4535 Development of a Mouse Model to study interactions between parental history of alcohol use and early life adversity on behavioral and neurobiological development of offspring

OBJECTIVES/GOALS: Individuals with a family history of alcoholism (FH+) are more likely to develop an alcohol use disorder than those with no such history. Early life adversity has a high coincidence with FH+ making pathogenic studies difficult in clinical studies. Here, we developed a mouse model to study pathogenic mechanisms underlying these risk factors. METHODS/STUDY POPULATION: Male and female C57BL6/J mice were exposed to increasing concentrations of ethanol (3-21%) or water for 15 days prior to breeding. Ethanol was not present during gestation. Offspring were either removed from the home cage and isolated for 3 hours or left undisturbed from postnatal days 1-21. Beginning on PND 56 offspring mice were assessed for clinically relevant behavioral disruptions in social behavior, cognitive working memory, locomotor activity, anxiety-like phenotypes, ethanol preference and binge drinking behavior. In a separate experiment, brains of Cx3cr2+/GFPxCcr2+/RFP mice from ELA or control conditions were collected every 7 days after birth for assessment of neuroinflammation and central immune cell morphology and density. RESULTS/ANTICIPATED RESULTS: Mice with a family history of ethanol exposure and ELA are predicted to exhibit behavioral changes (impaired working memory, reduced social behavior, increased anxiety-like behaviors, increased ethanol consumption) to a greater extent than mice with a family history of ethanol exposure or ELA alone. We expect markers of neuroinflammation (cytokine expression, immune cell activation) to predict the behavioral changes in these mice. DISCUSSION/SIGNIFICANCE OF IMPACT: Alcohol consumption and stressful life events are known environmental precipitants to neuroinflammation, which in turns may predispose individuals to anti-social and risky behavior. A mouse model of these early postnatal conditions will allow basic scientists to unravel the biological underpinnings of the behaviors driven by these factors.

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Blunted stress reactivity reveals vulnerability to early life adversity in young adults with a family history of alcoholism

Addiction ◽

10.1111/add.14501 ◽

2018 ◽

Vol 114 (5) ◽

pp. 798-806 ◽

Cited By ~ 3

Author(s):

William R. Lovallo ◽

Andrew J. Cohoon ◽

Ashley Acheson ◽

Kristen H. Sorocco ◽

Andrea S. Vincent

Keyword(s):

Young Adults ◽

Family History ◽

Early Life ◽

Stress Reactivity ◽

Early Life Adversity ◽

History Of

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T91. NOVEL INFLUENCE OF EARLY-LIFE ADVERSITY ACROSS FUNCTIONAL NETWORKS DURING WORKING MEMORY IN SCHIZOPHRENIA

Schizophrenia Bulletin ◽

10.1093/schbul/sbz019.371 ◽

2019 ◽

Vol 45 (Supplement_2) ◽

pp. S239-S239

Author(s):

Maria Dauvermann ◽

David Mothersill ◽

Karolina Rokita ◽

Laura Costello ◽

Jessica Holland ◽

...

Keyword(s):

Working Memory ◽

Early Life ◽

Functional Networks ◽

Early Life Adversity

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The Role of Phonological Working Memory and Environmental Factors in Lexical Development in Italian-Speaking Late Talkers: A One-Year Follow-Up Study

Journal of Speech Language and Hearing Research ◽

10.1044/2017_jslhr-l-15-0415 ◽

2017 ◽

Vol 60 (12) ◽

pp. 3462-3473 ◽

Cited By ~ 6

Author(s):

Andrea Marini ◽

Milena Ruffino ◽

Maria Enrica Sali ◽

Massimo Molteni

Keyword(s):

Working Memory ◽

Family History ◽

Home Literacy Environment ◽

Home Literacy ◽

Semantic Fluency ◽

Literacy Environment ◽

Follow Up Study ◽

Late Talkers ◽

History Of

Purpose This follow-up study assessed (a) the influence of phonological working memory (pWM), home literacy environment, and a family history of linguistic impairments in late talkers (LTs); (b) the diagnostic accuracy of a task of nonword repetition (NWR) in identifying LTs; and (c) the persistence of lexical weaknesses after 10 months. Method Two hundred ninety-three children were assessed at approximately 32 (t1) and 41 (t2) months. At t1, they were administered the Italian adaptation of the Language Development Survey, an NWR task (used to assess pWM), and questionnaires assessing home literacy environment and family history of language impairments. Thirty-three LTs were identified. The linguistic skills of the participants were evaluated at t2 by administering tasks assessing Articulation, Naming, Semantic Fluency, and Lexical Comprehension. Results At t2, LTs performed more poorly as compared with age-matched typically developing peers in articulatory and naming skills, had reduced lexical comprehension abilities, and had limited lexical knowledge. Their performance on the NWR task at t1 correlated with the extension of their vocabularies at t2 (as estimated with a Semantic Fluency task). Conclusions The Language Development Survey recently adapted to Italian is sensitive to LTs. Former LTs still have a mild lexical delay at approximately 40 months. As an indirect measure of pWM, the task of NWR is an early indicator of future lexical deficits.

