Structural and functional alterations in the prefrontal cortex after post-weaning social isolation: relationship with species-typical and deviant aggression

Abstract

Although the inhibitory control of aggression by the prefrontal cortex (PFC) is the cornerstone of current theories of aggression control, a number of human and laboratory studies showed that the execution of aggression increases PFC activity; moreover, enhanced activation was observed in aggression-related psychopathologies and laboratory models of abnormal aggression. Here, we investigated these apparently contradictory findings in the post-weaning social isolation paradigm (PWSI), an established laboratory model of abnormal aggression. When studied in the resident-intruder test as adults, rats submitted to PWSI showed increased attack counts, increased share of bites directed towards vulnerable body parts of opponents (head, throat, and belly) and reduced social signaling of attacks. These deviations from species-typical behavioral characteristics were associated with a specific reduction in the thickness of the right medial PFC (mPFC), a bilateral decrease in dendritic and glial density, and reduced vascularization on the right-hand side of the mPFC. Thus, the early stressor interfered with mPFC development. Despite these structural deficits, aggressive encounters enhanced the activation of the mPFC in PWSI rats as compared to controls. A voxel-like functional analysis revealed that overactivation was restricted to a circumscribed sub-region, which contributed to the activation of hypothalamic centers involved in the initiation of biting attacks as shown by structural equation modeling. These findings demonstrate that structural alterations and functional hyperactivity can coexist in the mPFC of rats exposed to early stressors, and suggest that the role of the mPFC in aggression control is more complex than suggested by the inhibitory control theory.

The link between aberrant hypothalamic–pituitary–adrenal axis activity during development and the emergence of aggression—Animal studies

“…Although addressing this question is beyond the scope of the present review (for more information, see and a precise answer will require further studies, existing evidence indicates that abnormal glucocorticoid levels during key developmental periods can have detrimental effects on brain structure and function Feldman and Weidenfeld, 1998;Eiland and Romeo, 2013), including changes in brain regions involved in both the 20 regulation of the HPA axis and aggression (e.g. amygdala, prefrontal cortex, and hypothalamus) Haller, 2014a;Biro et al, 2016). Additionally, neuromodulators that are critically implicated in aggression -e.g., serotonin (5-HT) -may also be affected by differential HPA axis development .…”

Alterations in brain microstructure in rats that develop abnormal aggression following peripubertal stress

“…Identification of sources of diffusivity fluctuations may be complicated by concurrent changes in several such parameters (Tu et al, 2016). In accordance with this, speciesatypical aggressive behaviour displayed by rats exposed to postweaning social isolation was associated with several structural alterations in the mPFC, including a reduction in thickness, a decrease in dendritic and glial density, and reduced vascularization (Biro et al, 2017).…”

The Role of the Lateral Hypothalamus in Violent Intraspecific Aggression—The Glucocorticoid Deficit Hypothesis

“…In this model of abnormal aggression, rats attack vulnerable body parts of opponents (head, throat band belly) without appropriately signaling attack intentions by social signals. We also showed that a subpopulation of prefrontal neurons specifically project to, and influence violent aggression controlled by the lateral hypothalamus (Biro et al, 2017 , 2018 ). We recently proposed that the control mechanisms of violent forms of aggression are combinations of the mechanisms that subserve intraspecific (rivalry) and interspecific (predatory) aggressions (Haller, 2017 ; Figure 1 ).…”