Antidepressant use during pregnancy and serotonin transporter genotype (SLC6A4) affect newborn serum reelin levels.

This study was undertaken to determine whether altered early serotonin signaling either via gestational serotonin reuptake inhibitor (SRI) exposure or genetic variations in the serotonin transporter promoter region (SLC6A4) alters levels of reelin, an important glycoprotein in neurodevelopment, in mothers and their neonates. Serum reelin protein expression was quantified by immunoblot from maternal and neonatal blood collected at delivery from women taking either an SRI during gestation or controls. SRI-exposed mothers had higher levels of one reelin fragment, while SRI-exposed neonates had lower total reelin levels, particularly in females and reelin levels differed with SLC6A4 genotype. Lower neonatal reelin levels predicted less time spent sleeping and more irritability during neonatal behavioral assessment on Day 6 of life. Our results suggest that prenatal SRI exposure and the SLC6A4 genotype influences reelin protein expression in both the mother and newborn and that this may be reflected in neonatal behavior.

Elevated stress hormone levels and antidepressant treatment starting before pregnancy affect maternal care and litter characteristics in an animal model of depression.

Many women who take antidepressant medications become pregnant while taking their medication; however, the impact of depression and antidepressant medication on fetal development is not well understood. This study used a translational animal model of maternal depression to investigate the consequences of discontinuing antidepressant medication during pregnancy. First, rats received corticosterone (CORT; 40 mg/kg, s.c.) or vehicle to induce a depressive-like phenotype. After 16 days of treatment with CORT or vehicle, animals were treated with sertraline (a selective serotonin reuptake inhibitor, SSRI; 20 mg/kg) or vehicle via gavage. Following 21 days of CORT or oil treatment, rats were mated. One group receiving sertraline was discontinued from treatment on gestational day 16, and another group continued sertraline treatment throughout pregnancy to assess the effects of discontinuation. After weaning, dams were sacrificed via perfusion to investigate neurogenesis. As intended, CORT administration created a depressive-like phenotype with increased immobility in the Forced Swim Test and reduced body weight. Interestingly, sertraline treatment could not rescue these altered features. Pre-conceptional CORT exposure resulted in smaller litters and CORT dams that received sertraline until the end of gestation spent more time off of the nest compared to CORT dams that received vehicle or discontinued sertraline during gestation. There was no difference in hippocampal neurogenesis between any of the groups. Our results suggest that treatment with antidepressants may have different effects in healthy or depressed dams, however, we need more research to investigate the detailed and long-term effects of maternal depression and its treatment in translational animal models.

Developmental changes in serotonin signaling: Implications for early brain function, behavior and adaptation.

The neurotransmitter serotonin (5-HT) plays a central role in brain development, regulation of mood, stress reactivity and risk of psychiatric disorders, and thus alterations in 5-HT signaling early in life have critical implications for behavior and mental health across the life span. Drawing on preclinical and emerging human evidence this narrative review paper will examine three key aspects when considering the consequences of early life changes in 5-HT: (1) developmental origins of variations of 5-HT signaling; (2) influence of genetic and epigenetic factors; and (3) preclinical and clinical consequences of 5-HT-related changes associated with antidepressant exposure (SSRIs). The developmental consequences of altered prenatal 5-HT signaling varies greatly and outcomes depend on an ongoing interplay between biological (genetic/epigenetic variations) and environmental factors, both pre and postnatally. Emerging evidence suggests that variations in 5-HT signaling may increase sensitivity to risky home environments, but may also amplify a positive response to a nurturing environment. In this sense, factors that change central 5-HT levels may act as 'plasticity' rather than 'risk' factors associated with developmental vulnerability. Understanding the impact of early changes in 5-HT levels offers critical insights that might explain the variations in early typical brain development that underlies behavioral risk.

Effectiveness of different corticosterone administration methods to elevate corticosterone serum levels, induce depressive-like behavior, and affect neurogenesis levels in female rats.

