Judith R.A. van Rooij ^1,2* Monica van den Berg ^1,2 Tamara Vasilkovska ¹ Johan Van Audekerke ^1,2* Lauren Kosten ¹ Daniele Bertoglio ^1,2 Mohit Adhikari ^1,2 Marleen Verhoye ^1,2*

• ¹ Bio-Imaging Lab, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
• ² µNEURO Research Centre of Excellence, University of Antwerp, Antwerp, Antwerp, Belgium

Introduction: Dietary interventions such as caloric restriction (CR) exert positive effects on brain health. Unfortunately, poor compliance hinders the success of this approach. A proposed alternative is resveratrol (Rsv), a CR-mimetic known to promote brain health. Direct comparison between the effects of Rsv and CR on brain health is lacking, with limited knowledge on their sex-specific effects. Therefore, we aimed to compare and unravel the sex-specific impact of these dietary interventions on spontaneous brain activity.Methods: Here, we used resting-state fMRI to investigate functional connectivity (FC) changes in five prominent resting-state brain networks (RSNs) in healthy four month old male and female F344 rats supplemented to either 40% CR or daily Rsv supplementation (10 mg/kg, oral) for the duration of one month.Results: Our results demonstrated a decreased body weight (BW) in CR rats, as well as an increase in body weight in male Rsv supplemented rats, compared to female Rsv supplemented rats, whereas this difference between sexes was not observed in the control or CR groups. Furthermore, we found that both CR or Rsv supplementation induce a female-specific decrease of FC between the subcortical network and hippocampal network, and between the subcortical network and lateral cortical network. Moreover, Rsv supplementation lowered FC within the hippocampal network and between the hippocampal and the default mode like network, the lateral cortical network and the sensory network -an effect not observed for the CR rats. Finally, we observed an overall lower FC in male rats compared to females, irrespective of dietary intervention, within the subcortical network and between the subcortical, the sensory and default mode like network. Discussion: Our findings reveal that both CR and Rsv induce a similar female-specific decrease of FC in RSNs associated with memory and emotion, all the while CR and Rsv induce dissimilar changes in body weight and other within-and between RSN FC measures. Altogether, this study provides insight into the effects and comparability of short-term CR and Rsv supplementation on brain connectivity within and between RSNs in both male and female F344 rats, providing a FC reference for future research of dietary effects.