The impact of poor fetal growth and chronic hyperpalatable diet exposure in adulthood on hippocampal function and feeding patterns in male rats.

Poor fetal growth affects eating behavior and the mesocorticolimbic system; however, its influence on the hippocampus has been less explored. Brain insulin sensitivity has been linked to developmental plasticity in response to fetal adversity and to cognitive performance following high-fat diet intake. We investigated whether poor fetal growth and exposure to chronic hyperpalatable food in adulthood could influence the recognition of environmental and food cues, eating behavior patterns, and hippocampal insulin signaling. At 60 days of life, we assigned male offspring from a prenatal animal model of 50% food restriction (FR) to receive either a high-fat and -sugar (HFS) diet or standard chow (CON) diet. Behavioral tests were conducted at 140 days, then tissues were collected. HFS groups showed a diminished hippocampal pAkt/Akt ratio. FR-CON and FR-HFS groups had higher levels of suppressor of cytokine signaling 3, compared to control groups. FR groups showed increased exploration of a novel hyperpalatable food, independent of their diet, and HFS groups exhibited overall lower entropy (less random, more predictable eating behavior) when the environment changed. Poor fetal growth and chronic HFS diet in adulthood altered hippocampal insulin signaling and eating patterns, diminishing the flexibility associated with eating behavior in response to extrinsic changes in food availability in the environment.

Parental and child genetic burden of glycaemic dysregulation and early-life cognitive development: an Asian and European prospective cohort study.

Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (ß = -0. 141, p-value = 0.024, 95% CI -0. 264 to -0. 018) and a lower WIAT-III mean score at ~9 years (ß = -0.222, p-value = 0.001, 95% CI -0.357 to -0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (ß = -0.172, p-value = 0.002, 95% CI -0.280 to -0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.

How are overweight and obesity associated with reinforcement learning deficits? A systematic review.

Reinforcement learning (RL) refers to the ability to learn stimulus-response or response-outcome associations relevant to the acquisition of behavioral repertoire and adaptation to the environment. Research data from correlational and case-control studies have shown that obesity is associated with impairments in RL. The aim of the present study was to systematically review how obesity and overweight are associated with RL performance. More specifically, the relationship between high body mass index (BMI) and task performance was explored through the analysis of specific RL processes associated with different physiological, computational, and behavioral manifestations. Our systematic analyses indicate that obesity might be associated with impairments in the use of aversive outcomes to change ongoing behavior, as revealed by results involving instrumental negative reinforcement and extinction/reversal learning, but further research needs to be conducted to confirm this association. Hypotheses regarding how obesity might be associated with altered RL were discussed.

Development of risk prediction models for depression combining genetic and early life risk factors.

Background: Both genetic and early life risk factors play important roles in the pathogenesis and progression of adult depression. However, the interplay between these risk factors and their added value to risk prediction models have not been fully elucidated. Methods: Leveraging a meta-analysis of major depressive disorder genome-wide association studies (N = 45,591 cases and 97,674 controls), we developed and optimized a polygenic risk score for depression using LDpred in a model selection dataset from the UK Biobank (N = 130,092 European ancestry individuals). In a UK Biobank test dataset (N = 278,730 European ancestry individuals), we tested whether the polygenic risk score and early life risk factors were associated with each other and compared their associations with depression phenotypes. Finally, we conducted joint predictive modeling to combine this polygenic risk score with early life risk factors by stepwise regression, and assessed the model performance in identifying individuals at high risk of depression. Results: In the UK Biobank test dataset, the polygenic risk score for depression was moderately associated with multiple early life risk factors. For instance, a one standard deviation increase in the polygenic risk score was associated with 1.16-fold increased odds of frequent domestic violence (95% CI: 1.14-1.19) and 1.09-fold increased odds of not having access to medical care as a child (95% CI: 1.05-1.14). However, the polygenic risk score was more strongly associated with depression phenotypes than most early life risk factors. A joint predictive model integrating the polygenic risk score, early life risk factors, age and sex achieved an AUROC of 0.6766 for predicting strictly defined major depressive disorder, while a model without the polygenic risk score and a model without any early life risk factors had an AUROC of 0.6593 and 0.6318, respectively. Conclusion: We have developed a polygenic risk score to partly capture the genetic liability to depression. Although genetic and early life risk factors can be correlated, joint predictive models improved risk stratification despite limited improvement in magnitude, and may be explored as tools to better identify individuals at high risk of depression.

