Topiramate and anterior cingulate cortex high-frequency stimulation mitigate aggression and promote sociability in socially isolated male mice.

Abstract

Excessive aggression induced by social isolation (SI) has been closely linked to dysfunction in prefrontal circuits, particularly the anterior cingulate cortex (ACC). Topiramate, an antiepileptic drug known to enhance GABAergic and inhibit glutamatergic transmission, has demonstrated antiaggressive effects. In our previous work, we showed that topiramate's antiaggressive effects were associated with reduced neuronal death, improved neuronal morphology, and attenuated neuroinflammation in the ACC following SI. However, its impact on ACC neuronal activity remains poorly understood. In this study, we investigated the effects of topiramate on the spontaneous activity of ACC neurons in a mouse model of SI-induced aggression. Additionally, we explored whether direct restoration of ACC activity via high-frequency stimulation could similarly reduce excessive aggression. Systemic administration of topiramate (30 mg/kg, intraperitoneally) significantly increased attack latency, reduced attack frequency, and enhanced sociability. In vivo extracellular recording of spontaneous activity revealed a 50% reduction in ACC firing in isolated mice, which was partially restored (∼30%) by topiramate treatment. Moreover, high-frequency stimulation applied to the ACC markedly decreased aggressive behavior and robustly promoted social interaction. Together, these results provide convergent behavioral and electrophysiological evidence that SI-induced aggression is associated with ACC hypoactivity. The finding that both topiramate treatment and high-frequency stimulation of the ACC effectively reversed these deficits highlights the ACC as a key target for therapeutic interventions to treat aggression-related neuropsychiatric conditions. (PsycInfo Database Record (c) 2026 APA, all rights reserved).