Intermittent fasting produces antidepressant-like effects by modulating dopamine D1 receptors in the medial prefrontal cortex

Nutritional psychiatry has gained increasing attention, particularly in exploring dietary interventions for depression treatment. As a potential non-drug intervention, intermittent fasting (IF) has gradually attracted the interest of researchers, but its specific neurobiological mechanisms in depression remain unclear. The medial prefrontal cortex (mPFC) dopamine D1 receptors (Drd1) are significant in stress response and serve as a molecular target for rapid-acting antidepressants. Our previous study indicated that 9-h fasting produces an antidepressant-like effect by modulating dopamine (DA) receptors. However, whether IF produces antidepressant-like effects through actions on DA receptor-mediated mechanisms remains unclear. Here, we investigated the effects of IF on improving depression-like behavior induced by Chronic Unpredictable Mild Stress (CUMS) in mice and explored whether these effects are regulated by Drd1. We found that IF alleviated CUMS-induced depression-like behavior, increased c-Fos expression in the mPFC and hippocampus of CUMS mice, and activated the Drd1-cAMP-PKA-DARPP-32-CREB-BDNF signaling pathway. The antidepressant-like effects of IF were reversed by the Drd1 antagonist SCH23390. Additionally, optogenetic activation of Drd1-expressing neurons in the mPFC improved CUMS-induced depression-like behavior, while optogenetic inhibition suppressed the IF-induced antidepressant-like effects. These findings imply that Drd1 plays a crucial role in the antidepressant-like effects of IF and offer valuable insights into the potential application of IF in clinical depression treatment.