Structural Degradation in Midcingulate Cortex Is Associated with Pathological Aggression in Mice.

Sabrina Van Heukelum,Jan K Buitelaar,Martha N Havenith,Arthur S C França,Sanne Van Dulm,Kerli Tulva,Brent A Vogt,Jeffrey C Glennon,Femke E Geers,Christian F Beckmann

doi:10.3390/brainsci11070868

Abstract

Pathological aggression is a debilitating feature of many neuropsychiatric disorders, and cingulate cortex is one of the brain areas centrally implicated in its control. Here we explore the specific role of midcingulate cortex (MCC) in the development of pathological aggression. To this end, we investigated the structural and functional degeneration of MCC in the BALB/cJ strain, a mouse model for pathological aggression. Compared to control animals from the BALB/cByJ strain, BALB/cJ mice expressed consistently heightened levels of aggression, as assessed by the resident-intruder test. At the same time, immunohistochemistry demonstrated stark structural degradation in the MCC of aggressive BALB/cJ mice: Decreased neuron density and widespread neuron death were accompanied by increased microglia and astroglia concentrations and reactive astrogliosis. cFos staining indicated that this degradation had functional consequences: MCC activity did not differ between BALB/cJ and BALB/cByJ mice at baseline, but unlike BALB/cByJ mice, BALB/cJ mice failed to activate MCC during resident-intruder encounters. This suggests that structural and functional impairments of MCC, triggered by neuronal degeneration, may be one of the drivers of pathological aggression in mice, highlighting MCC as a potential key area for pathologies of aggression in humans.

Highlights

Aggression is a fundamental feature of the behavioral repertoire across species, ranging from fish to rodents, primates and humans [1,2]
In line with previous studies [16,17], BALB/cJ mice showed more aggression than BALB/cByJ mice across all behavioral measurements derived from the RI test (Figure 1a)
While BALB/cJ mice did inflict back bites more frequently than BALB/cByJ mice (F (1, 15) = 7.2, p = 0.02, η2 = 0.32), the most dramatic increase was observed in the frequency of species-atypical bites (F (1, 15) = 10.62, p = 0.008, Brain Sci. 2021, 11, x FOR PEERηR2EV=IE0W.42; Figure 1b)

Summary

Introduction

Aggression is a fundamental feature of the behavioral repertoire across species, ranging from fish to rodents, primates and humans [1,2] While it can clearly serve an adaptive role, e.g., in situations that require protecting one’s own or one’s offspring’s survival, aggression can quickly lose its adaptive benefits if used out of context or proportion [3]. Such maladaptive aggressive behavior is observed as a symptom in a multitude of psychiatric conditions, including psychopathy, anti-social or borderline personality disorder, and even Alzheimer’s disease [4,5,6,7]. Since rodent MCC has so far rarely been studied in isolation from ACC [16,17,20,21,23,24], there are few mechanistic insights into MCC’s specific role in the control of aggressive behavior

Methods

Results

Conclusion