The chronic unpredictable mild stress (CUMS) Paradigm: Bridging the gap in depression research from bench to bedside

•CUMS is a method used on rodents.•It induces depression-like behaviors.•It helps validate antidepressant effectiveness.•It reveals underlying mechanisms of depression. Depression is a complicated neuropsychiatric condition with an incompletely understoodetiology, making the discovery of effective therapies challenging. Animal models have been crucial in improving our understanding of depression and enabling antidepressant medication development. The CUMS model has significant face validity since it induces fundamental depression symptoms in humans, such as anhedonia, behavioral despair, anxiety, cognitive impairments, and changes in sleep, food, and social behavior. Its construct validity is demonstrated by the dysregulation of neurobiological systems involved in depression, including monoaminergic neurotransmission, the hypothalamic–pituitary–adrenal axis, neuroinflammatory processes, and structural brain alterations. Critically, the model’s predictive validity is demonstrated by the reversal of CUMS-induced deficits following treatment with clinically effective antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. This review comprehensivelyassesses the multifarious depressive-like phenotypes in the CUMS model using behavioral paradigms like sucrose preference, forced swim, tail suspension, elevated plus maze, and novel object recognition tests. It investigates the neurobiological mechanisms that underlie CUMS-induced behaviors, including signaling pathways involving tumor necrosis factor-alpha, brain-derived neurotrophic factor and its receptor TrkB, cyclooxygenase-2, glycogen synthase kinase-3 beta, and the kynurenine pathway. This review emphasizes the CUMS model’s importance as a translationally relevant tool for unraveling the complex mechanisms underlying depression and facilitating the development of improved and targeted interventions for this debilitating neuropsychiatric disorder by providing a comprehensive overview of its validity, behavioral assessments, and neurobiological underpinnings.