Sex differences in the programming effects of prenatal stress on psychopathology and stress responses: an evolutionary perspective

There is strong evidence from animal studies that prenatal stress has different effects on male and female offspring. In general, although not always, prenatal stress increases anxiety, depression and stress responses, both hypothalamic–pituitary–adrenal and cardiovascular, in female offspring rather than in male. Males are more likely to show learning and memory deficits. There have been few studies so far in humans which differentiate effects of prenatal stress on male and female psychopathology. Some studies support the animal models, but the evidence is inconsistent. The mediating mechanisms for any sex specific effects are little understood, but there is evidence that placental function can differ depending on the sex of the fetus. We suggest that there may be an evolutionary reason for any sex differences in the long term effects of prenatal stress. In a stressful environment it may be adaptive for females, who are more likely to stay in one place and look after children, to be more vigilant, alert to danger and thus show more stress responsiveness. This can give rise to a more anxious or depressed phenotype. With males it may be more adaptive to go out and explore new environments, compete with other males, and be more aggressive. For this it may help to be less responsive to external stressors. More research is needed into sex differences in the effects of prenatal stress in humans, to test these ideas.

Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Gestational protein restriction induces CA3 dendritic atrophy in dorsal hippocampal neurons but does not alter learning and memory performance in adult offspring

Studies have demonstrated that nutrient deficiency during pregnancy or in early postnatal life results in structural abnormalities in the offspring hippocampus and in cognitive impairment. In an attempt to analyze whether gestational protein restriction might induce learning and memory impairments associated with structural changes in the hippocampus, we carried out a detailed morphometric analysis of the hippocampus of male adult rats together with the behavioral characterization of these animals in the Morris water maze (MWM). Our results demonstrate that gestational protein restriction leads to a decrease in total basal dendritic length and in the number of intersections of CA3 pyramidal neurons whereas the cytoarchitecture of CA1 and dentate gyrus remained unchanged. Despite presenting significant structural rearrangements, we did not observe impairments in the MWM test. Considering the clear dissociation between the behavioral profile and the hippocampus neuronal changes, the functional significance of dendritic remodeling in fetal processing remains undisclosed. © 2012 ISDN.

Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide

The aim of the present study was to evaluate the behavioral patterns associated with autism and the prevalence of these behaviors in males and females, to verify whether our model of lipopolysaccharide (LPS) administration represents an experimental model of autism. For this, we prenatally exposed Wistar rats to LPS (100 mu g/kg, intraperitoneally, on gestational day 9.5), which mimics infection by gram-negative bacteria. Furthermore, because the exact mechanisms by which autism develops are still unknown, we investigated the neurological mechanisms that might underlie the behavioral alterations that were observed. Because we previously had demonstrated that prenatal LPS decreases striatal dopamine (DA) and metabolite levels, the striatal dopaminergic system (tyrosine hydroxylase [TH] and DA receptors D1a and D2) and glial cells (astrocytes and microglia) were analyzed by using immunohistochemistry, immunoblotting, and real-time PCR. Our results show that prenatal LPS exposure impaired communication (ultrasonic vocalizations) in male pups and learning and memory (T-maze spontaneous alternation) in male adults, as well as inducing repetitive/restricted behavior, but did not change social interactions in either infancy (play behavior) or adulthood in females. Moreover, although the expression of DA receptors was unchanged, the experimental animals exhibited reduced striatal TH levels, indicating that reduced DA synthesis impaired the striatal dopaminergic system. The expression of glial cell markers was not increased, which suggests that prenatal LPS did not induce permanent neuroinflammation in the striatum. Together with our previous finding of social impairments in males, the present findings demonstrate that prenatal LPS induced autism-like effects and also a hypoactivation of the dopaminergic system. (c) 2012 Wiley Periodicals, Inc.

The Effects of Altered Prenatal Melatonin Signaling on Adult Behavior and Hippocampal Gene Expression of the Male Rat: A Circadioneuroendocrine-Axis Hypothesis of Psychopathology

