Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis
Introduction
According to the DSM-5, perinatal depression is defined as depression during pregnancy and the early postpartum. As with major depression, one of the most common treatments for perinatal depression is pharmacological antidepressants, such as selective serotonin reuptake inhibitors (SSRIs; Oberlander et al., 2006, Kim et al., 2014). As more women receive antidepressants to treat perinatal depression, the population of children who have been exposed to antidepressants during the perinatal period also increases (Oberlander et al., 2006). However, maternal SSRI use may be problematic as SSRIs such as fluoxetine (Prozac) can cross the placental barrier (Hendrick et al., 2003) and pass into breast milk (Wisner et al., 1996, Weissman et al., 2004), potentially affecting the developing offspring. Indeed, perinatal SSRI exposure is associated with adverse outcomes in the infant such as reduced weight gain (Chambers et al., 1999), levels of reelin required for normal brain development (Brummelte et al., 2013), psychomotor scores during the first year (Santucci et al., 2014), increased hypertension (Chambers et al., 2006), cardiac defects (Malm et al., 2011), and risk for autism (Croen et al., 2011). However, the negative effects of perinatal fluoxetine may outweigh the detrimental effects of untreated maternal depression on child development. Specifically, children of mothers with postpartum depression (PPD) are more likely to develop depression, anxiety, and attention deficits even long after the mother's depression has remitted (Pilowsky et al., 2006, Murray et al., 2011). Thus, the potential therapeutic effect of maternal SSRIs may mitigate these negative effects on child development. In fact, maternal SSRI use is associated with enhanced infant readiness to interact with their mother (3 mo infants; Weikum et al., 2013b), accelerated perceptual development (6 mo and 10 mo infants; Weikum et al., 2012), and improved executive function (6 yo; Weikum et al., 2013a). However, it is unclear whether the effects of maternal fluoxetine are advantageous in the long term or precede negative behavioral outcomes that emerge later in life. This study aims to fill this gap.
Preclinical research investigating the long term effects of perinatal fluoxetine on emotional behavior has yielded mixed results, likely due to methodological differences including timing and method of administration. For example, direct administration of fluoxetine to pups during the postnatal period increased anxiety-like behavior (Yu et al., 2014), while maternal exposure to fluoxetine (gestation and lactation) resulted in no significant effect on anxiety-like behavior in adult offspring (Lisboa et al., 2007, Francis-Oliveira et al., 2013). Additionally, direct administration of fluoxetine to pups during the postnatal period decreased depressive-like behavior in adult rats (Mendes-da-Silva et al., 2002) whereas maternal fluoxetine (gestation and postpartum) increased depressive-like behavior in adult female but not male mice offspring (Lisboa et al., 2007). In addition, the current state of research examining neonatal fluoxetine exposure is hindered by a general lack of preclinical research investigating maternal fluoxetine exposure within a model of depression or PPD. Because mothers typically use SSRIs to treat depression, there is a need for preclinical research to address how maternal fluoxetine influences offspring within a concurrent model of depression or stress in order to contribute valid conclusions regarding the use of SSRIs to treat PPD. To this end, there are a few studies examining how gestational stress followed by maternal postpartum fluoxetine normalizes immobility in the forced swim test in adolescent male and female offspring (Rayen et al., 2011) as well as blunts serum corticosterone (CORT; primary glucocorticoid in rats) levels in adolescent male, but not female, offspring (Pawluski et al., 2012c). However, gestational stress did not result in a depressive phenotype in the dam in this study (Pawluski et al., 2012b), so it is unclear whether these results can be interpreted as modeling maternal depression. Moreover, it is unknown how modeling depression and antidepressant treatment occurring exclusively in the postpartum affect offspring development. This is an important problem to investigate because approximately 40% of perinatal depression arises solely in the postpartum period (Wisner et al., 2013) and treatment and outcome for mother and child differ depending on the timing of depression onset (Cooper and Murray, 1995). Thus, there is a need to study postpartum antidepressant treatment in animal models of depression based on postpartum and antenatal depression, respectively.
