Omega-3 polygenic score protects against altered eating behavior in intrauterine growth-restricted children.

BACKGROUND: Alterations in eating behavior are common in infants with intrauterine growth restriction (IUGR); omega-3 polyunsaturated fatty acids (PUFA) could provide protection. We hypothesized that those born IUGR with a genetic background associated with increased production of omega-3-PUFA will have more adaptive eating behaviors during childhood. METHODS: IUGR/non-IUGR classified infants from MAVAN and GUSTO cohorts were included at the age of 4 and 5 years, respectively. Their parents reported child's eating behaviors using the child eating behavior questionnaire-CEBQ. Based on the GWAS on serum PUFA (Coltell 2020), three polygenic scores were calculated. RESULTS: Significant interactions between IUGR and polygenic score for omega-3-PUFA on emotional overeating (ß = -0.15, P = 0.049 GUSTO) and between IUGR and polygenic score for omega-6/omega-3-PUFA on desire to drink (ß = 0.35, P = 0.044 MAVAN), pro-intake/anti-intake ratio (ß = 0.10, P = 0.042 MAVAN), and emotional overeating (ß = 0.16, P = 0.043 GUSTO) were found. Only in IUGR, a higher polygenic score for omega-3-PUFA associated with lower emotional overeating, while a higher polygenic score for omega-6/omega-3-PUFA ratio was associated with a higher desire to drink, emotional overeating, and pro-intake/anti-intake. CONCLUSION: Only in IUGR, the genetic background for higher omega-3-PUFA is associated with protection against altered eating behavior, while the genetic score for a higher omega-6/omega-3-PUFA ratio is associated with altered eating behavior. IMPACT: A genetic background related to a higher polygenic score for omega-3 PUFA protected infants born IUGR against eating behavior alterations, while a higher polygenic score for omega-6/omega-3 PUFA ratio increased the risk of having eating behavior alterations only in infants born IUGR, irrespective of their adiposity in childhood. Genetic individual differences modify the effect of being born IUGR on eating outcomes, increasing the vulnerability/resilience to eating disorders in IUGR group and likely contributing to their risk for developing metabolic diseases later in life.

Safety, Tolerability, and Pharmacokinetics of ß-Cryptoxanthin Supplementation in Healthy Women: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: ß-cryptoxanthin is a dietary carotenoid for which there have been few studies on the safety and pharmacokinetics following daily oral supplementation. METHODS: 90 healthy Asian women between 21 and 35 years were randomized into three groups: 3 and 6 mg/day oral ß-cryptoxanthin, and placebo. At 2, 4, and 8 weeks of supplementation, plasma carotenoid levels were measured. The effects of ß-cryptoxanthin on blood retinoid-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition were investigated. RESULTS: ß-cryptoxanthin supplementation for 8 weeks (3 and 6 mg/day) was found to be safe and well tolerated. Plasma ß-cryptoxanthin concentration was significantly higher in the 6 mg/day group (9.0 ± 4.1 µmol/L) compared to 3 mg/day group (6.0 ± 2.6 µmol/L) (p < 0.03), and placebo (0.4 ± 0.1 µmol/L) (p < 0.001) after 8 weeks. Plasma all-trans retinol, α-cryptoxanthin, α-carotene, ß-carotene, lycopene, lutein, and zeaxanthin levels were not significantly changed. No effects were found on blood retinol-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition. CONCLUSIONS: Oral ß-cryptoxanthin supplementation over 8 weeks lead to high plasma concentrations of ß-cryptoxanthin, with no impact on other carotenoids, and was well tolerated in healthy women.

Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more.

The authors highlight, from a firsthand perspective, Bruce S. McEwen's seminal influence on the field of stress neurobiology and beyond, and how these investigations have yielded important insights, principles and critical questions that continue to guide stress research today. Featured are discussion of: 1) the important inverted-U relationship between stress/glucocorticoids and optimal physiological function, 2) stress adaptation and the role of adaptive stress responses, 3) mechanisms by which the short-term stress response promotes heightened immune function and immunity, and 4) the far reaching impact of the theoretical framework of allostasis and allostatic load-concepts that have created new bridges between stress physiology, biomedical sciences, health psychology and sociology.

Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse.

BACKGROUND: Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects. METHODS: Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA. RESULTS: A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor. CONCLUSIONS: Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life.

