Investigation of the neurobiology of depression in humans depends on animal models that attempt to mimic specific features of the human disorder. However, frequently-used paradigms based on social stress cannot be easily applied to female mice which has led to a large sex bias in preclinical studies of depression. Furthermore, most studies focus on one or only a few behavioral assessments, with time and practical considerations prohibiting a comprehensive evaluation. In this study, we demonstrate that predator stress effectively induced depression-like behaviors in both male and female mice. By comparing predator stress and social defeat models, we observed that the former elicited a higher level of behavioral despair and the latter elicited more robust social avoidance. Furthermore, the use of machine learning (ML)-based spontaneous behavioral classification can distinguish mice subjected to one type of stress from another, and from non-stressed mice. We show that related patterns of spontaneous behaviors correspond to depression status as measured by canonical depression-like behaviors, which illustrates that depression-like symptoms can be predicted by ML-classified behavior patterns. Overall, our study confirms that the predator stress induced phenotype in mice is a good reflection of several important aspects of depression in humans and illustrates that ML-supported analysis can simultaneously evaluate multiple behavioral alterations in different animal models of depression, providing a more unbiased and holistic approach for the study of neuropsychiatric disorders.

Chronic predator stress (CPS) is an important and ecologically relevant tool for inducing anhedonia in animals, but the neural circuits underlying the associated neurobiological changes remain to be identified. Using cell-type-specific manipulations, we found that corticotropin-releasing hormone (CRH) neurons in the medial subthalamic nucleus (mSTN) enhance struggle behaviors in inescapable situations and lead to anhedonia, predominately through projections to the external globus pallidus (GPe). Recordings of in vivo neuronal activity revealed that CPS distorted mSTN-CRH neuronal responsivity to negative and positive stimuli, which may underlie CPS-induced behavioral despair and anhedonia. Furthermore, we discovered presynaptic inputs from the bed nucleus of the stria terminalis (BNST) to mSTN-CRH neurons projecting to the GPe that were enhanced following CPS, and these inputs may mediate such behaviors. This study identifies a neurocircuitry that co-regulates escape response and anhedonia in response to predator stress. This new understanding of the neural basis of defensive behavior in response to predator stress will likely benefit our understanding of neuropsychiatric diseases.