Differential progression of cognitive and mood-related phenotypes in a mouse model of chronic depression

Abstract

Depressive disorders remain highly prevalent and lack effective treatments. Mounting evidence suggests that disrupted cognitive processes, such as uninhibited negative thought patterns (“rumination”), play a significant role in the development of Major Depressive Disorder (MDD), either alongside or preceding serotonin-related mood imbalances. However, the underlying mechanisms of prodromal cognitive symptoms necessitate further investigation. This study explored the differential progression of cognitive and mood-related phenotypes in BALB/c mice subjected to the unpredictable chronic mild stress (UCMS) model. Following two UCMS durations—short-term (2–3 weeks) and long-term (5–6 weeks)—we observed the emergence of distinct symptom sets. Differences in neurobiological processes and substrates were also seen, including alterations to regional metabolic activity. Additionally, sex differences in behavioural measures were identified, in line with previous research pointing to sex-specific vulnerabilities to chronic stress. Altogether, our findings demonstrate the emergence of cognitive deficits associated with dysregulated inhibitory mechanisms in the early stages of depressive-like symptom onset, and may inform the development of preventive treatment strategies.