Gradient of Parvalbumin- and Somatostatin-Expressing Interneurons Across Cingulate Cortex Is Differentially Linked to Aggression and Sociability in BALB/cJ Mice.

Sabrina Van Heukelum,Christian F Beckmann,Jeffrey C Glennon,Arthur S.C França,Martha N Havenith,Jan K Buitelaar,Melissa A.E Van De Wal,Femke E Geers,Floriana Mogavero

doi:10.3389/fpsyt.2019.00809

Sabrina Van Heukelum, Christian F Beckmann + Show 7 more

Open Access

https://doi.org/10.3389/fpsyt.2019.00809

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Abstract

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.

Highlights

Aggression is part of the essential evolutionary survival tool kit for most animals—in specific contexts, e.g., during competition for crucial resources, it can greatly facilitate an animal’s chance of survival [1]
A lack of specificity in the distribution of SOM and PV interneurons across cingulate cortex was mostly associated with decreased sociability, while a decreased concentration of PV interneurons in midcingulate cortex (MCC) was most predictive of aggressive behavior. These results demonstrate that the balance of excitatory and inhibitory activity across anterior cingulate cortex (ACC) and MCC can be differentially related to both asocial and aggressive behavior, highlighting the importance of separately studying the sub-areas of cingulate cortex and their individual contributions to behavior
We first used the resident intruder test (RI) test to confirm that BALB/cJ mice engaged in more aggressive behavior than control animals from the BALB/ cByJ strain, as indicated by previous studies [12, 31]

Summary

Introduction

Aggression is part of the essential evolutionary survival tool kit for most animals—in specific contexts, e.g., during competition for crucial resources, it can greatly facilitate an animal’s chance of survival [1]. Aggression is subject to strong inhibitory mechanisms, mainly mediated by prefrontal regions [2]. Autism spectrum disorder (ASD), though primarily characterized by problems in reciprocal social interaction and communication, often goes along with increased levels of aggression [7, 8]. This link between aggression and abnormal social behavior seems to extend beyond patient populations to preclinical animal models: changes in social behavior in rodents often co-occur with increased aggression (e.g., 9, 10), and the BALB/cJ strain, a popular mouse model of aggressive behavior, shows reduced levels of social interest [11, 12]

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