Maternal Brain Research Articles

Valproic acid induces nuclear factor erythroid 2-related factor 2 expression in fetal and neonatal brains but not in adult brain: evidence of the gamma-aminobutyric acid-shift hypothesis.

The gamma-aminobutyric acid (GABA)-shift hypothesis proposes that GABA agonist action is excitatory early in development and transitions to an inhibitory role later in life. In experiment 1, the nonspecific GABA agonist, valproic acid (VPA), was administered to pregnant C57BL/6 mice on embryonic day 13. Fetal and maternal brains were harvested 2 h post-VPA exposure and assayed for nuclear factor erythroid 2-related factor 2 (NRF2) and H3 expression through western blot analysis. In experiment 2, VPA was administered to neonatal pups on P14 and adult mice on P60. In both experiments, it was observed that NRF2 expression was increased in fetal and neonatal brains, but not in the adult brain. Because NRF2 expression is activated by oxidative stress, these results imply support of the GABA-shift hypothesis in that VPA may exert its developmental damage in the fetal and neonatal periods through excitotoxicity.

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome \u2013 a pilot study

During pregnancy, substantial alterations in cerebral plasticity, vascular remodeling and neuronal growth occur in the maternal brain. We investigated whether concentrations of selected neurodiagnostic biomarkers in the cerebrospinal fluid of women with preeclampsia/HELLP syndrome differ from those in healthy controls using enzyme-linked immunosorbent assay technique. We found that tau protein concentrations (p = 0.016) and phospho-tau/tau ratio (p < 0.001) in cerebrospinal fluid were significantly lower in 39 preeclamptic women compared to 44 healthy controls during third trimester of pregnancy. Beta-amyloid(1-40)/(1-42) ratio was significantly higher in HELLP syndrome than in severe preeclampsia (8.49 + 2.73 vs. 4.71 + 1.65; p = 0.007). We conclude that beta-amyloid(1-40)/(1-42) ratio in cerebrospinal fluid can discriminate severe preeclampsia and HELLP syndrome. High beta-amyloid peptide and low tau protein concentrations are associated with impaired development of the materno-feto-placental unit and correlate with placental dysfunction.

Adaptive Resetting of Tuberoinfundibular Dopamine (TIDA) Network Activity during Lactation in Mice.

Giving birth triggers a wide repertoire of physiological and behavioral changes in the mother to enable her to feed and care for her offspring. These changes require coordination and are often orchestrated from the CNS, through as of yet poorly understood mechanisms. A neuronal population with a central role in puerperal changes is the tuberoinfundibular dopamine (TIDA) neurons that control release of the pituitary hormone, prolactin, which triggers key maternal adaptations, including lactation and maternal care. Here, we used Ca2+ imaging on mice from both sexes and whole-cell recordings on female mouse TIDA neurons in vitro to examine whether they adapt their cellular and network activity according to reproductive state. In the high-prolactin state of lactation, TIDA neurons shift to faster membrane potential oscillations, a reconfiguration that reverses upon weaning. During the estrous cycle, however, which includes a brief, but pronounced, prolactin peak, oscillation frequency remains stable. An increase in the hyperpolarization-activated mixed cation current, Ih, possibly through unmasking as dopamine release drops during nursing, may partially explain the reconfiguration of TIDA rhythms. These findings identify a reversible plasticity in hypothalamic network activity that can serve to adapt the dam for motherhood.SIGNIFICANCE STATEMENT Motherhood requires profound behavioral and physiological adaptations to enable caring for offspring, but the underlying CNS changes are poorly understood. Here, we show that, during lactation, neuroendocrine dopamine neurons, the "TIDA" cells that control prolactin secretion, reorganize their trademark oscillations to discharge in faster frequencies. Unlike previous studies, which typically have focused on structural and transcriptional changes during pregnancy and lactation, we demonstrate a functional switch in activity and one that, distinct from previously described puerperal modifications, reverses fully on weaning. We further provide evidence that a specific conductance (Ih) contributes to the altered network rhythm. These findings identify a new facet of maternal brain plasticity at the level of membrane properties and consequent ensemble activity.

Regulation of uterine genes during the peri-implantation period, and its relationship to the maternal brain in gestating mice.

