Social isolation and aggression training lead to escalated aggression and hypothalamus-pituitary-gonad axis hyperfunction in mice

Abstract

Although the participation of sex hormones and sex hormone-responsive neurons in aggressive behavior has been extensively studied, the role of other systems within the hypothalamus-pituitary-gonadal (HPG) axis remains elusive. Here we assessed how the gonadotropin-releasing hormone (GnRH) and kisspeptin systems are impacted by escalated aggression in male mice. We used a combination of social isolation and aggression training (IST) to exacerbate mice’s aggressive behavior. Next, low-aggressive (group-housed, GH) and highly aggressive (IST) mice were compared regarding neuronal activity in the target populations and hormonal levels, using immunohistochemistry and ELISA, respectively. Finally, we used pharmacological and viral approaches to manipulate neuropeptide signaling and expression, subsequently evaluating its effects on behavior. IST mice exhibited enhanced aggressive behavior compared to GH controls, which was accompanied by elevated neuronal activity in GnRH neurons and arcuate nucleus kisspeptin neur