Effects of oxytocin and intermittent fasting on cognitive functions in rats fed a high-fat diet: a behavioral and molecular study

Abstract Obesity and high-fat diet (HFD) consumption are associated with cognitive deficits and anxiety-like behaviors. This study investigated the effects of oxytocin (OXY) and intermittent fasting (IF) on anxiety, learning, memory, and social behavior in rats fed a long-term HFD. Thirty-five male rats (110 ± 20 g) were fed either a standard diet (CTL) or an HFD for 23 weeks. The IF group (HFD + IF) underwent intermittent fasting from weeks 15 to 23. The OXY group (HFD + OXY) received oxytocin treatment from weeks 20 to 22. The combined group (HFD + IF + OXY) received both intermittent fasting and oxytocin treatment. Serum MDA, TAC levels, hippocampal mRNA gene expression ( Bdnf, Bax, and Bcl-2 ), and histopathology of CA1 were measured at week 23. HFD impaired locomotor activity, increased anxiety, reduced social interaction and novel object recognition, decreased TAC, and increased MDA, percentage of degenerative CA1 neurons, and Bax/Bcl-2 mRNA expression ratio. IF and OXY, individually and combined, significantly reversed these deficits and increased Bdnf mRNA expression. In conclusion, HFD-induced cognitive deficits persisted throughout the 23-week feeding period. Both interventions ameliorated these impairments by reducing oxidative stress, upregulating Bdnf mRNA expression, and shifting apoptosis-related gene expression toward a pro-survival profile, alongside histopathological evidence of reduced neuronal degeneration. These results suggest potential neuroprotective effects consistent with improvements in behavioral performance, redox indices, and mRNA-level correlates, although protein-level confirmation is required.