We conducted an integrated analysis of gene expression and chromatin structure of mouse uterus to understand the regulation of uterine-expressed genes on gestation day 4 (GD4) during the peri-implantation period. The genes expressed in the uterus showed a significant association (p < .0001) with the presence of the nucleosome-free region (open chromatin) in the 5'-untranslated region of the genes. The majority of these upstream open chromatins harbored a common class of regulatory elements known as upstream open reading frames. We also compared the gene expression profiles between the uterus and brain which showed that specific gene pairs were expressed in a correlated manner, either positively or negatively. In addition, specific ligand/receptor genes showed coordinated patterns of expression between the uterus and brain on GD4, and the level of expression of these ligand/receptors altered significantly in the brain during late pregnancy (GD15) compared with the peri-implantation period (GD4). Collectively, these results suggest that regulation of the uterine genes during the peri-implantation period is likely to have a functional link with the maternal brain in pregnant mice.

Characterizing the Effects of Diabetes and Obesity on Insulin and Leptin Levels amongst Pregnant Women.

In this study, we assess the impact of obesity and diabetes on maternal brain and periphery, as well as fetal exposure to insulin and leptin, and two hormones that play an important role in regulating energy homeostasis. Fasting maternal plasma, fetal cord vein and artery plasma, and maternal cerebrospinal fluid (CSF) were collected in 37 women (12 lean, nondiabetic [prepregnancy body mass index (BMI): 22.9 ± 1.7 kg/m2]; 12 overweight/obese nondiabetic [BMI: 37.8 ± 7.3 kg/m2]; 13 gestational/type 2 diabetes mellitus [BMI: 29.8 ± 7.3 kg/m2]) with uncomplicated singleton pregnancies undergoing elective Cesarean delivery. HbA1C, insulin, glucose, and leptin levels were measured. Compared with lean mothers, mothers with obesity and diabetes mellitus (DM) had significantly lower CSF-to-plasma ratios of insulin. Moreover, mothers with obesity and DM had significantly lower cord arterial and cord venous to maternal plasma ratios of insulin, but not leptin, compared with lean mothers. There were no differences in CSF and cord blood insulin and leptin levels between obese and DM mothers. Compared with lean individuals, mothers with obesity and DM have relative deficiencies in insulin exposure. The patterns observed in mothers with obesity and diabetes were similar highlighting the importance of the maternal metabolic environment in obesity and suggesting obese patients warrant further clinical focus.

Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus

(Anesth Analg. 2019;128(6):1190–1198) Maternal fever during labor is a complication that poses many risks for the infant being delivered, and is frequently associated with epidural analgesia. Elevated levels of a proinflammatory cytokine called interleukin-6 (IL-6) are found in the maternal serum and umbilical cord blood of patients with fevers who received an epidural. These investigators have demonstrated through previous studies that higher IL-6 levels can cause temperature increases in rats, and are also connected with microglial activation and subventricular inflammation. In addition, the authors have conducted prior research that connected a higher IL-6 measurement to maternal systemic and fetal brain inflammation. This current study aimed to examine the effect of maternally administered IL-6 on neonatal brain development.

Lactation ameliorates neurobehavioral outcomes in the ischemic rat dams

Aims Cardiac arrest and stroke as a life-threatening event that may occur in throughout the female life, especially during pregnancy or after delivery. Previous studies demonstrated that cerebral ischemia during pregnancy or the puerperium is a rare occurrence but is associated with significant mortality and high morbidity. This study was designed to assess the effects of pregnancy and lactation on behavioral deficits, neural density, and angiogenesis in rat dams undergoing global ischemia. Materials and methods Thirty-two female Wistar rats were divided into four groups: virgin-Sham (Vir-Sham) group, virgin-ischemic (Vir-Isc) group, pregnancy-lactation-sham (P-L-Sham) group, and pregnancy-lactation-ischemic (P-L-Isc) group. Global brain ischemia was induced in ischemic groups by using the 2-vessel occlusion (2-VO) model at the end of lactation phase. Seven days after 2-VO, anxiety-like signals and passive avoidance memory tests were assessed in animals. Key findings We found that the lactation significantly improved memory and reduced anxiety-like signals in P-L-Isc group as compared with Vir-Isc group. Moreover, angiogenesis and neural density significantly increased in the P-L-Isc group as compared with the Vir-Isc group. Significance This finding for the first time indicated that lactation protects the maternal brain against ischemic insult partly through promoting angiogenesis and neurogenesis.

