Background: Emerging evidence suggests a central role of mitochondria in psychiatric disorders. We have previously shown that high anxious (HA) rats exhibit reduced active coping behavior under adversity and competitiveness. HA animals also show alterations in the neural circuits involved in motivation such as nucleus accumbens (Nac), at both the cellular and organelle level. We have identified an essential role for mitochondria and energy metabolism in NAc function in effort-related and motivated behaviors, suggesting that boosting mitochondrial function in the NAc could lead to enhanced performance in these behavioral domains. Here, we investigated the efficiency of a mitochondrial booster in high anxious rats.Methods: Using a dietary supplement, we investigated the efficacy of a mitochondrial booster on anxiety-related behaviors (motivation, social behavior, and stress response) as well as the changes of Nac at morphological (dendritic arborization, spine density), functional (electrophysiology) and at gene (transcriptomic) levels.Results: We confirmed that HA animals exhibit motivational deficits to exert effort under adversity, a predisposition to social subordination and a higher corticosterone response to acute stress. They also showed Nac alterations at the morphological and functional level, especially in the D1 medium spiny neurons. The mitochondrial booster reversed these phenotypes and normalized the Nac transcriptomic signature observed in HA animals.Conclusions: Our results demonstrated the efficiency of the mitochondrial booster on the regulation of anxiety-related behaviors through genomic modification, the mitophagy process, and the structure and function of medium spiny neurons.