Brain insulin signaling as a potential mediator of early life adversity effects on physical and mental health.

In numerous brain structures, insulin signaling modulates the homeostatic processes, sensitivity to reward pathways, executive function, memory, and cognition. Through human studies and animal models, mounting evidence implicates central insulin signaling in the metabolic, physiological, and psychological consequences of early life adversity. In this review, we describe the consequences of early life adversity in the brain where insulin signaling is a key factor and how insulin may moderate the effects of adversity on psychiatric and cardio-metabolic health outcomes. Further understanding of how early life adversity and insulin signaling impact specific brain regions and mental and physical health outcomes will assist in prevention, diagnosis, and potential intervention following early life adversity.

Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing.

BACKGROUND: There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established. METHODS: In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region). FINDINGS: We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS). INTERPRETATION: Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS. FUNDING: This work was supported by funding from the Hope for Depression Research Foundation (MJM).

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction.

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

Examining resting-state network connectivity in children exposed to perinatal maternal adversity using anatomically weighted functional connectivity (awFC) analyses; A preliminary report.

Introduction: Environmental perturbations during critical periods can have pervasive, organizational effects on neurodevelopment. To date, the literature examining the long-term impact of early life adversity has largely investigated structural and functional imaging data outcomes independently. However, emerging research points to a relationship between functional connectivity and the brain's underlying structural architecture. For instance, functional connectivity can be mediated by the presence of direct or indirect anatomical pathways. Such evidence warrants the use of structural and functional imaging in tandem to study network maturation. Accordingly, this study examines the impact of poor maternal mental health and socioeconomic context during the perinatal period on network connectivity in middle childhood using an anatomically weighted functional connectivity (awFC) approach. awFC is a statistical model that identifies neural networks by incorporating information from both structural and functional imaging data. Methods: Resting-state fMRI and DTI scans were acquired from children aged 7-9 years old. Results: Our results indicate that maternal adversity during the perinatal period can affect offspring's resting-state network connectivity during middle childhood. Specifically, in comparison to controls, children of mothers who had poor perinatal maternal mental health and/or low socioeconomic status exhibited greater awFC in the ventral attention network. Discussion: These group differences were discussed in terms of the role this network plays in attention processing and maturational changes that may accompany the consolidation of a more adult-like functional cortical organization. Furthermore, our results suggest that there is value in using an awFC approach as it may be more sensitive in highlighting connectivity differences in developmental networks associated with higher-order cognitive and emotional processing, as compared to stand-alone FC or SC analyses.

New Research Perspectives on the Interplay Between Genes and Environment on Executive Function Development.

Executive functions (EFs) are a set of skills responsible for the cognitive control of emotional states and behavior as well as for information processing required for learning and memory. Impairments in these abilities, such as focused attention, working memory, cognitive flexibility, and self-regulation, are implicated in a variety of psychopathologies across the lifespan. EF development shows a protracted course that begins in early childhood and continues throughout adolescence and into early adulthood. Maturation of EFs is subject to environmental influences such that adversity during development can affect multiple EF-mediated processes and outcomes. In this review, we describe sensitive periods for the development of EFs and the effects of adverse environmental exposures, with consideration of the underlying neurobiological mechanisms. However, there is considerable interindividual variation in the impact of adversity, with some individuals more vulnerable and some more resilient to its effects. We explore the evidence for the genetic contribution to interindividual variation in EFs, providing an overview of classic studies, followed by the results of recent genome-wide association studies and innovative genomic methods. Finally, we review studies investigating the interdependence between early-life adversities and genetic factors on EFs. We discuss the importance of novel functional genomics approaches, multilevel analyses, and big data to elucidate the complexity of the relationships between genes, environment, and the development of EFs.

A sex-specific genome-wide association study of depression phenotypes in UK Biobank.

There are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date, no studies seek to identify sex-specific markers and pathways. In this study, we performed a sex-stratified genome-wide association analysis for broad depression with the UK Biobank total participants (N = 274,141), including only non-related participants, as well as with males (N = 127,867) and females (N = 146,274) separately. Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways. We identified 11 loci passing genome-level significance (P < 5 × 10-8) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males. Gene-based analysis revealed "Regulation of Gene Expression" as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific polygenic risk scores (PRSs) for broad depression outperformed total and the opposite sex PRSs in the prediction of broad major depressive disorder. These findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression.

Linking specific biological signatures to different childhood adversities: findings from the HERO project.

