EARLY-LIFE SOCIAL AND METABOLIC STRESS DIFFERENTIALLY ENGAGE OXYTOCIN SIGNALLING TO SHAPE HIPPOCAMPAL MEMORY AND PLASTICITY IN JUVENILE MALES AND FEMALES

Early-life metabolic and social challenges can alter juvenile hippocampal maturation in a sex-dependent manner, yet how these stressors interact and whether oxytocinergic signaling confers vulnerability or resilience remain unclear. We examined the independent and combined effects of a short-term post-weaning high-fat diet-HFD and social isolation on hippocampal-dependent spatial memory and CA1 synaptic plasticity in juvenile male and female rats. Spatial memory was assessed using the object location memory-OLM task, and synaptic plasticity was measured using in vivo recordings of Schaffer collateral–CA1 LTP. To probe mechanism, the selective oxytocin receptor-OXTR agonist TGOT was microinjected into CA1 in impaired groups, and OXTRs were pharmacologically blocked in key conditions to assess endogenous oxytocin involvement.

HFD and isolation independently impaired OLM and LTP in both sexes. In contrast, combined exposure dissociated behavioral and synaptic outcomes: OLM was preserved in both sexes, while LTP recovery emerged selectively in females. In males, TGOT failed to rescue isolation-induced OLM deficits but restored LTP under the combined condition. In females, TGOT did not rescue HFD- or isolation-induced OLM or LTP impairments. However, OXTR blockade abolished OLM resilience under the combined condition in both sexes, indicating a necessary role for endogenous oxytocin. At the synaptic level, TGOT restored LTP following isolation alone and in combination with HFD, but not after HFD or isolation alone in females; importantly, OXTR blockade eliminated LTP recovery in females under the combined condition. Together, these findings reveal sex-specific oxytocin-dependent gating of resilience and a behavioral–synaptic dissociation during concurrent metabolic and social challenge.