Baby cry recognition is independent of motherhood but improved by experience and exposure.

Neurobiological changes affecting new mothers are known to support the development of the mother-infant relationship (the 'maternal brain'). However, which aspects of parenting are actually mother-specific and which rely on general cognitive abilities remains debated. For example, refuting earlier findings, a recent study demonstrated that fathers identify their own baby from their cries just as well as mothers. Here we show that this performance is independent not only of sex, but also of parenthood status. We found that mothers' ability to recognize their newborn from their cries increased rapidly within few days postpartum, with highly multiparous mothers performing better. However, both male and female non-parents could similarly recognize an assigned baby, even after a very short exposure. As in mothers, both the initial amount of experimental exposure to the baby's cries (learning opportunity) and prior experience of caring for infants (auditory expertise) affected participants' performance. We thus suggest that, rather than being female-specific or motherhood-dependent, the ability to recognize a baby from their cries derives from general auditory and learning skills. By being available to non-parents of both sexes, it may contribute to the caregiving flexibility required for efficient cooperative breeding in humans.

Canadian Arctic Contaminants and Their Effects on the Maternal Brain and Behaviour: A Scoping Review of the Animal Literature.

Background: Environmental toxicants such as methylmercury, polychlorinated biphenyls, and organochlorine pesticides are potentially harmful pollutants present in contaminated food, soil, air, and water. Exposure to these ecologically relevant toxicants is prominent in Northern Canadian populations. Previous work focused on toxicant exposure during pregnancy as a threat to fetal neurodevelopment. However, little is known about the individual and combined effects of these toxicants on maternal health during pregnancy and post-partum. Methods: A scoping review was conducted to synthesize the current knowledge regarding individual and combined effects of methylmercury, polychlorinated biphenyls, and organochlorine pesticides on maternal behaviour and the maternal brain. Relevant studies were identified through the PubMed, Embase, and Toxline databases. Literature involving animal models and one human cohort were included in the review. Results: Research findings indicate that exposures to these environmental toxicants are associated with neurochemical changes in rodent models. Animal models provided the majority of information on toxicant-induced alterations in maternal care behaviours. Molecular and hormonal changes hypothesized to underlie these alterations were also addressed, although studies assessing toxicant co-exposure were limited. Conclusion: This review speaks to the limited knowledge regarding effects of these persistent organic pollutants on the maternal brain and related behavioural outcomes. Further research is required to better comprehend any such effects on maternal brain and behaviour, as maternal care is an important contributor to offspring neurodevelopment.

Association of Prenatal Maternal Psychological Distress With Fetal Brain Growth, Metabolism, and Cortical Maturation

Prenatal maternal stress is increasingly associated with adverse outcomes in pregnant women and their offspring. However, the association between maternal stress and human fetal brain growth and metabolism is unknown. To identify the association between prenatal maternal psychological distress and fetal brain growth, cortical maturation, and biochemical development using advanced 3-dimensional volumetric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS). This cohort study prospectively recruited pregnant women from low-risk obstetric clinics in Washington, DC, from January 1, 2016, to April 17, 2019. Participants were healthy volunteers with a normal prenatal medical history, no chronic or pregnancy-induced physical or mental illnesses, and normal results on fetal ultrasonography and biometry studies. Fetal brain MRI studies were performed at 2 time points between 24 and 40 weeks' gestation. Prenatal maternal stress, anxiety, and depression. Volumes of fetal total brain, cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampus were measured from 3-dimensional reconstructed T2-weighted MRI scans. Cortical folding measurements included local gyrification index, sulcal depth, and curvedness. Fetal brain N-acetylaspartate, creatine, and choline levels were quantified using 1H-MRS. Maternal stress, depression, and anxiety were measured with the Perceived Stress Scale (PSS), Edinburgh Postnatal Depression Scale (EPDS), Spielberger State Anxiety Inventory (SSAI), and Spielberger Trait Anxiety Inventory (STAI). A total of 193 MRI studies were performed in 119 pregnant women (67 [56%] carrying male fetuses and 52 [44%], female fetuses; maternal mean [SD] age, 34.46 [5.95] years) between 24 and 40 gestational weeks. All women were high school graduates, 99 (83%) were college graduates, and 100 (84%) reported professional employment. Thirty-two women (27%) had positive scores for stress, 31 (26%) for anxiety, and 13 (11%) for depression. Maternal trait anxiety was associated with smaller fetal left hippocampal volume (STAI score: -0.002 cm3; 95% CI, -0.003 to -0.0008 cm3; P = .004). Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.006; P = .002]; β for STAI score: 0.004 [95% CI, 0.002-0.006; P < .001]; β for PSS score: 0.005 [95% CI, 0.001-0.008; P = .005]) and temporal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.007; P = .004]; β for STAI score: 0.004 [95% CI, 0.0008-0.006; P = .01]). Elevated maternal depression was associated with decreased creatine (EPDS score: -0.04; 95% CI, -0.06 to -0.02; P = .005) and choline (EPDS score: -0.03; 95% CI, -0.05 to -0.01; P = .02) levels in the fetal brain. This study found that the prevalence of maternal psychological distress in healthy, well-educated, and employed pregnant women was high, underappreciated, and associated with impaired fetal brain biochemistry and hippocampal growth as well as accelerated cortical folding. These findings appear to support the need for routine mental health surveillance for all pregnant women and targeted interventions in women with elevated psychological distress.