BACKGROUND: Although investigations have begun to differentiate biological and neurobiological responses to a variety of adversities, studies considering both endocrine and immune function in the same datasets are limited. METHODS: Associations between proximal (family functioning, caregiver depression, and anxiety) and distal (SES-D; socioeconomic disadvantage) early-life adversities with salivary inflammatory biomarkers (IL-1ß, IL-6, IL-8, and TNF-α) and hair HPA markers (cortisol, cortisone, and dehydroepiandrosterone) were examined in two samples of young U.S. children (N = 142; N = 145). RESULTS: Children exposed to higher SES-D had higher levels of TNF-α (B = 0.13, p = 0.011), IL-1ß (B = 0.10, p = 0.033), and DHEA (B = 0.16, p = 0.011). Higher family dysfunction was associated with higher cortisol (B = 0.08, p = 0.033) and cortisone (B = 0.05, p = 0.003). An interaction between SES-D and family dysfunction was observed for cortisol levels (p = 0.020) whereby children exposed to lower/average levels of SES-D exhibited a positive association between family dysfunction and cortisol levels, whereas children exposed to high levels of SES-D did not. These findings were partially replicated in the second sample. CONCLUSIONS: Our results indicate that these biological response systems may react differently to different forms of early-life adversity. IMPACT: Different forms of early-life adversity have varied stress signatures, and investigations of early-life adversities with inflammation and HPA markers are lacking. Children with higher socioeconomic disadvantage had higher TNF-α, IL-1ß, and DHEA. Higher family dysfunction was associated with higher hair cortisol and cortisone levels, and the association between family dysfunction and cortisol was moderated by socioeconomic disadvantage. Biological response systems (immune and endocrine) were differentially associated with distinct forms of early-life adversities.

Examining the biological mechanisms of human mental disorders resulting from gene-environment interdependence using novel functional genomic approaches.

We explore how functional genomics approaches that integrate datasets from human and non-human model systems can improve our understanding of the effect of gene-environment interplay on the risk for mental disorders. We start by briefly defining the G-E paradigm and its challenges and then discuss the different levels of regulation of gene expression and the corresponding data existing in humans (genome wide genotyping, transcriptomics, DNA methylation, chromatin modifications, chromosome conformational changes, non-coding RNAs, proteomics and metabolomics), discussing novel approaches to the application of these data in the study of the origins of mental health. Finally, we discuss the multilevel integration of diverse types of data. Advance in the use of functional genomics in the context of a G-E perspective improves the detection of vulnerabilities, informing the development of preventive and therapeutic interventions.

Emotional eating in women with generalized anxiety disorder.

INTRODUCTION: Individuals diagnosed with generalized anxiety disorder (GAD) seek pleasurable foods to avoid their negative emotional experiences. Ineffective regulation of negative emotions may be a risk factor for emotional eating (EE), leading to suffering, dysfunctional behaviors, and weight gain. OBJECTIVES: The aim of this study is to understand the relationship between emotional dysregulation and EE, investigating potential mediators such as the intensity of the worry, avoidance of internal experiences, mindfulness, and self-compassion in female patients with anxiety. METHODS: In this cross-sectional study, participants from a randomized clinical trial diagnosed with GAD answered the following instruments at baseline: the Difficulties in Emotion Regulation Scale (DERS), the Three Factor Eating Questionnaire (TFEQ-R21), the Penn State Worry Questionnaire (PSWQ), the Action and Acceptance Questionnaire (AAQ), the Five Facet Mindfulness Questionnaire (FFMQ), and the Self-Compassion Scale (SCS). We estimated Pearson correlation coefficients and performed mediation analyses. RESULTS: We evaluated 51 female individuals, 34 of whom completed all the questionnaires. Our data showed that EE was positively correlated with emotional dysregulation (r = 0.593; p < 0.001), worry trait (r = 0.402; p = 0.018), and avoidance of internal experiences (r = 0.565; p < 0.001), whereas it was negatively correlated with self-compassion (r = -0.590; p < 0.001) and mindful state (r = -0.383; p = 0.026). Moreover, we demonstrated that self-compassion mediates the relationship between emotional dysregulation and EE (ab product estimate = 0.043, 95% confidence interval [95%CI] 0.003-0.084). CONCLUSION: Our findings contribute to the literature by identifying psychological factors that could mediate the association between emotional dysregulation and EE, enabling identification of more effective eating behavior intervention targets for patients with GAD.