Long-chain polyunsaturated fatty acid status during pregnancy and maternal mental health in pregnancy and the postpartum period: results from the GUSTO study.

OBJECTIVE: Studies have demonstrated a relationship between lower omega-3 long-chain polyunsaturated fatty acid (LC-PUFA) status and anxiety and depression. It is uncertain whether similar associations occur in pregnant women, when anxiety and depression could have long-term effects on the offspring. We examined the associations between plasma LC-PUFA status during pregnancy and perinatal mental health. METHOD: At 26-28 weeks' gestation, plasma LC-PUFAs were measured in mothers of the Growing Up in Singapore Toward healthy Outcomes (GUSTO) mother-offspring cohort study, who were recruited between June 2009 and September 2010. Maternal symptoms of anxiety and depression were assessed with the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3 months' postpartum. The STAI-state subscale was used as a continuous measure of current anxiety, while EPDS scores ≥ 15 during pregnancy or ≥ 13 postpartum were indicative of symptoms of probable depression. RESULTS: In adjusted regression analyses (n = 698), lower plasma total omega-3 PUFA concentrations (ß = -6.49 STAI-state subscale scores/unit increase of omega-3 fatty acid; 95% CI, -11.90 to -1.08) and higher plasma omega-6:omega-3 PUFA ratios (ß = 6.58 scores/unit increase of fatty acid ratio; 95% CI, 1.19 to 12.66), specifically higher arachidonic acid (AA):docosahexaenoic acid, AA:eicosapentaenoic acid, and AA:docosapentaenoic acid ratios, were associated with increased antenatal anxiety (P < .05 for all), but not postpartum anxiety. There was no association between plasma PUFAs and perinatal probable depression. CONCLUSIONS: No association was found with probable depression in pregnancy or postpartum. Lower plasma omega-3 fatty acids and higher omega-6:omega-3 fatty acid ratios were associated with higher antenatal anxiety, but not postpartum anxiety. Replication in other studies is needed to confirm the findings and determine the direction of causality. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01174875.

Poor infant inhibitory control predicts food fussiness in childhood - A possible protective role of n-3 PUFAs for vulnerable children.

Intrauterine growth restriction (IUGR) children are more impulsive towards a sweet reward and have altered feeding behavior in adulthood. We hypothesized that early life inhibitory control predicts feeding behaviors later on in childhood, and the consumption of n-3 PUFAs during infancy may protect IUGR children from developing problematic feeding behaviors. 156 children had information on the Early Childhood Behavior Questionnaire (ECBQ) at 18 months, Food Frequency Questionnaire at 48 months and Children׳s Eating Behavior Questionnaire (CEBQ) at 72 months. There was a significant negative correlation between inhibitory control at 18 months and food fussiness at 72 months. A GLM model predicting food fussiness at 72 months showed significant interaction between n-3 PUFAs, inhibitory control and IUGR, with higher intakes associated with decreased risk for fussiness in IUGR children with poor inhibitory control. Deficits in early inhibitory control predict later food fussiness, and higher intakes of n-3 PUFAs in infancy may protect IUGR children from developing such behavior later.

Developmental synchrony of thalamocortical circuits in the neonatal brain.

The thalamus is a deep gray matter structure and consists of axonal fibers projecting to the entire cortex, which provide the anatomical support for its sensorimotor and higher-level cognitive functions. There is limited in vivo evidence on the normal thalamocortical development, especially in early life. In this study, we aimed to investigate the developmental patterns of the cerebral cortex, the thalamic substructures, and their connectivity with the cortex in the first few weeks of the postnatal brain. We hypothesized that there is developmental synchrony of the thalamus, its cortical projections, and corresponding target cortical structures. We employed diffusion tensor imaging (DTI) and divided the thalamus into five substructures respectively connecting to the frontal, precentral, postcentral, temporal, and parietal and occipital cortex. T2-weighted magnetic resonance imaging (MRI) was used to measure cortical thickness. We found age-related increases in cortical thickness of bilateral frontal cortex and left temporal cortex in the early postnatal brain. We also found that the development of the thalamic substructures was synchronized with that of their respective thalamocortical connectivity in the first few weeks of the postnatal life. In particular, the right thalamo-frontal substructure had the fastest growth in the early postnatal brain. Our study suggests that the distinct growth patterns of the thalamic substructures are in synchrony with those of the cortex in early life, which may be critical for the development of the cortical and subcortical functional specialization.

Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder.

BACKGROUND: Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors. METHODS: Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans. RESULTS: Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs' lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD. CONCLUSIONS: Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.

Functional networks in parallel with cortical development associate with executive functions in children.

Children begin performing similarly to adults on tasks requiring executive functions in late childhood, a transition that is probably due to neuroanatomical fine-tuning processes, including myelination and synaptic pruning. In parallel to such structural changes in neuroanatomical organization, development of functional organization may also be associated with cognitive behaviors in children. We examined 6- to 10-year-old children's cortical thickness, functional organization, and cognitive performance. We used structural magnetic resonance imaging (MRI) to identify areas with cortical thinning, resting-state fMRI to identify functional organization in parallel to cortical development, and working memory/response inhibition tasks to assess executive functioning. We found that neuroanatomical changes in the form of cortical thinning spread over bilateral frontal, parietal, and occipital regions. These regions were engaged in 3 functional networks: sensorimotor and auditory, executive control, and default mode network. Furthermore, we found that working memory and response inhibition only associated with regional functional connectivity, but not topological organization (i.e., local and global efficiency of information transfer) of these functional networks. Interestingly, functional connections associated with "bottom-up" as opposed to "top-down" processing were more clearly related to children's performance on working memory and response inhibition, implying an important role for brain systems involved in late childhood.

Morphology and microstructure of subcortical structures at birth: a large-scale Asian neonatal neuroimaging study.

This paper presents the growth pattern and sexual dimorphism of the thalamus and basal ganglia in a large-scale Asian neonatal cohort using both T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Our study observed a robust growth of the thalamus and basal ganglia (caudate, putamen, globus pallidus, and anterior limb of internal capsule) beyond the overall brain growth in the early postnatal period (36-43 weeks of the gestational age). Additionally, the microstructure of the two structures was integrated as reflected by an increase in fractional anisotropy (FA) and a decrease in axial and radial water diffusivities in the first few weeks of life. Sexual dimorphism was only observed in the whole brain growth and the left thalamic volume but not in the other volumes or DTI measures of the basal ganglia and thalamus at birth. Even though the pattern of sexual dimorphism in the total brain volume is present at birth and persists throughout postnatal brain development, sexual dimorphisms of the basal ganglia and thalamus differ from those found in later stages of brain development, indicating that regionally distinct patterns of postnatal brain development between males and females arise after birth.

Maternal programming of defensive responses through sustained effects on gene expression.

There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype. In this paper we review data from the rat that suggest comparable forms of maternal effects on defensive responses stress, which are mediated by the effects of variations in maternal behavior on gene expression. Under conditions of environmental adversity maternal effects enhance the capacity for defensive responses in the offspring. In mammals, these effects appear to 'program' emotional, cognitive and endocrine systems towards increased sensitivity to adversity. In environments with an increased level of adversity, such effects can be considered adaptive, enhancing the probability of offspring survival to sexual maturity; the cost is that of an increased risk for multiple forms of pathology in later life.

Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.

Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 1(7) glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acid L-methionine, a precursor to S-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 1(7) promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible in the adult brain.

Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring.

In a series of studies on the long-term consequences of neonatal rearing, we compared hypothalamic and extrahypothalamic central corticotropin-releasing factor (CRF) systems in male rats reared under conditions of animal facility rearing, nonhandling (HMS0), handling with brief maternal separation for 15 min (HMS15), or handling with moderate maternal separation for 180 min (HMS180) daily from postnatal days 2-14. CRF-like immunoreactivity (CRFir) was elevated in lumbar cerebrospinal fluid of adult HMS180 and HMS0 rats relative to the other groups. In the paraventricular nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and locus coeruleus, CRFir and CRF mRNA levels were significantly elevated in HMS0 and HMS180 rats. Neonatal maternal separation was associated with regionally specific alterations in CRF receptor type 1 (CRF1) mRNA density in HMS180 rats. No rearing-associated differences in CRF2alpha binding were apparent in either the lateral septum or the ventromedial hypothalamus. These findings indicate that early rearing conditions can permanently alter the developmental set-point of central CRF systems, and potentially influence the expression of behavioral and endocrine responses to stress throughout life, thereby providing a possible neurobiological substrate for the relationship between early life events and increased vulnerability for hypothalamic-pituitary-adrenal axis and coping skill alterations and the frequency of mood disorders in patients with a history of such experiences.