From baby brain to mommy brain: Widespread gray matter gain after giving birth

Pregnancy results in obvious physiological changes to the female body, but data as to what happens to the maternal brain after giving birth are sparse as well as inconsistent. The overall goal of this study is to determine the nature of cerebral change in the postpartum period. For this purpose, we analyzed T1-weighted brain images of 14 healthy women (age range: 25–38 years) at two time points, specifically within 1–2 days of childbirth (immediate postpartum) and at 4–6 weeks after childbirth (late postpartum). When comparing voxel-wise gray matter between these two time points, there was no evidence of any significant decrease. Instead, we detected a pronounced gray matter increase involving both cortical and subcortical regions, such as the pre- and postcentral gyrus, the frontal and central operculum, the inferior frontal gyrus, the precuneus, and the middle occipital gyrus, as well as the thalamus and caudate. These structural changes occurring within only 4–6 weeks after delivery are reflective of a high degree of neuroplasticity and massive adaptations in the maternal brain. They may suggest a restoration of brain tissue following pregnancy and/or a substantial brain reorganization, possibly to accommodate a multi-faceted repertoire of complex behaviors associated with being a mother.

Placental effects on the maternal brain revealed by disrupted placental gene expression in mouse hybrids.

The mammalian placenta is both the physical interface between mother and fetus, and the source of endocrine signals that target the maternal hypothalamus, priming females for parturition, lactation and motherhood. Despite the importance of this connection, the effects of altered placental signalling on the maternal brain are insufficiently studied. Here, we show that placental dysfunction alters gene expression in the maternal brain, with the potential to affect maternal behaviour. Using a cross between the house mouse and the Algerian mouse, in which hybrid placental development is abnormal, we sequenced late-gestation placental and maternal medial preoptic area transcriptomes and quantified differential expression and placenta-maternal brain co-expression between normal and hybrid pregnancies. The expression of Fmn1 and Drd3 was significantly altered in the brains of females exposed to hybrid placentas. Most strikingly, expression patterns of placenta-specific gene families and Drd3 in the brains of house mouse females carrying hybrid litters matched those of female Algerian mice, the paternal species in the cross. Our results indicate that the paternally derived placental genome can influence the expression of maternal-fetal communication genes, including placental hormones, suggesting an effect of the offspring's father on the mother's brain.

Relating anthropometric indicators to brain structure in 2-month-old Bangladeshi infants growing up in poverty: A pilot study

