# Vicarious learned helplessness: a translationally relevant novel model of stress contagion elucidating sex-dependent prefrontal cortex pathology

## TL;DR

This study introduces a new mouse model showing how witnessing others' stress can lead to depression-like symptoms, with different brain changes in males and females.

## Contribution

A novel rodent model of vicarious stress reveals sex-specific molecular and physiological changes in depression-like behavior.

## Key findings

- Vicarious stress induces depression-like symptoms in both sexes, comparable to direct trauma.
- Shared molecular changes include reduced mGluR2 and elevated Il6 in the prefrontal cortex.
- Sex-specific differences include male neurotrophic deficits and female social bonding impairments.

## Abstract

Vicarious trauma, the psychological distress from witnessing others’ suffering, is an increasingly recognized precursor to depression and anxiety. However, the underlying neurobiological mechanisms remain poorly understood and appear to be sex-dependent. This study investigated the behavioral, physiological, and molecular consequences of purely psychological stress using a novel rodent model of vicarious learned helplessness (VLH).

Male and female C57BL/6J mice were used to establish VLH paradigm. Observer mice witnessed conspecifics receiving inescapable foot shocks through a partitioned chamber allowing multisensory interaction. Following 7 days of conditioning, behavioral assays assessed anxiety and depressive symptoms. Prefrontal cortex tissue was analyzed using RT-qPCR and immunoblotting to identify molecular alterations.

Vicarious stress induced depression phenotype in both sexes, characterized by active avoidance deficits, anhedonia and anxiety, comparable to direct physical trauma. Physiological assessments revealed hypothalamic-pituitary-adrenal (HPA) axis hyperactivity with elevated plasma corticosterone in both sexes. While molecular analysis showed shared downregulation of metabotropic glutamate receptor 2 (mGluR2) and elevated Il6 mRNA in the prefrontal cortex, distinct sexual dimorphism emerged. Males displayed specific deficits in neurotrophic support (Bdnf and BDNF) and glucocorticoid signaling (Nr3c1), whereas females exhibited impairments in social bonding pathways (Oxtr) and postsynaptic scaffolding proteins (PSD-95 and SHANK3).

Vicarious trauma is sufficient to drive depression-like pathology through distinct molecular trajectories in males and females. These findings are suggestive of the critical necessity for sex-specific therapeutic strategies when treating trauma-related psychiatric disorders.