Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum.

Early-life stress and biological predispositions are linked to mood and personality disorders related to aggressive behavior. We previously showed that exposure to peripubertal stress leads to increased anxiety-like behaviors and aggression against males and females, as well as increased aggression against females in their male offspring. Here, we investigated whether paternal (pS) and individual (iS) exposure to peripubertal stress may exert additive effects on the long-term programming of anxiety-like and aggressive behaviors in rats. Given the key role of the lateral septum (LS) in the regulation of anxiety and aggressive behaviors and the hypothesized alterations in balance between neural excitation and inhibition in aggression-related disorders, markers for these processes were examined in the LS. Peripubertal stress was applied both in naïve male rats and in the offspring of peripubertally stressed males, and anxiety-like and aggressive behaviors were assessed at adulthood. Proton magnetic resonance spectroscopy at 6-months, and post-mortem analysis of glutamic acid decarboxylase 67 (GAD67) at 12-months were conducted in LS. We confirmed that aggressive behavior was increased by pS and iS, while only iS increased anxiety-like behavior. Individual stress led to reduced GABA, confirmed by reduced GAD67 immunolabelling, and increased glutamate, N-acetyl-aspartate, phosphocholine and creatine; while pS specifically led to reduced phosphocreatine. pS and iS do not interact and exert a differential impact on the analyzed aspects of brain function and anxiety-like behaviors. These data support the view that early-life stress can affect the behavioral and neurodevelopmental trajectories of individuals and their offspring, which may involve different neurobiological mechanisms.