High levels of chronic stress or stress hormones are associated with depressive-like behavior in animal models. However, slight elevations in corticosterone (CORT) - the major stress hormone in rodents - have also been associated with improved performances, albeit in a sex-dependent manner. Some of the discrepancies in the literature regarding the effects of high CORT levels may be due to different administrations methods. The current study aims to compare the effects of ∼40mg/kg given either via subcutaneous injection, through an implanted pellet, or in the drinking water, for ∼21days on CORT serum levels, depressive-like behavior in the forced swim test (FST), and neurogenesis levels in the dentate gyrus (DG) in adult female rats. We found that animals exposed to the daily injections showed elevated CORT levels throughout the administration period, while the pellet animals showed only a transient increase, and drinking water animals revealed no elevation in CORT in serum. In addition, only the injection group exhibited higher levels of immobility in the FST. Interestingly, animals receiving CORT via injection or drinking water had lower numbers of doublecortin-positive cells in the ventral DG one week after the last CORT administration compared to animals implanted with a CORT pellet. These results will contribute to the growing literature on the effects of chronic CORT exposure and may help to clarify some of the discrepancies among previous studies, particularly in females.

Postpartum corticosterone administration reduces dendritic complexity and increases the density of mushroom spines of hippocampal CA3 arbours in dams.

Postpartum depression (PPD) affects approximately 15% of mothers after giving birth. A complete understanding of depression during the postpartum period has yet to be established, although disruptions in the hypothalamic-pituitary-adrenal axis and stress during the postpartum may be involved. To model these components in rats, we administered high corticosterone (CORT) postpartum, which increases immobility in the forced swim test (FST), and reduces maternal care, body weight and hippocampal cell proliferation in dams. The hippocampus is altered in response to chronic stress, exposure to high glucocorticoids and in major depression in humans. In the present study, we examined whether high CORT reduced dendritic complexity and spines in the CA3 region of the hippocampus. Additionally, housing complexity was manipulated so that dams and litters were housed either with tubes (complex) or without tubes (impoverished) to investigate the consequences of new animal care regulations. Dams received 40 mg/kg/day of CORT or oil starting on day 2 postpartum for 23 days. Maternal behaviours were assessed on postpartum days 2-8 and dams were tested using the FST on days 21 and 22. Dams were killed on day 24 and brains were processed for Golgi impregnation. Pyramidal cells in the CA3 subfield were traced using a camera lucida and analysed for branch points and dendritic complexity, as well as spine density and type on both basal and apical arbours. As previously established, high CORT postpartum reduced maternal care and increased immobility in the FST, which is a measure of depressive-like behaviour. High CORT postpartum reduced the complexity of basal arbours and increased mushroom spines on both apical and basal dendrites. Housing complexity had no effect on spines of CA3 pyramidal cells but modest effects on cell morphology. These data show that chronic high CORT in postpartum females alters hippocampal morphology and may provide insight regarding the neurobiological consequences of high stress or CORT during the postpartum period, as well as be relevant for postpartum stress or depression.

Elevated corticosterone levels during the first postpartum period influence subsequent pregnancy outcomes and behaviours of the dam.

Postpartum depression affects 15% of new mothers and previous depressive episodes increase the risk for postpartum depression. Chronic administration of corticosterone (CORT) to dams during the postpartum period causes depressive-like behaviour and has been used as a model of postpartum depression. To better understand the subsequent progress of this model, we examined whether there were persistent effects of CORT treatment during the dam's first postpartum period on maternal care and mood following a subsequent pregnancy. Sprague-Dawley female rats received either sesame oil (control) or CORT (40 mg/kg) injections for 22 days during their first postpartum period. Subsequently, all females were re-mated for a second time and neither group received treatment during the second postpartum period. Maternal care was observed from days 2-8 of each postpartum period and dams were tested in the forced-swim test on days 21 and 22 of the first and days 4 and 21 of the second postpartum period. As expected, the amount of time spent immobile in the forced-swim test was increased in CORT dams at the end of the first postpartum period; however, the amount of time spent immobile was decreased at the end of the second postpartum period relative to oil dams. Furthermore, dams treated with CORT in first postpartum period gave birth to a smaller litter with a larger male/female sex ratio after their second pregnancy. This implies that elevated stress hormone levels during the first postpartum period have a substantial influence on subsequent postpartum behaviour and litter characteristics. Further investigations are necessary to fully understand the effect of parity, experience during first motherhood, and hypothalamic-pituitary-adrenal axis regulation on postpartum depression.

Depression during pregnancy and postpartum: contribution of stress and ovarian hormones.

