Too Depressed to Swim or Too Afraid to Stop? A Reinterpretation of the Forced Swim Test as a Measure of Anxiety-Like Behavior

Depression is one of the most common forms of mental illness. Despite decades of research, the mechanisms underlying this disorder remain unknown. To help elucidate the pathophysiology of depression, researchers are developing animal models of psychiatric disorders, including depression, and assessing for mood-related phenotypes. There are a limited number of behavioral assays available to assess depression-like behaviors in rodents but by far the most common is the forced swim test (FST). Although the FST is considered the gold standard for studying depression-like behaviors, there are strong reasons to question the interpretation that immobility represents ‘despair’ and escape-directed behaviors such as climbing represent the absence of a depression-like phenotype. It has recently been proposed that immobility in the FST is an adaptive learned response and reflects a switch from active to passive coping strategies (De Kloet and Molendijk, 2016). Although we agree with De Kloet and Molendijk (2016) that immobility is adaptive, we disagree on the interpretation of active versus passive coping strategies. Instead, we believe that escape-directed behaviors are driven by anxiety. We argue this perspective on the basis of comorbidity, gene targeting, and pharmacological studies

Mifepristone Prevents Stress-Induced Apoptosis in Newborn Neurons and Increases AMPA Receptor Expression in the Dentate Gyrus of C57/BL6 Mice

Chronic stress produces sustained elevation of corticosteroid levels, which is why it is considered one of the most potent negative regulators of adult hippocampal neurogenesis (AHN). Several mood disorders are accompanied by elevated glucocorticoid levels and have been linked to alterations in AHN, such as major depression (MD). Nevertheless, the mechanism by which acute stress affects the maturation of neural precursors in the dentate gyrus is poorly understood. We analyzed the survival and differentiation of 1 to 8 week-old cells in the dentate gyrus of female C57/BL6 mice following exposure to an acute stressor (the Porsolt or forced swimming test). Furthermore, we evaluated the effects of the glucocorticoid receptor (GR) antagonist mifepristone on the cell death induced by the Porsolt test. Forced swimming induced selective apoptotic cell death in 1 week-old cells, an effect that was abolished by pretreatment with mifepristone. Independent of its antagonism of GR, mifepristone also induced an increase in the percentage of 1 week-old cells that were AMPA+. We propose that the induction of AMPA receptor expression in immature cells may mediate the neuroprotective effects of mifepristone, in line with the proposed antidepressant effects of AMPA receptor potentiators