Molecular insights into long-term behavioral effects of perinatal serotonergic manipulation

Serotonin (5-HT) plays a crucial role in brain development [1] and perturbations during perinatal stages can affect brain functioning and lead to neuropsychiatric disorders later in life. To investigate the complex interplay between 5-HT and the pathophysiology of these diseases we exposed male and female rats to fluoxetine (FLX) (15mg/Kg/day in drinking water) during gestation (prenatal-FLX) or breastfeeding (postnatal-FLX). We first assessed three behaviors and observed a late onset of diverse pathological-like phenotypes that became manifest in adulthood, but not in adolescence, which appear to be sex- and timing-dependent. Indeed, adult males developed an anhedonic-like phenotype (sucrose preference test: p<0.01 vs vehicle. One-way ANOVA with Tukey) when exposed to prenatal-FLX, while females were more sensitive to postnatal manipulation showing cognitive deficits (novel object recognition test: p<0.05 vs vehicle. One-way ANOVA with Tukey). At the molecular level, we looked for potential peripheral markers providing indications on windows of vulnerability that could give insights into what is going on in the brain and we observed symptom-related molecular alterations and blood-specific brain area associations [2]. Moreover, since it’s known that exposure to a challenge during crucial periods of vulnerability may reveal changes preceding the behavioral outcomes, we evaluated in adolescent males whether prenatal-FLX influences the capability to respond to acute restraint stress (ARS). Our analyses were focused on the hypothalamic-pituitary-adrenal axis, given its key role in stress response. We observed increased levels of plasmatic corticosterone levels (p<0.01. Two-way ANOVA with Tukey) one hour after ARS in the prenatal-FLX group compared to the no-stress counterpart, and not in controls, suggesting prenatal 5-HT manipulation may prime the response to challenging events during adolescence [3]. Additionally, to clarify the molecular mechanisms explaining the behavioral outcomes observed at adulthood we investigated trigger and brake markers involved in the dynamics of sensitive periods at three distinct ages (postnatal day (PND) 21, 35, 70). We found alterations of Bdnf and Ncan expression in a sex- and brain region-specific way that could influence the development of pathological conditions later in life. In conclusion, our findings suggest that the perinatal manipulation of the serotonergic system leads to pathological-like conditions later in life that are sex- and timing-dependent and that may be due to changes in sensitive periods dynamics. These results should be further investigated to better understand the etiological mechanisms underpinning neuropsychiatric disorders.