Disturbances in melatonin - the neurohormone that signals environmental darkness as part of the circadian circuit of mammals - have been implicated in various psychopathologies in humans. At present, experimental evidence linking prenatal melatonin signaling to adult physiology, behavior, and gene expression is lacking. We hypothesized that administration of melatonin (5 mg/kg) or the melatonin receptor antagonist luzindole (5 mg/kg) to rats in utero would permanently alter the circadian circuit to produce differential growth, adult behavior, and hippocampal gene expressionin the male rat. Prenatal treatment was found to increase growth in melatonin-treated animals. In addition, subjects exposed to melatonin prenatally displayed increased rearing in the open field test and an increased right turn preference in the elevated plusmaze. Rats administered luzindole prenatally, however, displayed greater freezing and grooming behavior in the open field test and improved learning in the Morris water maze. Analysis of relative adult hippocampal gene expression with RT-PCR revealed increasedexpression of brain-derived neurotrophic factor (BDNF) with a trend toward increased expression of melatonin 1A (MEL1A) receptors in melatonin-exposed animals whereas overall prenatal treatment had a significant effect on microtubule-associated protein 2(MAP2) expression. Our data support the conclusion that the manipulation of maternal melatonin levels alters brain development and leads to physiological and behavioral abnormalities in adult offspring. We designate the term circadioneuroendocrine (CNE)axis and propose the CNE-axis hypothesis of psychopathology.

Alteration in 5HT1A Receptor Activity from a Prenatal Exposure to Dexamethasone in a Stressed and Non-Stressed Adult Male Rat

Synthetic glucocorticoids (GC) are used as a clinical therapeutic to stimulate lung development in fetuses that present the risk of preterm delivery. Previous studies have shown that a prenatal exposure to Dexamethasone (DEX) causes a disturbance in normal GC mediation of neuritic outgrowth, cell signaling, and serotonergic systems. Our hypothesis is that a prenatal exposure to DEX during the third trimester of pregnancy alters 5HT1A receptor function. Pregnant dams were injected daily with 150μg/ml/kg of DEX from gestation day 14 through 19. Control dams were treated with and equal volume of saline. Swim stress followed by elevated plus maze testing was conducted on male rats an hour and a half prior to being sacrificed to induce postnatal acute stress. The non-stressed group was also tested and allowed to return to baseline before sacrifice. Hippocampi were analyzed using a radioligand-receptor binding assay and GTPγS35 incorporation (3H-MPPF antagonist and 8-OH-DPAT agonist, respectively). A significant increase in Kd was found in non-stressed DEX-exposed animals compared to non-stressed controls (p

The Effects of Prenatal Exposure to Altered Melatonin Levels on Hippocampal Gene Expression in the Male Rat

The stability of the circadian rhythm for mammals depends on the levels of serotonin and melatonin, neurohormones that signal for lightness and darkness, respectively. Disruption in the stability of neurohormones has been shown to be a critical factor in psychopathological disorders in humans. For example, altering levels of melatonin in utero through administration of melatonin or the melatonin receptor antagonist, luzindole, has been shown to cause changes in developmental growth and adult behavior in the male rat. Analysis of relative adult hippocampal gene expression with RT-PCR revealed differences in ARNTL expression that suggested abnormality in clock gene expression of the rats that were prenatally exposed to altered levels of melatonin. Differences in the degree of plasticity as suggested by previous behavior testing did not result in differences in gene expression for GABA receptors or NMDA receptors. Morevoer, growth associated protein 43, GAP-43, a protein that is necessary for neuronal growth cones as well as long term learning has been found to be critical for axon and presynaptic terminal formation and retention in other studies, but hippocampal gene expression in our study showed no significant alteration after exposure to various maternal melatonin levels. However, ARNTL is a key regulatory component of clock genes and the circadian cycle so that alterations in the expression of thi critical gene may lead to critical changes in neuronal growth and plasticity. Our data support the conclusion that the manipulation of maternal melatonin levels alters the brain development and the circadian cycles that may lead to physiological and behavioral abnormalities in adult offspring.

Spatial Learning and Stress Response of Male Rats Prenatally Exposed to Dexamethasone

Dexamethasone is routinely administered to women at risk for a preterm birth in order to enhance fetal lung development and reduce uterine contractions. Research has demonstrated possible behavioral abnormalities in adulthood as a result of dexamethasone treatment. Using nonlinear mixed effects modeling, this study found thatprenatal dexamethasone treatment impaired spatial learning and memory of adult male Sprague-Dawley rats. Prenatal dexamethasone treatment also led to more anxiety related behaviors on Elevated Plus Maze testing 1.5 hours after a stress challenge. Because theassumptions underlying the independent samples t-test were violated, the randomization test was used to compare groups on the Elevated Plus Maze.

