Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence

Abstract

Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

Figure 1. Timeline of experiment.

Stress was administered between GD15-21. Fluoxetine treatment to the mother began 1 day after birth and continued until weaning (P21). Between P32 and P39, offspring were subjected to behavioral tasks. At P42, offspring were sacrificed.

Figure 2. Photomicrographs of representative A) Ki67-ir cells and B) DCX-ir cells in the GCL/SGZ and mean (± SEM) number of C) Ki67-ir cells and D) DCX-ir cells in the GCL/SGZ.

C) PSV adolescent offspring had significantly fewer Ki-67-ir cells in the GCL/SVZ compared to all other groups (.0001≤p≤.01). CF adolescent offspring had significantly more Ki67-ir cells in the GCL/SVZ compared to PSV offspring (p≤.0001), but significantly fewer Ki67-ir cells in the GCL/SVZ compared to CV and PSF offspring (.002≤p≤.04), regardless of sex. D) PSV adolescent offspring had significantly fewer number of DCX-ir cells in the GCL/SGZ of the hippocampus compared to all other groups (.006≤p≤.03), regardless of sex. ‘*’denotes significantly different from all other groups. (n = 5/sex/group).

Figure 3. Mean (± SEM) percentage in weight change from P29 to P42.

CF and PSF offspring gained significantly less weight than CV and PSV offspring, regardless of stress (p≤.0002). Overall, male adolescent offspring gained significantly more weight than female offspring (p≤.0001). ‘*’denotes CF and PSF significantly different from CV and PSV groups. ‘**’ denotes males significantly different from females. (n = 9–11/sex/group).

Figure 4. Mean (± SEM) A) number of central entries (OFT) and B) time spent immobile (FST).

A) PSV male offspring made significantly fewer central entries compared to CF and PSV female offspring (.007≤p≤.02). There was also a significant main effect of sex with male offspring making significantly fewer central entries compared to female offspring (p≤.05). Further analysis by sex revealed that PSV males made fewer central entries than CV, CF and PSF adolescent males, however this did not reach significance (p≥0.09) and there were no significant effect of treatment or condition in female adolescent offspring (p≥0.14). B) PSV adolescent offspring spent significantly less time immobile compared to CV and PSF offspring (.02≤p≤.04). (n = 9–11/sex/group).