Behavioural outcomes of adult female offspring following maternal stress and perinatal fluoxetine exposure

Highlights

• Behaviour of female mice perinatally exposed to fluoxetine and stress was examined.

• Maternal intake of fluoxetine improves spatial memory in female offspring.

• Maternal stress leads to hyperactivity and an increase in prepulse inhibition.

• Maternal fluoxetine intake does not worsen or reverse maternal stress effects.

Abstract

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, especially in female offspring. The present study investigated the combined effects of maternal stress during pregnancy and perinatal exposure to Flx on the behaviour of female mice as adults.

Methods

Mouse dams were exposed to either chronic unpredictable stress (embryonic (E) day 7 to E18), or FLX (E15- postnatal day 12), or a combination of stress and FLX or left untreated. At two months of age, the female offspring went through a comprehensive behavioural test battery.

Results

Maternal stress led to increased activity and alterations of prepulse inhibition in the adult female offspring. 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. These results suggest that gestational Flx exposure may have a limited negative impact on female offspring.

Introduction

Stress-related disorders such as depression and anxiety are common in pregnant women: 10–18% of pregnant women present with symptoms of depression, and 6–14% present with symptoms of anxiety disorders [1], [2], [3], [4]. This prevalence is even higher in pregnant women with lower socioeconomic status due to, in part, increased frequency of stressful life events [5], [6], [7], [8]. Depression is a very stressful experience, it impacts a woman's sleep, eating, and self-care and the level of care she can provide to her child. Stress, depression, and anxiety during pregnancy can also lead to adverse obstetric outcomes and affect fetal and neonatal development and behaviour [9], [10].

Primary pharmacological treatments for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) [11]. Out of the 6% of pregnant women who are prescribed an SSRI at some point during their pregnancy, between 20 and 25% will receive fluoxetine (Flx; brand names Prozac, Sarafem, Rapiflux) [12].

Maternal intake of antidepressants and maternal anxiety, depression, and stress can affect obstetric outcomes and child's development and behaviour. Early exposure to these environmental events are linked with a decrease in gestational length and a reduction in birth weight [13], [14], [15], and may lead to changes in emotional behaviour, including anxiety, in children [16], [17]. Beyond the childhood years, effects of maternal anxiety, depression, and stress and maternal Flx exposure are not yet fully understood. Animal studies have been essential in uncovering these effects [18,19][for a review see 18, 19].

Animal studies utilize maternal stress as a model of maternal depression and anxiety. Studies show that maternal stress and maternal exposure to Flx both have long-term effects on the mouse and rat offspring. These maternal experiences alter offspring's learning and memory (stress: [20], [21], [22], [23], [24], [25]; Flx: [26], [27], [28]), aggression levels (stress: [29], [30], [31], [32]; Flx: [28], [32], [33], [34]), circadian behaviours (stress: [35]; Flx: [36]), and depressive- and anxiety-like behaviours (stress: [25], [37], [38], [39]; Flx: [26], [27], [28], [40], [41], [42], [43]).

While necessary, examining the offspring of healthy animals is of minor ethological validity when attempting to draw inferences about exposed humans. This is because Flx exposure in humans does not typically happen in isolation; Flx exposure is concurrent with maternal stress, anxiety, and/or depression. Animal studies are beginning to examine combined effects of perinatal stress and Flx exposure on adult offspring outcomes. Some studies demonstrate that Flx and stress have specific long-term effects on the offspring. They have distinct effects on reproductive behaviour [44], [45], sexual brain differentiation [44], and depressive-like behaviour [46] in rats, and anxiety-like behaviour [32], [46] and hippocampal and cortical BDNF signaling in rats and mice [32], [46]. Other studies demonstrate that while maternal exposure to stress and Flx can have distinct effects, treatment with Flx early in life can counteract some of the effects of maternal stress. In mice, these include alterations in spatial learning [47], HPA-axis reactivity [48], aggressive behaviours [32], and circadian behaviours [35], while in rats, it includes sensitivity to post-operative pain [49]. In both rodent models, Flx counteracts stress-induced alterations in hippocampal morphology [47], [50]. However, most behavioural studies were conducted in male offspring; behaviours of adult female offspring have not yet been examined aside from reproductive [45] and depressive-like behaviours of rats [46]. A thorough assessment of outcomes in female offspring is warranted. Past studies provided indications that outcomes of female offspring may differ from that of males. First, behavioural baselines show sexual dimorphism [51], [52], [53]. Second, male and female animals are differently affected by stress [54], [55], [56], [57] and Flx administration [58], [59], [60]. And, most importantly, male and female mice show different patterns of behavioural changes following maternal stress [22], [23], [61], [62], [63], [64], [65] and perinatal Flx administration [43], [63], [66].

The goal of the present study was to investigate the effects of prenatal stress and effects of perinatal exposure to Flx, separately and in combination, on the behaviour of the adult female offspring. This study sought to provide a more complete insight by conducting an in-depth behavioural analysis of the offspring's cognitive ability, memory, anxiety, sensorimotor information processing, and exploratory and risk assessment behaviours.