Emotional eating in women with generalized anxiety disorder

Abstract Introduction Individuals diagnosed with generalized anxiety disorder (GAD) seek pleasurable foods to avoid their negative emotional experiences. Ineffective regulation of negative emotions may be a risk factor for emotional eating (EE), leading to suffering, dysfunctional behaviors, and weight gain. Objectives The aim of this study is to understand the relationship between emotional dysregulation and EE, investigating potential mediators such as the intensity of the worry, avoidance of internal experiences, mindfulness, and self-compassion in female patients with anxiety. Methods In this cross-sectional study, participants from a randomized clinical trial diagnosed with GAD answered the following instruments at baseline: the Difficulties in Emotion Regulation Scale (DERS), the Three Factor Eating Questionnaire (TFEQ-R21), the Penn State Worry Questionnaire (PSWQ), the Action and Acceptance Questionnaire (AAQ), the Five Facet Mindfulness Questionnaire (FFMQ), and the Self-Compassion Scale (SCS). We estimated Pearson correlation coefficients and performed mediation analyses. Results We evaluated 51 female individuals, 34 of whom completed all the questionnaires. Our data showed that EE was positively correlated with emotional dysregulation (r = 0.593; p < 0.001), worry trait (r = 0.402; p = 0.018), and avoidance of internal experiences (r = 0.565; p < 0.001), whereas it was negatively correlated with self-compassion (r = -0.590; p < 0.001) and mindful state (r = -0.383; p = 0.026). Moreover, we demonstrated that self-compassion mediates the relationship between emotional dysregulation and EE (ab product estimate = 0.043, 95% confidence interval [95%CI] 0.003-0.084). Conclusion Our findings contribute to the literature by identifying psychological factors that could mediate the association between emotional dysregulation and EE, enabling identification of more effective eating behavior intervention targets for patients with GAD.

Leptin receptor co-expression gene network moderates the effect of early life adversity on eating behavior in children.

Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (ß = 61.58, p = 0.015) and 72 months (ß = 97.78, p = 0.001); food responsiveness at 48 months (ß = 83.79, p = 0.009) satiety at 48 months (ß = -43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (ß = 30.48, p = 0.006) food fussiness score (ß = -24.07, p = 0.02) and satiety score at 60 months (ß = -17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life.

Thrifty-Eating Behavior Phenotype at the Food Court - Programming Goes Beyond Food Preferences.

Introduction: Prenatal growth impairment leads to higher preference for palatable foods in comparison to normal prenatal growth subjects, which can contribute to increased body fat mass and a higher risk for developing chronic diseases in small-for-gestational-age (SGA) individuals throughout life. This study aimed to investigate the effect of SGA on feeding behavior in children and adolescents, as well as resting-state connectivity between areas related to reward, self-control, and value determination, such as orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), amygdala and dorsal striatum (DS). Methods: Caregivers and their offspring were recruited from two independent cohorts in Brazil (PROTAIA) and Canada (MAVAN). Both cohorts included anthropometric measurements, food choice tasks, and resting-state functional magnetic resonance imaging (fMRI) data. Results: In the Brazilian sample (17 ± 0.28 years, n=70), 21.4% of adolescents were classified as SGA. They exhibited lower monetary-related expenditure to buy a snack compared to controls in the food choice test. Decreased functional connectivity (n=40) between left OFC and left DL-PFC; and between right OFC and: left amygdala, right DS, and left DS were observed in the Brazilian SGA participants. Canadian SGA participants (14.9%) had non-significant differences in comparison with controls in a food choice task at 4 years old ( ± 0.01, n=315). At a follow-up brain scan visit (10.21 ± 0.140 years, n=49), SGA participants (28.6%) exhibited higher connectivity between the left OFC and left DL-PFC, also higher connectivity between the left OFC and right DL-PFC. We did not observe significant anthropometric neither nutrients' intake differences between groups in both samples. Conclusions: Resting-state fMRI results showed that SGA individuals had altered connectivity between areas involved in encoding the subjective value for available goods and decision-making in both samples, which can pose them in disadvantage when facing food options daily. Over the years, the cumulative exposure to particular food cues together with the altered behavior towards food, such as food purchasing, as seen in the adolescent cohort, can play a role in the long-term risk for developing chronic non-communicable diseases.

Investigation of metabolomic biomarkers for childhood executive function and the role of genetic and dietary factors: The GUSTO cohort.

