Ventromedial hypothalamus IL-6 signaling mediates the excessive aggressive behavior induced by late-gestational sleep deprivation in male mice.

BACKGROUND: Aggressive behavior is an evolutionarily conserved trait that supports resource acquisition and survival; however, excessive or dysregulated aggression is closely associated with neuropsychiatric disorders and social dysfunction. Maternal sleep deprivation (SD) during late gestation is a common yet underexplored environmental stressor that may disrupt offspring neurodevelopment through immune-mediated pathways. The present study investigated whether SD during late pregnancy alters aggressive behavior in offspring during early adulthood, explored the underlying neuroimmune mechanisms, and evaluated the potential of a post-weaning ketogenic diet (KD) as a non-pharmacological intervention.

RESULTS: Behavioral analyses revealed that late-gestational SD significantly increased both defensive and proactive aggressive behaviors in offspring mice during early adulthood. Peripheral immune assessment revealed that serum IL-6 levels were elevated in male offspring, while no significant change was observed in females. Pharmacological experiments demonstrated a causal role of IL-6 in aggression regulation, as peripheral administration of IL-6 increased aggression in control male offspring mice, whereas administration of anti-IL-6 in sleep deprivation-exposed male offspring normalized aggressive behavior. Neurobiological analyses identified enhanced neuronal activation, increased IL-6 and IL-6R expression, and pronounced microglial activation in the ventromedial hypothalamus (VMH). Consistently, VMH administration of IL-6 increased aggressive behavior, while injection of anti-IL-6 antibody attenuated the heightened aggression in SD-exposed male offspring mice. Chemogenetic inhibition of VMH neurons effectively attenuated the heightened aggression, indicating a critical role for this neural circuit. Importantly, post-weaning KD suppressed microglial overactivation and reduced IL-6 signaling in the VMH, restored neuroimmune homeostasis, and reversed abnormal aggressive behaviors.

CONCLUSIONS: These findings demonstrate that late-gestational maternal SD promotes excessive aggression in male offspring mice through IL-6-mediated neuroimmune dysregulation within the VMH. Moreover, post-weaning KD intervention effectively rescues both immune imbalance and behavioral abnormalities. This study highlights the long-term behavioral consequences of prenatal sleep loss and identifies dietary modulation of neuroimmune pathways as a promising non-pharmacological strategy for mitigating pathological aggression induced by early-life stress.