Anthropometric indicators, including stunting, underweight, and wasting, have previously been associated with poor neurocognitive outcomes. This link may exist because malnutrition and infection, which are known to affect height and weight, also impact brain structure according to animal models. However, a relationship between anthropometric indicators and brain structural measures has not been tested yet, perhaps because stunting, underweight, and wasting are uncommon in higher-resource settings. Further, with diminished anthropometric growth prevalent in low-resource settings, where biological and psychosocial hazards are most severe, one might expect additional links between measures of poverty, anthropometry, and brain structure. To begin to examine these relationships, we conducted an MRI study in 2-3-month-old infants growing up in the extremely impoverished urban setting of Dhaka, Bangladesh. The sample size was relatively small because the challenges of investigating infant brain structure in a low-resource setting needed to be realized and resolved before introducing a larger cohort. Initially, fifty-four infants underwent T1 sequences using 3T MRI, and resulting structural images were segmented into gray and white matter maps, which were carefully evaluated for accurate tissue labeling by a pediatric neuroradiologist. Gray and white matter volumes from 29 infants (79 ​± ​10 days-of-age; F/M ​= ​12/17), whose segmentations were of relatively high quality, were submitted to semi-partial correlation analyses with stunting, underweight, and wasting, which were measured using height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) scores. Positive semi-partial correlations (after adjusting for chronological age and sex and correcting for multiple comparisons) were observed between white matter volume and HAZ and WAZ; however, WHZ was not correlated with any measure of brain volume. No associations were observed between income-to-needs or maternal education and brain volumetric measures, suggesting that measures of poverty were not associated with total brain tissue volume in this sample. Overall, these results provide the first link between diminished anthropometric growth and white matter volume in infancy. Challenges of conducting a developmental neuroimaging study in a low-resource country are also described.

Chapter 2 - Neurophysiological and cognitive changes in pregnancy

The hormonal fluctuations in pregnancy drive a wide range of adaptive changes in the maternal brain. These range from specific neurophysiological changes in the patterns of activity of individual neuronal populations, through to complete modification of circuit characteristics leading to fundamental changes in behavior. From a neurologic perspective, the key hormone changes are those of the sex steroids, estradiol and progesterone, secreted first from the ovary and then from the placenta, the adrenal glucocorticoid cortisol, as well as the anterior pituitary peptide hormone prolactin and its pregnancy-specific homolog placental lactogen. All of these hormones are markedly elevated during pregnancy and cross the blood-brain barrier to exert actions on neuronal populations through receptors expressed in specific regions. Many of the hormone-induced changes are in autonomic or homeostatic systems. For example, patterns of oxytocin and prolactin secretion are dramatically altered to support novel physiological functions. Appetite is increased and feedback responses to metabolic hormones such as leptin and insulin are suppressed to promote a positive energy balance. Fundamental physiological systems such as glucose homeostasis and thermoregulation are modified to optimize conditions for fetal development. In addition to these largely autonomic changes, there are also changes in mood, behavior, and higher processes such as cognition. This chapter summarizes the hormonal changes associated with pregnancy and reviews how these changes impact on brain function, drawing on examples from animal research, as well as available information about human pregnancy.

Chapter 4 - Physiology of the cerebrovascular adaptation to pregnancy

The adaptation of the cerebral circulation to pregnancy is unique compared with other organs and circulatory systems, because the brain requires relatively constant blood flow and water and solute composition to maintain homeostasis. Thus, a major adaptation of the maternal cerebrovasculature to pregnancy is to maintain normalcy in the face of expanded plasma volume, increased cardiac output, and high levels of permeability factors. In this chapter, the effect of pregnancy on critical functions of the cerebral circulation is discussed, including changes occurring at the endothelium and blood-brain barrier (BBB), which protect the maternal brain from changes in BBB permeability. Further, pregnancy-induced changes in the structure and function of cerebral arteries, arterioles, and veins will be discussed as they relate to cerebral vascular resistance, hemodynamics, and cerebral blood flow autoregulation.

805: Fetal brain cholinergic regulation following maternal inflammation and magnesium neuroprotection

