Maternal depressive symptoms during pregnancy are associated with amygdala hyperresponsivity in children.

Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child's brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6-9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology.

Morphological maturation of the mouse brain: An in vivo MRI and histology investigation.

With the wide access to studies of selected gene expressions in transgenic animals, mice have become the dominant species as cerebral disease models. Many of these studies are performed on animals of not more than eight weeks, declared as adult animals. Based on the earlier reports that full brain maturation requires at least three months in rats, there is a clear need to discern the corresponding minimal animal age to provide an "adult brain" in mice in order to avoid modulation of disease progression/therapy studies by ongoing developmental changes. For this purpose, we have studied anatomical brain alterations of mice during their first six months of age. Using T2-weighted and diffusion-weighted MRI, structural and volume changes of the brain were identified and compared with histological analysis of myelination. Mouse brain volume was found to be almost stable already at three weeks, but cortex thickness kept decreasing continuously with maximal changes during the first three months. Myelination is still increasing between three and six months, although most dramatic changes are over by three months. While our results emphasize that mice should be at least three months old when adult animals are needed for brain studies, preferred choice of one particular metric for future investigation goals will result in somewhat varying age windows of stabilization.

PRENATAL EXPOSURE TO MATERNAL AND PATERNAL DEPRESSIVE SYMPTOMS AND BRAIN MORPHOLOGY: A POPULATION-BASED PROSPECTIVE NEUROIMAGING STUDY IN YOUNG CHILDREN.

BACKGROUND: Prenatal depressive symptoms have been associated with multiple adverse outcomes. Previously, we demonstrated that prenatal depressive symptoms were associated with impaired growth of the fetus and increased behavioral problems in children aged between 1.5 and 6 years. In this prospective study, we aimed to assess whether prenatal maternal depressive symptoms at 3 years have long-term consequences on brain development in a cohort of children aged 6-10 years. As a contrast, the association of paternal depressive symptoms during pregnancy and brain morphology was assessed to serve as a marker of background confounding due to shared genetic and environmental family factors. METHODS: We assessed parental depressive symptoms during pregnancy with the Brief Symptom Inventory. At approximately 8 years of age, we collected structural neuroimaging data, using cortical thickness, surface area, and gyrification as outcomes (n = 654). RESULTS: We found that exposure to prenatal maternal depressive symptoms during pregnancy was associated with a thinner superior frontal cortex in the left hemisphere. Additionally, prenatal maternal depressive symptoms were related to larger caudal middle frontal area in the left hemisphere. Maternal depressive symptoms at 3 years were not associated with cortical thickness, surface area, or gyrification in the left and right hemispheres. No effects of paternal depressive symptoms on brain morphology were observed. CONCLUSIONS: Prenatal maternal depressive symptoms were associated with differences in brain morphology in children. It is important to prevent, identify, and treat depressive symptoms during pregnancy as it may have long-term consequences on child brain development.

Beyond classical inheritance: the influence of maternal genotype upon child's brain morphology and behavior.

Genetic variance has been associated with variations in brain morphology, cognition, behavior, and disease risk. One well studied example of how common genetic variance is associated with brain morphology is the serotonin transporter gene polymorphism within the promoter region (5-HTTLPR). Because serotonin is a key neurotrophic factor during brain development, genetically determined variations in serotonin activity during maturation, in particular during early prenatal development, may underlie the observed association. However, the intrauterine microenvironment is not only determined by the child's, but also the mother's genotype. Therefore, we hypothesized that maternal 5-HTTLPR genotype influences the child's brain development beyond direct inheritance. To test this hypothesis, we investigated 76 children who were all heterozygous for the 5-HTTLPR (sl) and who had mothers who were either homozygous for the long (ll) or the short allele (ss). Using MRI, we assessed brain morphology as a function of maternal genotype. Gray matter density of the somatosensory cortex was found to be greater in children of ss mothers compared with children of ll mothers. Behavioral assessment showed that fine motor task performance was altered in children of ll mothers and the degree of this behavioral effect correlated with somatosensory cortex density across individuals. Our findings provide initial evidence that maternal genotype can affect the child's phenotype beyond effects of classical inheritance. Our observation appears to be explained by intrauterine environmental differences or by differences in maternal behavior.

Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case-control studies suggested an association between prenatal SSRI exposure with childhood autism. AIMS: To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study. METHOD: A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264). RESULTS: Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13-3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08-0.22) compared with those exposed to depressive symptoms only. CONCLUSIONS: Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible.

Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats.

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring's brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.

Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus.

Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal nucleus (EWcp), a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART)-producing EWcp-neurons would depend on the animal's energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24 h fasting, normal chow and leptin injection, respectively) on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db) mice, the number of CART producing neurons in this nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal's energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.