The underestimated sex: A review on female animal models of depression

Major depression (MD) is the most common psychiatric disorder, predicted to affect around 264 million people worldwide. Although the etiology of depression remains elusive, the interplay between genetics and environmental factors, such as early life events, stress, exposure to drugs and health problems appears to underlie its development. Whereas depression is twice more prevalent in women than in men, most preclinical studies are performed in male rodents. In fact, females' physiology and reproductive experience are associated with changes to brain, behavior and endocrine profiles that may influence both stress, an important precipitating factor for depression, and response to treatment. These specificities emphasize the need to choose the most suitable models and readouts in order to better understand the pathophysiological mechanisms of depression in females. With this review, we aim to provide an overview of female animal models of depression highlighting the major differences between models, regarding behavioral, physiological, and molecular readouts, but also the major gaps in research, attending to the role of etiological factors, protocol variability and sex.