHD and CD.