Behavioural characteristics and sex differences of a treatment-resistant depression model: Chronic mild stress in the Wistar-Kyoto rat

Depression affects 20% of the general population and is a leading cause of disability worldwide, with a strong female prevalence. Current pharmacotherapies have significant limitations, and one third of patients are unresponsive. Male Wistar-Kyoto rats exposed to chronic mild stress (CMS) were recently proposed as a model to study antidepressant resistance. However, sex differences and interindividual vulnerability to stress are yet unexplored in this model. We aimed to investigate these in the context of the behavioural impact of CMS in the sucrose preference test, elevated plus maze (EPM), forced swim test (FST), open field test and daily locomotor activity rhythms, in male and female WKY rats exposed or not to a 4-week CMS protocol. CMS-exposed animals were clustered through K-means into subgroups based on the EPM and FST results. In both sexes, one subgroup behaved similarly to non-stressed animals and was labelled stress-non vulnerable; the second exhibited less open arms exploration in the EPM and higher immobility in the FST and was named stress-vulnerable. Vulnerable males presented phase delay in daily locomotor activity following CMS, but no significant rhythm could be determined in females. CMS-exposed males of both groups showed hyperlocomotion in reaction to novelty and slower weight gain through the course of CMS, while CMS-exposed females showed smaller sucrose intake. Unexpectedly, CMS did not affect sucrose preference. Our findings strengthen the view that in models of psychiatric pathologies based on stress exposure it is important to consider the effect of sex and to differentiate the non vulnerable and vulnerable subpopulations.