To determine pregnancy ontogeny of AChE and its regulator miR-132 expression in maternal serum and fetal brain under basal and inflammatory conditions and to study the effect of Magnesium (Mg), a known neuroprotective agent, on AChE and miR-132 expression in the fetal brain. Pregnant rats at 16, 18 and 20 days of gestation (60 total: 8 groups, n=5) received injections of i.p. lipopolysaccharide (LPS; 500 ug/kg) or saline (SAL) at time 0. Dams were randomized to s.c. saline or Mg (270 mg/kg loading followed by 27 mg/kg q20 min) for 2 hours prior to and 2 hours following LPS /saline injections. Rats were sacrificed 4 hours following LPS/SAL injection. Fetal brains were harvested from the treatment groups (LPS/SAL, LPS/Mg, SAL/Mg, SAL/SAL) for AChE and miR-132 mRNA expression (real-time RT-PCR) and maternal serum analyzed for AChE levels. Maternal serum AChE increased from e16 to e18 and e20 (169+25, 232+51,263+59 mg/ml, p< 0.05, respectively). Fetal brain AChE and miR-132 mRNA expression increased (p< 0.05) from e16 to e18 and then decreased at e20 (p< 0.05) (AChE 1.0±0.01, 1.21±.0.02, 0.78±0.16; miR-132 1.0±0.01, 1.19±0.03, 0.86±0.1, respectively). At e16 maternal LPS decreased fetal brain AChE (0.62±0.1), and miR-132 mRNA expression (0.72±0.11) compared to control (p< 0.05). Maternal Mg alone increased both fetal brain AChE and miR-132 mRNA expression at e16 (AChE1.7±0.15; miR-132 1.7±0.16) compared to both control and LPS fetal brains (p< 0.05). Mg treatment to LPS dams (LPS/Mg) increased fetal brain AChE and miR-132 levels (1.15±0.04;1.25±0.1 respectively, p< 0.05) compared to both LPS/SAL and SAL/SAL groups. The same pattern was demonstrated at e18 and e20. No significant change was demonstrated in maternal serum AChE levels following LPS or Mg compared to control. These findings suggest that fetal brain AChE activity is not regulated by miR-132. Mg treatment increases fetal brain AChE mRNA levels under basal conditions and in response to maternal LPS, suggesting that reduced ACh may increase fetal brain inflammatory responses.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Neglectful maternal caregiving involves altered brain volume in empathy-related areas.

The maternal brain undergoes adaptations to sensitive caregiving that are critical for infant well-being. We investigated structural alterations associated with neglectful caregiving and their effects on mother-child interactive behavior. High-resolution 3D volumetric images were obtained on 25 neglectful (NM) and 23 non-neglectful control (CM) mothers. Using voxel-based morphometry, we compared differences in gray and white matter (GM and WM, respectively) volume. Mothers completed an empathy scale and participated with their children in a play task (Emotional Availability Scale, EA). Neglectful mothers showed smaller GM volume in the right insula, anterior/middle cingulate (ACC/MCC), and right inferior frontal gyrus and less WM volume in bilateral frontal regions than did CM. A greater GM volume was observed in the right fusiform and cerebellum in NM than in CM. Regression analyses showed a negative effect of greater fusiform GM volume and a positive effect of greater right frontal WM volume on EA. Mediation analyses showed the role of emotional empathy in the positive effect of the insula and right inferior frontal gyrus and in the negative effect of the cerebellum on EA. Neglectful mothering involves alterations in emotional empathy-related areas and in frontal areas associated with poor mother-child interactive bonding, indicating how critical these areas are for sensitive caregiving.

Acute sleep deprivation during pregnancy in rats: Rapid elevation of placental and fetal inflammation and kynurenic acid

The kynurenine pathway (KP) is the dominant pathway for tryptophan degradation in the mammalian body and emerging evidence suggests that acute episodes of sleep deprivation (SD) disrupt tryptophan metabolism via the KP. Increases in the neuroactive KP metabolite kynurenic acid (KYNA) during pregnancy may lead to a higher risk for disrupted neurodevelopment in the offspring. As pregnancy is a critical period during which several factors, including sleep disruptions, could disrupt the fetal environment, we presently explored the relationship between maternal SD and KP metabolism and immune pathways in maternal, placenta, and fetal tissues. Pregnant Wistar rat dams were sleep deprived by gentle handling for 5 h from zeitgeber time (ZT) 0 to ZT 5. Experimental cohorts included: i) controls, ii) one session of SD on embryonic day (ED) 18 or iii) three sessions of SD occurring daily on ED 16, ED 17 and ED 18. Maternal (plasma, brain), placental and fetal (plasma, brain) tissues were collected immediately after the last session of SD or after 24 h of recovery from SD. Respective controls were euthanized at ZT 5 on ED 18 or ED 19. Maternal plasma corticosterone and fetal brain KYNA were significantly elevated only after one session of SD on ED 18. Importantly, maternal plasma corticosterone levels correlated significantly with fetal brain KYNA levels. In addition, placental levels of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) were increased following maternal SD, suggesting a relationship between placental immune response to SD and fetal brain KYNA accumulation. Collectively, our results demonstrate that sleep loss during the last week of gestation can adversely impact maternal stress, placental immune function, and fetal brain KYNA levels. We introduce KYNA as a novel molecular target influenced by sleep loss during pregnancy.

