Chronic unpredictable stress induces negative cognitive bias in rats with sex-specific changes in neurogenesis and functional connectivity

Background: Females are more likely to be diagnosed with major depressive disorder (MDD) than males. Cognitive symptoms of MDD include negative cognitive bias, the perception of ambiguous situations as negative, which predicts MDD episode onset and severity. MDD is associated with changes to functional connectivity between regions involved in cognition, emotion, attention, and memory. Methods: Here we examined the impact of chronic unpredictable stress (CUS) on negative cognitive bias in male (n=18) and female (n=22) Sprague-Dawley rats. We assessed hippocampal neurogenesis and c-Fos expression in response to an ambiguous context across 15 regions of the frontal cortex, amygdala, nucleus accumbens, and hippocampus, including in newborn dentate gyrus (DG) neurons, to examine functional connectivity during cognitive bias testing. We conducted a graph-based network analysis and constructed linear models to predict freezing in the ambiguous context based on regional activation. Results: CUS-exposed rats froze more to the ambiguous context than non-CUS-exposed rats, regardless of sex. CUS decreased neurogenesis in the ventral DG of both sexes, and increased activation of new neurons in the dorsal DG of males only. In response to the ambiguous context, CUS males had an increase in c-Fos expression in the amygdala. CUS produced extensive, sex-specific network reorganization, decreasing global network efficiency in males but not in females. Freezing in the ambiguous context was predicted by activation of new neurons in combination with the ventral CA1 in opposing directions across sex. Conclusions: These findings suggest that sex-specific pathways drive the expression of CUS-induced negative cognitive bias, underscoring the necessity of sex-stratified preclinical and clinical research on negative cognitive bias in depression.