The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is repeated forced swim stress on 5 consecutive days (5d-RFSS), which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared to non-stressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior towards non-stressed levels. These observations suggest that 5d-RFSS has no construct or face validity, but might have predictive validity to model human depression.
Significance Statement The development of valid animal models to model human depression has been a major challenge. One protocol that has been widely used for its presumptive effects to cause depression is 5 consecutive days of forced-swim stress (5d-RFSS) in mice. 5d-RFSS increases floating behavior during consecutive sessions, but whether this is depressive-like behavior or an adaptive response underlying survival is not clear. We subjected two mouse strains (C57BL/6J, BALB/cJ) to 5d-RFSS followed by a battery of reward-related, homeostatic, and behavioral tests. 5d-RFSS increased floating behavior over time but importantly, did not induce emotional, homeostatic, or psychomotor symptoms. These findings suggest that 5d-RFSS has no construct or face validity to model human depression in two mouse strains commonly used in neuropsychiatric research.
Authors report no conflict of interest.
DH | National Institute for Health Research (NIHR), R01-DK-099511, R01-DK-101043, 5P30-DK-36836; American Diabetes Association 7-08-MN-21.