Background <p>Depression is a prevalent mental disorder, and its pathogenesis has not yet been fully elucidated. Circular RNAs (CircRNAs) have exhibit critical regulatory role in depression, while Unc-51-like kinase 1 (ULK1)-mediated autophagy participates in the pathophysiology of the disorder. Nevertheless, the potential involvement of circRNAs in modulating ULK1-mediated autophagy in depression remains unclear.</p> Objectives <p>This study aimed to identify depression-associated circRNAs regulating ULK1-medaited autophagy, and uncover the underlying mechanisms.</p> Methods <p>The depression model was established in mice using chronic unpredictable mild stress (CUMS) procedure. RNA sequencing and bioinformatics analysis were carried out to screen signaling pathways, circRNAs and microRNAs (miRNAs) related to depression. Overexpression and knockdown of circRNAs or miRNAs were conducted by lentivirus microinjection and cell transfection. The depression-like phenotypes were assessed through behavioral tests. Western blot, immunofluorescence and transmission electron microscopy (TEM) were employed to evaluated ULK1-mediated autophagy. RNA pull-down and dual-luciferase reporter assay was executed to explore the underlying mechanisms.</p> Results <p>CircADAM9 exhibited the most significant downregulation in CUMS mice among the differentially expressed circRNAs. Overexpression of circADAM9 relieved depressive-like behaviors, and promoted ULK1-mediated autophagy in vivo and in vitro. Importantly, circADAM9 sponged miR-302b-3p to regulate Ulk1 gene expression, and miR-302b-3p mimics diminished the behavioral improvements and pro-autophagic effect modulated by circADAM9.</p> Conclusion <p>We identified circADAM9 as a novel regulator in depression, which activated autophagy via miR-302b-3p/ULK1 axis to improve depressive-like behaviors. Our findings would provide a new potential therapeutic target for the treatment of depression.</p>