cis-Resveratrol Reduces Male-Specific Anxiety-Like Behaviour and Facilitates Fear Extinction via mRNA Translation

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Abstract
Anxiety disorders are associated with dysfunction of amygdala circuits and altered mitochondrial homeostasis. Resveratrol (RSV), a naturally occurring polyphenol with antioxidant properties, produces anxiolytic-like effects in preclinical models. However, most studies have examined trans -RSV, whereas the neurobehavioural effects of its cis isomer remain poorly characterized. RSV can activate mechanistic/mammalian target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation through eukaryotic initiation factor 4E-binding proteins (4E-BPs), but it is unknown whether this pathway mediates its behavioural effects. Here, we investigated the behavioural and structural effects of chronic cis -RSV treatment in wild-type mice and mice lacking 4E-BP1 and 4E-BP2, Eif4ebp1 and Eif4ebp2 double-knockout mice ( Eif4ebp1/2 −/− ). Anxiety-like and stress-coping behaviours were assessed using the open-field test, elevated plus maze, light–dark box, and forced swim test. We evaluated fear learning and extinction using auditory fear-conditioning and extinction paradigms and examined basolateral amygdala (BLA) ultrastructure by focused ion beam-scanning electron microscopy. In males, cis -RSV reduced anxiety-like behaviour and enhanced fear-extinction retention in wild-type mice, but not in Eif4ebp1/2 −/− mice, indicating that these effects require 4E-BP-regulated mRNA translation. In females, cis -RSV produced no anxiolytic-like effects and modestly increased anxiety-like behaviour in some measures. Cis -RSV did not affect forced swim behaviour in either sex. In males, cis -RSV reduced BLA dendritic spine density independently of genotype but produced only modest changes in mitochondrial ultrastructure. Together, these findings identify sex-dependent effects of cis -RSV on anxiety-like behaviour and fear extinction and demonstrate that its behavioural, but not synaptic structural, effects require 4E-BP-regulated mRNA translation.

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