Z-score analysis of depressive-like and anxiety phenotypes in mice after early-life stress and serotonin depletion

Early-life stress is one of the major risk factors for the development of anxiety and depression, and at the same time, serotonin (5-HT) deficits have been linked to the origin of these mental disorders. To study the role of 5-HT in early-life stress effects, we sought to investigate the interaction between 5-HT depletion and maternal separation (MS) in mice. C57BL/6 pups were subjected to the MS protocol (3h/day) during a postnatal critical period (P2-P14) while receiving daily injections of a tryptophan hydroxylase inhibitor (PCPA, 100mg/kg/day s.c.). We then evaluated emotional responses to stress in a battery of behavioral paradigms at adulthood (from P80). Responses in these tasks were analyzed by the Z-score method and the results of the tests were integrated into an Anxiety and a Depressive-like score. Our study showed that male mice were more susceptible to the MS exposure, resulting in long-lasting higher levels of anxiety and depressive-like behaviors which couldn’t be reversed with the 5-HT depletion. Interestingly, in the anxiety score, females showed no response to MS alone but did have an increased score when 5-HT was depleted in addition to the stress. Notably, both MS and PCPA treatments increased the proportion of vulnerable vs resilient animals in both scores. Our results emphasize the emotional alterations caused by early-life stress and the interaction with the 5-HT transmission, in the search for understanding the development of psychiatric disorders.