A descriptive study of the sociodemographic, health and developmental factors associated with slow learning in children from upper to middle social class families in Texas

"Slow Learners" is a term used to describe children with an IQ range of 70-89 on a standardized individual intelligence test (i.e. with a standard deviation of either 15 or 16). They have above retarded, but below average intelligence and potential to learn. If the factors associated with the etiology of slow learning in children can be identified, it may be possible to hypothesize causal relationships which can be tested by intervention studies specifically designed to prevent slow learning. If effective, these may ultimately reduce the incidence of school dropouts and their cost to society. To date, there is little information about variables which may be etiologically significant. In an attempt to identify such etiologic factors this study examines the sociodemographic characteristics, prenatal history (hypertension, smoking, infections, medication, vaginal bleeding, etc.), natal history (length of delivery, Apgar score, birth trauma, resuscitation, etc.), neonatal history (infections, seizures, head trauma, etc.), developmental history (health problems, developmental milestones and growth during infancy and early childhood), and family history (educational level of the parents, occupation, history of similar condition in the family, etc.) of a series of children defined as slow learners. The study is limited to children from middle to high socioeconomic families in order to exclude the possible confounding variable of low socioeconomic status, and because a descriptive study of this group has not been previously reported. ^

Let their voices be heard: Understanding the barriers to seeking early prenatal care for low-income non-Hispanic Black women

Background: Receipt of early prenatal care, care during the first three months of pregnancy, is the standard in the United States. Sixty percent of non-Hispanic Black women who had a live birth in the Sunnyside community of Houston did not obtain early prenatal care in 2009. ^ This study's aims were to: 1) Describe the barriers to obtaining early prenatal care in non-Hispanic Black women who live in the Sunnyside community of Houston; and, 2) Describe the actions that could encourage non-Hispanic Black women who live in the Sunnyside Community to obtain early prenatal care. The goal was to provide information to organizations that promote early prenatal care use in non-Hispanic Black women in Harris County that may aid in developing interventions. ^ Methods: The Participatory Learning for Action rapid assessment qualitative method was used in a group setting to answer the research questions on behalf of women in the community. Women who participated in the group sessions also participated in an in-depth interview. Key informants who work in the community with pregnant women, or promote the use of prenatal care services, were also interviewed. An inductive analysis of the data was conducted to identify common themes that address the study's aims. ^ Results: Aim 1: Group participants identified fear of the reaction from family and/or the baby's daddy and shame, not having insurance or money, and lack of knowledge of the pregnancy and resources as the top three barriers to early prenatal care for women in the community. Aim 2: Group participants stated that to help women to overcome these barriers, communication, awareness and support; help, resources and services; and information and early education are needed. Participant in-depth interviewees echoed the themes of fear of the reaction from family and/or the baby's daddy and not knowing of the pregnancy. Key informants mentioned these themes as well, though not at the same priority level. Participants and key informants also mentioned similar themes for helping women to overcome barriers to early prenatal care. ^ Conclusion: A comprehensive approach is needed to improve early prenatal care use in the Sunnyside community. Education efforts must include all members of the community, young and old, to promote support for pregnant women. Community members must be a part of the process for developing education campaigns. Engaging the community builds a relationship with organizations that serve the community, which may promote use of the organizations' services, and build trust with the community. All efforts must be ongoing so that women and men of all ages in the community understand the importance of prenatal care and support women obtaining care early in the pregnancy.^

The Effect of Prenatal Auditory Enrichment on Perceptual Narrowing in Bobwhite Quail Neonates

The development of species-typical perceptual preferences has been shown to depend on a variety of socially and ecologically derived sensory stimulation during both the pre- and postnatal periods. The prominent mechanism behind the development of these seemingly innate tendencies in young organisms has been hypothesized to be a domain-general pan-sensory selectivity process referred to as perceptual narrowing, whereby regularly experienced sensory stimuli are honed in upon, while simultaneously losing the ability to effectively discriminate between atypical or unfamiliar sensory stimulation. Previous work with precocial birds has been successful in preventing the development of species-typical perceptual preferences by denying the organism typical levels of social and/or self-produced stimulation. The current series of experiments explored the mechanism of perceptual narrowing to assess the malleability of a species-typical auditory preference in avian embryos. By providing a variety of different unimodal and bimodal presentations of a mixed-species vocalizations at the onset of prenatal auditory function, the following project aimed to 1) keep the perceptual window from narrowing, thereby interfering with the development of a species-typical auditory preference, 2) investigate how long differential prenatal stimulation can keep the perceptual window open postnatally, 3) explore how prenatal auditory enrichment effected preferences for novelty, and 4) assess whether prenatal auditory perceptual narrowing is affected by modality specific or amodal stimulus properties during early development. Results indicated that prenatal auditory enrichment significantly interferes with the emergence of a species-typical auditory preference and increases openness to novelty, at least temporarily. After accruing postnatal experience in an environment rich with species-typical auditory and multisensory cues, the effect of prenatal auditory enrichment rapidly was found to rapidly fade. Prenatal auditory enrichment with extraneous non-synchronous light exposure was shown to both keep the perceptual narrowing window open and impede learning in the postnatal environment, following hatching. Results are discussed in light of the role experience plays in perceptual narrowing during the perinatal period.