The hippocampus exhibits morphological alterations long after exposure to developmental stress (reviewed in Korosi et al., 2012; reviewed in Loi et al., 2014). Although maternal depression does not predict significant changes in hippocampal volume in children (Lupien et al., 2011), childhood maltreatment (Chaney et al., 2014) and low maternal bonding (Buss et al., 2007) are associated with reduced hippocampal volume in adulthood, which both may be present in PPD. Reduction in hippocampal volume can be attributed to a number of factors such as lower levels of hippocampal neurogenesis. Broadly speaking, stress reduces adult hippocampal neurogenesis depending on age at the time of stress exposure and sex of the subject (reviewed in Gobinath et al., 2014). For example, maternal deprivation diminished expression of doublecortin (an endogenous protein expressed in immature neurons) in adult male but not female rat offspring (Oomen et al., 2010, Oomen et al., 2011). Furthermore, adult hippocampal neurogenesis may play an important role in the etiology of mood-related disorders such as depression (reviewed in DeCarolis and Eisch, 2010; reviewed in Eisch and Petrik, 2012), as well as regulation of the hypothalamic-pituitary-adrenal (HPA) axis (Snyder et al., 2011). Despite evidence that antidepressants can normalize HPA axis activity (Ising et al., 2007) and increase hippocampal neurogenesis (Malberg et al., 2000, Santarelli et al., 2003, Boldrini et al., 2009, Epp et al., 2013), little is known about how maternal fluoxetine affects HPA axis and adult neurogenesis in the hippocampus of offspring beyond the time they are exposed to the drug. Maternal postpartum fluoxetine reversed the detrimental effects of prenatal stress on hippocampal doublecortin expression in both male and female adolescent rat offspring (Rayen et al., 2011). However, by adulthood, maternal postpartum fluoxetine only diminished doublecortin expression after prenatal stress exposure, particularly in adult male offspring (Rayen et al., 2015). Thus, hippocampal neurogenesis represents a neurobiological intersection of developmental exposure to stress, antidepressants, and adult behavioral outcomes and will be investigated in the present study.
We have previously shown that chronic CORT administered to the dam postpartum increases maternal depressive-like behavior and diminishes maternal care (Brummelte et al., 2006, Brummelte et al., 2010, Brummelte and Galea, 2010, Workman et al., 2013b, Workman et al., 2015b). Interestingly, maternal postpartum CORT decreases hippocampal cell proliferation in male offspring at weaning (Brummelte et al., 2006) and increases anxiety-like behavior in adolescent male, but not female, offspring (Brummelte et al., 2012). However, it is unclear whether these sex differences or effects on offspring brain and behavior persist when the dam is exposed to concurrent maternal antidepressant exposure. The present study investigates whether high levels of maternal postpartum CORT and concurrent fluoxetine administered to dams differentially affect adult male and female offspring outcome at the behavioral (anxiety- and depression-like behavior, locomotion), endocrine (HPA axis dysregulation), and neural (doublecortin expression) levels. We hypothesized that maternal postpartum fluoxetine would negatively affect behavior, HPA axis regulation, and hippocampal neurogenesis in the affected adult offspring. Further, we expect that both sexes will be differentially affected by maternal postpartum fluoxetine and CORT.
Section snippets
Animals
Thirty-two adult female Sprague–Dawley rats (2–3 months old) and 16 adult male Sprague–Dawley rats (2–3 months old, Charles River) were initially housed in same-sex pairs in opaque polyurethane bines (24 × 16 × 46 cm) with aspen chip bedding. Rats were maintained in a 12 h: 12 h light/dark cycle (lights on at 7:00 a.m) and given rat chow (Jamieson's Pet Food Distributors Ltd, Delta, BC, Canada) and tap water ad libitum. All protocols were in accordance with ethical guidelines set by Canada
Maternal postpartum fluoxetine increased anxiety-like behavior in the elevated plus and novelty suppressed feeding task in adult male, but not female, offspring
In the elevated plus maze, maternal postpartum fluoxetine increased the ratio of time spent in the closed arms versus open arms + center in comparison to maternal postpartum saline in adult male (a priori; p = 0.023), but not female offspring (p = 0.946; Fig. 2A). Overall males had a higher ratio of time spent in the closed arms versus open arms + center compared to females (main effect of sex; p = 0.027). There was a trend for maternal postpartum fluoxetine to increase ratio of time spent in
Discussion
Here we show that maternal exposure to fluoxetine during the postpartum period can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and hippocampal neurogenesis in adult offspring depending on sex. In adult male offspring, maternal postpartum fluoxetine increased anxiety-like behavior in the elevated plus maze and novelty suppressed feeding test and density of doublecortin-expressing cells in the dorsal hippocampus. Maternal postpartum fluoxetine also impaired HPA
Conclusions
Our data indicate that maternal postpartum fluoxetine can have long-lasting effects on behavioral, endocrine, and neural outcomes of adult offspring in a sex-specific manner. Specifically, adult male offspring were more vulnerable to the effect of maternal postpartum fluoxetine than the female offspring with regards to anxiety-like behavior, HPA axis negative feedback regulation, and hippocampal neurogenesis. However, both adult male and female offspring exhibited more serotonin-dependent
Conflicts of interest
The authors have nothing to declare.
Acknowledgments
The authors would like to thank Lucille Hoover, Nikki Kitay, Robin Richardson, and Cara Tweed for their assistance and contributions throughout the experiment. This work was funded by a CIHR operating grant to LAMG (IGO-103692) and Coast Capital funding to JLW and LAMG.
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Present address: University at Albany, State University of New York, Department of Psychology, 1400 Washington Ave., Albany, NY 12222, USA.