From Struggling (With) Screening Tests to Mouse Models of Depression-Relevant Neurobehavioral States

A major, serendipitous psychiatric discovery is monoamine-transporter reuptake inhibition as an antidepressant mechanism of action. Chronic treatment with such antidepressants is efficacious, with onset requiring 1-2 weeks, in many but by no means all patients with major depressive or another stress-related neuropsychiatric disorder. The forced swim test (FST) in rats and mice involves the acute, moderate stressor of placement in a container of water: at test onset, the predominant reaction is swimming, interpreted cautiously as active "struggling"; over minutes, this is replaced by floating, described objectively as immobility. Acute administration of monoamine transporter inhibitors immediately prolongs "struggling." Although this readout is of behavioral pharmacological interest, the FST has no (back-)translational relevance to the neurobiological and neuropsychological symptoms/states of stress-related psychiatric disorders. The persistent adoption of the FST to measure "depression-like state," based on interpretation of immobility as "despair," "helplessness," or "passive coping," is a major weakness in applied behavioral neuroscience. Rodents do have a concept of learned uncontrollability, such that tests showing this depict an adaptive, not a "depression-like," state. Recent psychiatry-neuroscience initiatives, such as the Research Domain Criteria framework, increase the accessibility of specific, transdiagnostic symptoms/states to behavioral neuroscience methods, thereby facilitating the establishment of animal models. Such animal models must incorporate clinically valid (1) etiological factors, such as prolonged psychosocial stress, and (2) neurobehavioral readouts with face and construct validity for specific symptoms/states. Increased reactivity to an acute threat, measured as increased Pavlovian aversion learning-memory (PALM), is a neurobehavioral state common in major depression and other disorders. Mice that have undergone chronic social stress exhibit generalized excessive PALM. Therefore, although stating that the FST measures "depression-like state" is erroneous, mouse models of specific symptoms/states can be achieved by back-translating etiology and neurobehavioral readouts. Though complex and moderately severe, such models have the potential to provide much-needed benefits in terms of preclinical neuropharmacological target discovery and validation. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC.