@article{pmid30081968,

title = {Polygenic differential susceptibility to prenatal adversity},

author = {Jay Belsky and Irina Pokhvisneva and Anu Sathyan Sathyapalan Rema and Birit F P Broekman and Michael Pluess and Kieran J O'Donnell and Michael J Meaney and Patrícia P Silveira},

doi = {10.1017/S0954579418000378},

issn = {1469-2198},

year  = {2019},

date = {2019-05-01},

journal = {Dev Psychopathol},

volume = {31},

number = {2},

pages = {439--441},

abstract = {A recent article in this journal reported a number of gene × environment interactions involving a serotonin transporter-gene network polygenic score and a composite index of prenatal adversity predicting several problem behavior outcomes at 48 months (e.g., anxious/depressed, pervasive developmental problems) and at 60 months (e.g., withdrawal, internalizing problems), yet did not illuminate the nature or form these genetic × environment interactions took. Here we report results of six additional analyses to evaluate whether these interactions reflected diathesis-stress or differential-susceptibility related processes. Analyses of the regions of significance and proportion of interaction index are consistent with the diathesis-stress model, seemingly because of the truncated nature of the adversity score (which did not extend to supportive/positive prenatal experiences/exposures); in contrast, the proportion (of cases) affected index favors the differential-susceptibility model. These results suggest the need for future studies to extend measurement of the prenatal environment to highly supportive experiences and exposures.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30771298,

title = {Methylphenidate administration reverts attentional inflexibility in adolescent rats submitted to a model of neonatal hypoxia-ischemia: Predictive validity for ADHD study},

author = {Patrícia Maidana Miguel and Bruna Ferrary Deniz and Heloísa Deola Confortim and Loise Peres Bronauth and Bruna Chaves de Oliveira and Márcio Bonesso Alves and Patrícia Pelufo Silveira and Lenir Orlandi Pereira},

doi = {10.1016/j.expneurol.2019.02.004},

issn = {1090-2430},

year  = {2019},

date = {2019-05-01},

journal = {Exp Neurol},

volume = {315},

pages = {88--99},

abstract = {Perinatal complications such as birth asphyxia were associated with a higher risk for Attention-Deficit/Hyperactivity Disorder (ADHD) in humans. Data from a rat model of neonatal hypoxia-ischemia (HI) have revealed inattention, impulsive behavior and dopamine (DA) disturbances in the prefrontal cortex (PFC), confirming the face validity and construct validity for ADHD study. However, the predictive validity (similar therapeutic efficacy of the pharmacological treatment available in the clinic) should be considered. Therefore, we aimed to investigate the effects of methylphenidate (MPH) - the treatment of choice for ADHD - on exploratory and attentional flexibility behaviors and DA-related proteins in the PFC of animals submitted to neonatal HI. Male Wistar rats were divided into four groups: control saline (CTS, n = 12), control MPH (CTMPH, n = 12), HI saline (HIS, n = 13) and HIMPH (n = 12). The HI procedure was conducted at postnatal day (PND) 7 and behavioral measures between PND 30-40, followed by protein analysis in the PFC. The MPH administration (2.5 mg/kg, i.p.) occurred 30 min prior each behavioral session and euthanasia for western blot analysis. We observed that the MPH increased the locomotor activity in the open field especially in HI rats. In the attentional-set shifting task, the MPH reversed the HI- induced attentional inflexibility, but impaired the task acquisition in control rats. Neonatal HI resulted in lower DA D2 receptors expression but also decreased DA transporter (responsible for DA reuptake) and increased pTH (phosphorylated-tyrosine hydroxylase) levels in the PFC, probably to compensate the dysfunctional DA transmission. This compensation was higher in the HIMPH group and it could explain the improvement in the attentional flexibility as well as the increased locomotor activity in this group. Taken this data together, we can assume the predictive validity of the HI model for the ADHD study concerning the impact of MPH treatment on attentional parameters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30922963,

title = {A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions},

author = {Shantala A Hari Dass and Kathryn McCracken and Irina Pokhvisneva and Lawrence M Chen and Elika Garg and Thao T T Nguyen and Zihan Wang and Barbara Barth and Moein Yaqubi and Lisa M McEwen and Julie L MacIsaac and Josie Diorio and Michael S Kobor and Kieran J O'Donnell and Michael J Meaney and Patricia P Silveira},

doi = {10.1016/j.ebiom.2019.03.051},

issn = {2352-3964},

year  = {2019},

date = {2019-04-01},

journal = {EBioMedicine},

volume = {42},

pages = {188--202},

abstract = {BACKGROUND: Activation of brain insulin receptors modulates reward sensitivity, inhibitory control and memory. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related mental disorders (attention deficit hyperactivity disorder or ADHD, addiction, dementia), in agreement with the high co-morbidity between insulin resistance and psychopathology. These neurobiological mechanisms can be explored using genetic studies. We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic and hippocampal insulin receptor-related gene networks, and investigate if it predicts endophenotypes (impulsivity, cognitive ability) in community samples of children, and psychopathology (addiction, dementia) in adults.nnMETHODS: Lists of genes co-expressed with the insulin receptor in the mesocorticolimbic system or hippocampus were created. SNPs from these genes (post-clumping) were compiled in a polygenic score using the association betas described in a conventional GWAS (ADHD in the mesocorticolimbic score and Alzheimer in the hippocampal score). Across multiple samples (n = 4502), the biologically informed, mesocorticolimbic or hippocampal specific insulin receptor polygenic scores were calculated, and their ability to predict impulsivity, risk for addiction, cognitive performance and presence of Alzheimer's disease was investigated.nnFINDINGS: The biologically-informed ePRS-IR score showed better prediction of child impulsivity and cognitive performance, as well as risk for addiction and Alzheimer's disease in comparison to conventional polygenic scores for ADHD, addiction and dementia.nnINTERPRETATION: This novel, biologically-informed approach enables the use of genomic datasets to probe relevant biological processes involved in neural function and disorders. FUND: Toxic Stress Research network of the JPB Foundation, Jacobs Foundation (Switzerland), Sackler Foundation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30571979,

title = {Maternal and post-natal obesity alters long-term memory and hippocampal molecular signaling of male rat},

author = {Amanda Brondani Mucellini and Daniela Pereira Laureano and Patrícia Pelufo Silveira and Gilberto Luiz Sanvitto},

doi = {10.1016/j.brainres.2018.12.021},

issn = {1872-6240},

year  = {2019},

date = {2019-04-01},

journal = {Brain Res},

volume = {1708},

pages = {138--145},

abstract = {The aim of this study was to investigate whether maternal cafeteria ingestion interferes with long-term memory-related behaviors and hippocampal brain-derived neurotrophic factor (BDNF) signaling in the offspring, and if there is a cumulative effect with the exposure to cafeteria diet during the life-course of the pups. Female rats were fed a control (CON, n = 20) or cafeteria diet (CAF, n = 24) from their weaning to weaning of their offspring. After that, their male offspring were divided into 4 groups (CON-CON, n = 36; CON-CAF, n = 38, CAF-CON, n = 46 and CAF-CAF, n = 39) so that all litters ingested CON or CAF, irrespective of maternal diet. At 30 days of age, all groups exposed to cafeteria diet at some stage in life showed a decline in performance on one or both object recognition and inhibitory avoidance tasks. At 120 days, CON-CAF and CAF-CAF groups continued to show memory impairment. There were no significant differences between groups in the hippocampal concentrations of BDNF and cAMP Response Element Binding protein (CREB) in puberty or adulthood, but the concentration of hippocampal Ras-Raf-MEK-mitogen-activated protein kinase (MAPK) was higher in CAF-CAF pubescent offspring when compared to the CON-CON group. These data suggest that maternal diet affects the behavior and the molecular signaling related to long-term memory of the offspring, and that its effects are influenced by postnatal diet.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30789933,

title = {Multi-behavioral obesogenic phenotypes among school-aged boys and girls along the birth weight continuum},

author = {Andre Krumel Portella and Catherine Paquet and Adrianne Rahde Bischoff and Roberta Dalle Molle and Aida Faber and Spencer Moore and Narendra Arora and Robert Levitan and Patricia Pelufo Silveira and Laurette Dube},

doi = {10.1371/journal.pone.0212290},

issn = {1932-6203},

year  = {2019},

date = {2019-01-01},

journal = {PLoS One},

volume = {14},

number = {2},

pages = {e0212290},

abstract = {Evidence shows that extremes of birth weight (BW) carry a common increased risk for the development of adiposity and related cardiovascular diseases, but little is known about the role of obesogenic behaviors in this process. Moreover, no one has empirically examined whether the relationship between BW, obesogenic behaviors and BMI along the full low-to-high birthweight continuum reflects the U-shape pattern expected from common risk at both BW extremes. Our objective was to characterize physical activity, screen time, and eating behavior and their relationship to BMI as a function of BW among school-aged boys and girls. In this cross-sectional study, 460 children aged 6 to 12 years (50% boys) from Montreal, Canada provided information on sleeping time, screen time, physical activity levels, eating behavior (emotional, external and restrained eating) and anthropometrics (height, weight, BW) through parent reported questionnaires. BMI was normalized using WHO Standards (zBMI), and BW expressed as ratio using Canadian population standards (BW for gestational age and sex). Analyses were conducted using generalized linear models with linear and quadratic terms for BW, stratified by sex and adjusted for age, ethnicity and household income. In boys, physical activity and screen time showed U-shaped associations with BW, while physical activity had an inverted U-shaped in girls. Emotional and restrained eating had positive linear relations with BW in boys and girls. Sleep time and external eating were not associated with BW. A U-shaped relationship between BW and zBMI was found in boys but no association was found in girls. Only sleep (in boys and girls), and emotional eating (girls only) were related to zBMI and mediation of the BW-zBMI relationship was only supported for emotional eating. In conclusion, BW relates to obesogenic behaviors and BMI in both non-linear and linear ways, and these associations differed by sex.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28105895,

title = {Prefrontal cortex dysfunction in hypoxic-ischaemic encephalopathy contributes to executive function impairments in rats: Potential contribution for attention-deficit/hyperactivity disorder},

author = {Patrícia Maidana Miguel and Bruna Ferrary Deniz and Iohanna Deckmann and Heloísa Deola Confortim and Ramiro Diaz and Daniela Pereira Laureano and Patrícia Pelufo Silveira and Lenir Orlandi Pereira},

doi = {10.1080/15622975.2016.1273551},

issn = {1814-1412},

year  = {2018},

date = {2018-10-01},

journal = {World J Biol Psychiatry},

volume = {19},

number = {7},

pages = {547--560},

abstract = {OBJECTIVES: The attention-deficit/hyperactivity disorder (ADHD) compromises the quality of life of individuals including adaptation to the social environment. ADHD aetiology includes perinatal conditions such as hypoxic-ischaemic events; preclinical studies have demonstrated attentional deficits and impulsive-hyperactive outcomes after neonatal hypoxic and/or ischaemic intervention, but data are missing to understand this relationship. Thus, the aim of this study was to evaluate executive function (EF) and impulsivity, and tissue integrity and dopaminergic function in the prefrontal cortex (PFC) of rats submitted to hypoxia-ischaemia (HI).nnMETHODS: At postnatal day (PND) 7, male Wistar rats were divided into control (n = 10) and HI groups (n = 11) and the HI procedure was conducted. At PND60, the animals were tested in the attentional set-shifting (ASS) task to EF and in the tolerance to delay of reward for assessment of impulsivity. After, morphological analysis and the dopaminergic system were evaluated in the PFC.nnRESULTS: Animals subjected to HI had impairments in EF evidenced by a behavioural inflexibility that was correlated to PFC atrophy. Moreover, HI animals presented reduced D2 receptors in the ipsilateral side of ischaemia in the PFC.nnCONCLUSIONS: Animals submitted to HI presented impaired EF associated with tissue atrophy and dopaminergic disturbance in the PFC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30293593,

title = {Moderating effect of PLIN4 genetic variant on impulsivity traits in 5-year-old-children born small for gestational age},

author = {Danitsa Marcos Rodrigues and Gisele Gus Manfro and Robert Daniel Levitan and Meir Steiner and Michael Joseph Meaney and Patrícia Pelufo Silveira},

doi = {10.1016/j.plefa.2018.07.013},

issn = {1532-2823},

year  = {2018},

date = {2018-10-01},

journal = {Prostaglandins Leukot Essent Fatty Acids},

volume = {137},

pages = {19--25},

abstract = {Poor fetal growth is associated with long-term behavioral, metabolic and psychiatric alterations, including impulsivity, insulin resistance, and mood disorders. However, the consumption of omega-3 polyunsaturated fatty acid (n-3 PUFA) seems to be protective for this population, improving inhibitory control and behavioral reactivity. We investigated whether the presence of the A allele of rs8887 SNP (PLIN4 gene), known to be associated with increased sensitivity to the consumption of n-3 PUFAs, interacts with fetal growth influencing inhibitory control. 152 five-year-old children were genotyped and performed the Stop Signal Task (SSRT). There was a significant interaction between birth weight and the presence of the A allele on SSRT performance, in which lower birth weight associated with poorer inhibitory control only in non-carriers. These results suggest that a higher responsiveness to n-3 PUFAS protects small for gestational age children from developing poor response inhibition, highlighting that optimizing n-3 PUFA intake may benefit this population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30209275,

title = {Birth weight and catch up growth are associated with childhood impulsivity in two independent cohorts},

author = {Patrícia P Silveira and Irina Pokhvisneva and Hélène Gaudreau and Anne Rifkin-Graboi and Birit F P Broekman and Meir Steiner and Robert Levitan and Carine Parent and Josie Diorio and Michael J Meaney},

doi = {10.1038/s41598-018-31816-5},

issn = {2045-2322},

year  = {2018},

date = {2018-09-01},

journal = {Sci Rep},

volume = {8},

number = {1},

pages = {13705},

abstract = {Individuals born after intrauterine growth restriction (IUGR) are more impulsive towards palatable foods, but it is not clear 1) if IUGR-related impulsivity is specific for foods and solely based on response inhibition and 2) if the development of impulsivity is due to being born IUGR per se or to growing up fast in the first few years of life (catch up growth). Children were classified in the IUGR group if the birth weight ratio was below 0.85. Delta z score for BMI was used as a measure of catch up growth. In MAVAN (N = 274), impulsivity was measured by the Information Sampling Task from the Cambridge Neuropsychological Test Automated Battery (IST - CANTAB), and in GUSTO using the Sticker Delay Task (N = 327). There is a significant effect of interaction between being born IUGR and the magnitude of catch up growth on the reflection impulsivity from IST-CANTAB at 60 months, in which greater catch up growth associates with greater impulsivity in the IST fixed condition in IUGR children. The finding was reproduced in children from the GUSTO cohort using the Sticker Delay Task. We confirmed that catch up growth interacts with IUGR, having a major role in the development of impulsivity in the first years of life and influencing inhibitory control and decision making processes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30089455,

title = {PRS-on-Spark (PRSoS): a novel, efficient and flexible approach for generating polygenic risk scores},

author = {Lawrence M Chen and Nelson Yao and Elika Garg and Yuecai Zhu and Thao T T Nguyen and Irina Pokhvisneva and Shantala A Hari Dass and Eva Unternaehrer and Hélène Gaudreau and Marie Forest and Lisa M McEwen and Julia L MacIsaac and Michael S Kobor and Celia M T Greenwood and Patricia P Silveira and Michael J Meaney and Kieran J O'Donnell},

doi = {10.1186/s12859-018-2289-9},

issn = {1471-2105},

year  = {2018},

date = {2018-08-01},

journal = {BMC Bioinformatics},

volume = {19},

number = {1},

pages = {295},

abstract = {BACKGROUND: Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach.nnRESULTS: We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%).nnCONCLUSIONS: PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29476706,

title = {Is willingness to exercise programmed in utero? Reviewing sedentary behavior and the benefits of physical activity in intrauterine growth restricted individuals},

author = {Adrianne Rahde Bischoff and Fábio da Silva Cunha and Roberta Dalle Molle and Paulo José Cauduro Maróstica and Patrícia Pelufo Silveira},

doi = {10.1016/j.jped.2017.12.015},

issn = {1678-4782},

year  = {2018},

date = {2018-01-01},

journal = {J Pediatr (Rio J)},

volume = {94},

number = {6},

pages = {582--595},

abstract = {OBJECTIVE: The literature suggests that a fetus will adapt to surrounding adversities by optimizing its use of energy to improve survival, ultimately leading to the programming of the individual's energy intake and expenditure. While recent reviews focused on the fetal programming of energy intake and food preferences, there is also some evidence that fetal adversity is associated with diminished physical activity levels. Therefore, we aimed to review (a) the evidence for an association between being born with intrauterine growth restriction and sedentarism over the life-course and (b) the potential benefits of physical activity over cardiometabolic risk factors for this population.nnSOURCES: PubMed, Scielo, Scopus and Embase.nnSUMMARY OF FINDINGS: Most clinical studies that used objective measures found no association between intrauterine growth restriction and physical activity levels, while most studies that used self-reported questionnaires revealed such relationships, particularly leisure time physical activity. Experimental studies support the existence of fetal programming of physical activity, and show that exposure to exercise during IUGR individuals' life improves metabolic outcomes but less effect was seen on muscle architecture or function.nnCONCLUSIONS: Alterations in muscle strength and metabolism, as well as altered aerobic performance, may predispose IUGR individuals to be spontaneously less physically active, suggesting that this population may be an important target for preventive interventions. Although very heterogeneous, the different studies allow us to infer that physical activity may have beneficial effects especially for individuals that are more vulnerable to metabolic modifications such as those with IUGR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}