Depression is the most common psychiatric disease among women, exhibiting a prevalence which is 2-3x higher than in men. The postpartum period is considered the time of greatest risk for women to develop major depression and postpartum depression affects approximately 15% of women. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is the most prominent endocrine change seen in depression and normalization of the HPA axis is a major target of recent therapies. Females exhibit different stress sensitivities than males which might contribute to their increased vulnerability for depression. Maternal stress or depression during pregnancy and/or postpartum is particularly concerning as early developmental influences can affect the maturation of the offspring as well as the mental health of the mother. Despite the urgent need for more information on depression in females, especially during pregnancy and postpartum, most animal models of depression have utilized only males. Given the sex differences in incidence of depression and treatment, it is vitally important to create or validate animal models of depression in females. This review will focus on the association between stress, glucocorticoids and depression in humans, with a special focus on depression in women during pregnancy and postpartum and on animal models of postpartum depression and the consequences for the offspring.

Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats.

Adult neurogenesis in the dentate gyrus of the hippocampus is altered with stress exposure and has been implicated in depression. High levels of corticosterone (CORT) suppress neurogenesis in the dentate gyrus of male rats. However both acute and chronic stress do not consistently reduce adult hippocampal neurogenesis in female rats. Therefore, this study was conducted to investigate the effect of different doses of corticosterone on hippocampal neurogenesis in male and female rats. Rats received 21 days of s.c. injections of either oil, 10 or 40 mg/kg CORT. Subjects were perfused 24 h after the last CORT injection and brains were analyzed for cell proliferation (Ki67-labeling) or immature neurons (doublecortin-labeling). Results show that in both males and females high CORT, but not low CORT, reduced both cell proliferation and the density of immature neurons in the dentate gyrus. Furthermore, high CORT males had reduced density in immature neurons in both the ventral and dorsal regions while high CORT females only showed the reduced density of immature neurons in the ventral hippocampus. The high dose of CORT disrupted the estrous cycle of females. Further, the low dose of CORT significantly reduced weight gain and increased basal CORT levels in males but not females, suggesting a greater vulnerability in males with the lower dose of CORT. Thus we find subtle sex differences in the response to chronic CORT on both body weight and on neurogenesis in the dorsal dentate gyrus that may play a role in understanding different vulnerabilities to stress-related neuropsychiatric disorders between the sexes.

Alteration in the GABAergic network of the prefrontal cortex in a potential animal model of psychosis.

The GABAergic input on cortical pyramidal cells has an important influence on the firing activity of the cortex and thus in regulating the behavioural outcome. The aim of the current study was to investigate the long-term neuroplastic adaptation of the GABAergic innervation pattern after an early severe systemic impact. Therefore 40 Mongolian gerbils (Meriones unguiculatus) were either reared under impoverished (IR) or enriched rearing conditions (ER) and received a single early (+)-methamphetamine (MA) challenge (50 mg/kg i.p.) or saline on postnatal day 14. The density of perisomatic immunoreactive GABAergic terminals surrounding layers III and V pyramidal neurons was quantified as well as the overall GABAergic fibre density in layers I/II and V of the medial prefrontal cortex (mPFC) of young adult animals (90 days). We found that IR in combination with an early MA administration led to a significant decrease in GABAergic bouton densities while the overall GABAergic fibre density increased in all investigated layers. The results indicate a shift in inhibition from somatic to dendritic innervation of pyramidal neurons in this potential animal model of psychosis. We conclude that IR combined with early MA trigger changes in the postnatal maturation of the prefrontal cortical GABAergic triggers innervation, which may interfere with proper signal processing within the prefrontal neural network.

Developmental pattern changes of prefrontal efferents in the juvenile gerbil (Meriones unguiculatus).

Previous findings of our group showed that early traumatisation leads to a dysfunctional organisation of prefrontocortical efferents in adulthood. To identify vulnerable time windows during maturation, we labelled either layer III- or layer V/VI-pyramidal cells with biocytin in the prefrontal cortex of gerbils (Meriones unguiculatus) from the age of postnatal day (PD) 15 up to adulthood (PD 90). The density of passing fibres and axonal terminals in distinct cortical columns in specific prefrontal projection areas was assessed by digital image analysis. Following layer III injections, fibre densities reached adult values between adolescence (PD 60) and adulthood (PD 90). However, layer V/VI-fibre densities decreased after eye-opening (PD 15), followed by an increase to adult values after weaning (PD 30). These findings are the first to describe dynamic structural changes even beyond adolescence of functionally diverse prefrontal output systems. External interventions might exert adverse influences on the establishment of integrated prefrontal networks especially during the early phase of re-arranging.