BACKGROUND: Few studies have investigated molecular biomarkers of specific executive function (EF) skills in children. We aimed to characterise the prospective associations between metabolome and multiple domains of EF using a bidirectional design. METHODS: This study was conducted within a longitudinal birth cohort, the Growing Up in Singapore Towards healthy Outcomes (GUSTO). Circulating levels of 165 metabolites were quantified using a nuclear magnetic resonance based metabolomics platform (n = 457 (∼6yrs) and n = 524 (∼8yrs)). Parent-reported EF was available for 495 children (∼7yrs). Multivariate linear regression was used to assess the metabolite-EF relationships. We examined the role of body composition, dietary factors, and genetics in the metabolite-EF associations. FINDINGS: Higher leucine level (∼6yrs) was associated with poorer EF (∼7yrs, Initiate (P = 0.003) and Working Memory (P = 0.004)). EF (∼7yrs) was not associated with leucine (∼8yrs). Importantly, we found weak evidence for associations of dietary factors (∼5yrs) with leucine (∼6yrs) and EF (∼7yrs). Each copy of C allele in rs1260326 (a leucine-related polymorphism) was associated with higher leucine level and poorer Initiate and Working Memory (P < 0.05). Amongst those with less strongly genetically influenced leucine, inverse association between leucine and cognitive regulation were weaker among those with higher BMI. INTERPRETATION: The observed association between higher leucine level and poorer EF may be determined by genetics and may not be easily amenable to dietary interventions. Further research is needed for validation and to understand mechanisms. FUNDING: Singapore National Research Foundation and Agency for Science, Technology and Research.

Translating the Biology of Adversity and Resilience Into New Measures for Pediatric Practice.

As the science of adversity and resilience advances, and public awareness of the health consequences of stress grows, primary care providers are being increasingly asked to address the effects of adverse experiences on child wellbeing. Given limited tools for assessing these effects early in life, the authors explore how enhanced capacity to measure stress activation directly in young children could transform the role and scope of pediatric practice. When employed within a trusted relationship between caregivers and clinicians, selective use of biological measures of stress responses would help address the documented limitations of rating scales of adverse childhood experiences as a primary indicator of individual risk and strengthen the ability to focus on variation in intervention needs, assess their effectiveness, and guide ongoing management. The authors provide an overview of the potential benefits and risks of such expanded measurement capacity, as well as an introduction to candidate indicators that might be employed in an office setting. The ultimate value of such measures for both pediatricians and parents will require vigilant attention to the ethical responsibilities of assuring their correct interpretation and minimizing the harm of inappropriate labeling, especially for children and families experiencing the hardships and threats of racism, poverty, and other structural inequities. Whereas much work remains to be done to advance measurement development and ensure its equitable use, the potential of validated markers of stress activation and resilience to strengthen the impact of primary health care on the lives of young children facing significant adversity demands increased attention.

Neonatal hypoxia-ischemia induces dysregulated feeding patterns and ethanol consumption that are alleviated by methylphenidate administration in rats.

Impulsivity, as observed in patients diagnosed with Attention-deficit/hyperactivity disorder (ADHD), can induce dysregulated behaviors such as binge eating and drug addiction. We previously demonstrated that neonatal hypoxia-ischemia (HI) resulted in ADHD-like behaviors in rats and that methylphenidate (MPH) administration (the first therapeutic option for ADHD) reversed these deficits. Here, we aimed at investigating addictive-like behaviors, such as the reward-based feeding behavior (using the BioDAQ monitor) and ethanol consumption (using the IA2BC procedure) in adult animals subjected to neonatal HI and treated with or without MPH. Male Wistar rats were divided into four groups (n = 10-12/group): control saline (CTS), CTMPH, HI saline (HIS) and HIMPH. The HI procedure was conducted at postnatal day (PND) 7 and behavioral analyses between PND 60-90, in which MPH (2.5 mg/kg, i.p.) was administered 30 min prior to each behavioral evaluation (6 sessions in BioDAQ and 12 sessions in the IA2BC protocol). HI animals had a dysregulated feeding intake shortly after eating a small piece of the palatable diet, and MPH reversed this dysregulated pattern. However, when the palatable diet was freely available, MPH stimulated a higher intake of this diet in the first exposure day, and this effect was potentialized in HIMPH rats. Increased ethanol intake was observed in HI rats, and MPH administration alleviated this behavior; contrarily, MPH treatment in control rats induced an increase in ethanol consumption. The present findings give additional support to the relationship between neonatal HI and ADHD but the differential response to MPH in control or HI animals highlights the importance of avoiding indiscriminate use of MPH by healthy individuals.