Long-Term Outcomes Resulting from Exposure to Stress and Fluoxetine During Development
Creators: name: Kiryanova, Veronika
Publisher: name: Graduate Studies
Year: 2017
Subjects: subject: Neuroscience
subject: Development
subject: Fluoxetine
subject: Stress
subject: SSRI
subject: Behavior
subject: Circadian
subject: Endocannabinoid
subject: Serotonin

description: Depression, anxiety, and stress are common in pregnant women. One of the primary pharmacological treatments for anxiety and depression is the antidepressant fluoxetine (Flx). Maternal stress, depression, and Flx exposure are known to effect neurodevelopment of the offspring; however, their combined effects have been scarcely studied. In this thesis, we examine the combined effects of maternal stress during pregnancy and perinatal exposure to Flx on the behaviour and the biochemical outcomes of mice as adults. Furthermore, we examine whether serotonin 1A (5-HT1A) receptors mediate the effects of maternal stress on mouse behaviour. In the adult male offspring, while perinatal exposure to Flx increased aggressive behaviour, prenatal maternal stress decreased aggressive behaviour. Interestingly, the combined effects of stress and Flx normalized aggressive behaviour. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behaviour in male offspring. In adult female offspring, maternal stress led to hyperactivity and alterations of prepulse inhibition. Maternal treatment with Flx had a potentially beneficial effect on spatial memory. The combination of prenatal stress and perinatal Flx exposure did not interact in their effects. Examination of the circadian behaviour demonstrated that mice exposed to prenatal stress had smaller light-induced phase-delays. Mice exposed to perinatal Flx required more days to re-entrainment to an 8-hour phase advance of their light-dark cycle. Mice subjected to either perinatal Flx or to PS had larger light-induced phase-advances and smaller phase advances to 8-OH-DPAT. Flx treatment partially reversed the effect of PS on phase shifts to late-night light exposure and to 8-OH-DPAT. An examination of the biochemical outcomes showed that the serotonergic, the endocannabinoid and the glucocorticoid systems were altered following exposure to perinatal stress and Flx. These alterations were long-lasting and sex-specific. Using the 5-HT1A receptor knockout mouse model, we show that, 5-HT1A receptor genotype moderated the effects of stress on social behaviour of male mice and on activity levels of females. Furthermore, independent of genotype, prenatal stress resulted in a change in locomotor activity and fear memory in male mice and a change in prepulse inhibition in female animals. 5-HT1A receptor knockout affected anxiety in male mice and fear memory and prepulse inhibition in female mice. Together, these data indicate that maternal exposure to stress and Flx have a number of sustained effects on the brain and behaviour of male and female offspring, however, females appear to be protected from the behavioural effects of Flx and some of the effects of stress. Our findings also indicate that 5-HT1A receptor availability can affect outcomes of the offspring following prenatal stress; these effects are highly sex specific.