Distribution of Phosphatidylethanol in Maternal and Fetal Compartments After Chronic Gestational Binge Alcohol Exposure.

Phosphatidylethanol (PEth) is a promising biomarker for gestational alcohol exposure. Studies show PEth accumulation in maternal and fetal blood following alcohol exposure; however, distribution of specific PEth homologues (16:0/18:1, 16:0/18:2, 16:0/20:4) in maternal and fetal blood is unknown. Additionally, PEth levels in highly vulnerable FASD targets in maternal and fetal compartments remain unexplored. We hypothesized that all 3 major PEth homologues will be detectable in the maternal and fetal blood, the maternal uterine artery (a reproductive tissue that delivers oxygen and nutrients to fetoplacental unit), and fetal brain regions following gestational binge alcohol exposure and that homologue distribution profiles will be tissue-specific. Pregnant rats received once-daily orogastric gavage of alcohol (Alcohol; BAC 216mg/dl@4.5g/kg/d; BAC 289mg/dl@6g/kg/d) or iso-caloric maltose dextrin (Pair-fed control) from gestation days (GD) 5 to 20 or 21. Following chronic exposure, maternal and fetal tissues were analyzed for PEth homologue concentrations utilizing LC-MS/MS technology. All 3 PEth homologues were detected in alcohol-exposed maternal blood, fetal blood, maternal uterine artery, and fetal brain regions (hippocampus, cerebral cortex, and cerebellum). In both maternal and fetal blood, respectively, PEth 16:0/18:2 was more abundant compared to 16:0/18:1 (p<0.0001,~66%,↑; p=0.0159, 20.4%↑) and 16:0/20:4 (p=0.0072,~25%↑; p=0.0187, 19.4%↑). Maternal PEth 16:0/20:4 was~42% higher than 16:0/18:1 (p=0.0015). Maternal PEth 16:0/18:2 and 16:0/20:4 were~25%↑ and~20%↑ higher than in fetal blood (p<0.05). No homologue differences were detected in the maternal uterine artery. In all fetal brain regions, PEth 16:0/18:1 was significantly higher (p<0.0001) than 16:0/18:2 (~48 to 78%↑) and 16:0/20:4 (~31 to 62%↑) concentrations. PEth 16:0/20:4 was~18% higher than 16:0/18:1 (p<0.05) in the fetal hippocampus and cortex. All major PEth homologues were detected in maternal and fetal blood following chronic gestational binge alcohol exposure; homologue distribution profiles were tissue-specific. This study also provides insights into PEth accumulation in critical FASD targets, specifically the maternal uterine artery and fetal brain.

Maternal Dietary Intake of Omega-3 Fatty Acids Correlates Positively with Regional Brain Volumes in 1-Month-Old Term Infants.

Maternal nutrition is an important factor for infant neurodevelopment. However, prior magnetic resonance imaging (MRI) studies on maternal nutrients and infant brain have focused mostly on preterm infants or on few specific nutrients and few specific brain regions. We present a first study in term-born infants, comprehensively correlating 73 maternal nutrients with infant brain morphometry at the regional (61 regions) and voxel (over 300 000 voxel) levels. Both maternal nutrition intake diaries and infant MRI were collected at 1month of life (0.9 ± 0.5months) for 92 term-born infants (among them, 54 infants were purely breastfed and 19 were breastfed most of the time). Intake of nutrients was assessed via standardized food frequency questionnaire. No nutrient was significantly correlated with any of the volumes of the 61 autosegmented brain regions. However, increased volumes within subregions of the frontal cortex and corpus callosum at the voxel level were positively correlated with maternal intake of omega-3 fatty acids, retinol (vitamin A) and vitamin B12, both with and without correction for postmenstrual age and sex (P < 0.05, q < 0.05 after false discovery rate correction). Omega-3 fatty acids remained significantly correlated with infant brain volumes after subsetting to the 54 infants who were exclusively breastfed, but retinol and vitamin B12 did not. This provides an impetus for future larger studies to better characterize the effect size of dietary variation and correlation with neurodevelopmental outcomes, which can lead to improved nutritional guidance during pregnancy and lactation.