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Inflammatory and Epigenetic Pathways for Perinatal Depression

Biological Research For Nursing ◽

10.1177/1099800415614892 ◽

2015 ◽

Vol 18 (3) ◽

pp. 331-343 ◽

Cited By ~ 14

Author(s):

Lindsey Garfield ◽

Herbert L. Mathews ◽

Linda Witek Janusek

Keyword(s):

Early Life ◽

Infant Health ◽

Perinatal Depression ◽

Life Experiences ◽

Perinatal Period ◽

Early Life Adversity ◽

Targeted Interventions ◽

Increased Risk ◽

History Of ◽

The Impact

Depression during the perinatal period is common and can have adverse consequences for women and their children. Yet, the biobehavioral mechanisms underlying perinatal depression are not known. Adverse early life experiences increase the risk for adult depression. One potential mechanism by which this increased risk occurs is epigenetic embedding of inflammatory pathways. The purpose of this article is to propose a conceptual model that explicates the linkage between early life adversity and the risk for maternal depression. The model posits that early life adversity embeds a proinflammatory epigenetic signature (altered DNA methylation) that predisposes vulnerable women to depression during pregnancy and the postpartum period. As proposed, women with a history of early life adversity are more likely to exhibit higher levels of proinflammatory cytokines and lower levels of oxytocin in response to the demands of pregnancy and new motherhood, both of which are associated with the risk for perinatal depression. The model is designed to guide investigations into the biobehavioral basis for perinatal depression, with emphasis upon the impact of early life adversity. Testing this model will provide a better understanding of maternal depressive risk and improve identification of vulnerable women who would benefit from targeted interventions that can reduce the impact of perinatal depression on maternal–infant health.

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Bedside clinical assessment predicts recurrence after hospitalization due to viral lower respiratory tract infection in young children

Journal of Investigative Medicine ◽

10.1136/jim-2019-001024 ◽

2019 ◽

Vol 68 (3) ◽

pp. 756-761 ◽

Cited By ~ 1

Author(s):

Maria Arroyo ◽

Kyle P Salka ◽

Geovanny F Perez ◽

Carlos E Rodriguez-Martinez ◽

Jose A Castro-Rodriguez ◽

...

Keyword(s):

Risk Factors ◽

Family History ◽

Tract Infection ◽

Young Children ◽

Early Life ◽

Lower Respiratory Tract ◽

Individual Risk ◽

Respiratory Illnesses ◽

History Of ◽

Individual Risk Factors

Infants requiring hospitalization due to a viral lower respiratory tract infection (LRTI) have a high risk of developing recurrent respiratory illnesses in early life and asthma beyond childhood. Notably, all validated clinical scales for viral LRTI have focused on predicting acute severity instead of recurrence. We present a novel clinical approach combining individual risk factors with bedside clinical parameters to predict recurrence after viral LRTI hospitalization in young children. A retrospective longitudinal cohort of young children (≤3 years) designed to define clinical predictive factors of recurrent respiratory illnesses within 12 months after hospitalization due to PCR-confirmed viral LRTI. Data collection was through electronic medical record. We included 138 children hospitalized with viral LRTI. Using automatic stepwise logistic model selection, we found that the strongest predictors of recurrence in infants hospitalized for the first time were severe prematurity (≤32 weeks’ gestational age, OR=5.19; 95% CI 1.76 to 15.32; p=0.002) and a clinical score that weighted hypoxemia, subcostal retractions and wheezing (OR=3.33; 95% CI 1.59 to 6.98; p<0.001). After the first hospitalization, the strongest predictors of subsequent episodes were wheezing (OR=5.62; 95% CI 1.03 to 30.62; p=0.04) and family history of asthma (OR=5.39; 95% CI 1.04 to 27.96; p=0.04). We found that integrating individual risk factors (eg, prematurity or family history of asthma) with bedside clinical assessment (eg, wheezing, subcostal retractions or hypoxemia) can predict the risk of recurrence after viral LRTI hospitalization in infants. This strategy may enable clinically oriented subsetting of infants with viral LRTI based on individual predictors for recurrent respiratory illnesses during early life.

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Associations of early-life exposure to famine with abdominal fat accumulation are independent of family history of diabetes and physical activity

British Journal Of Nutrition ◽

10.1017/s0007114520003414 ◽

2020 ◽

pp. 1-8

Author(s):

Xiang Hu ◽

Junping Wen ◽

Weihui Yu ◽

Lijuan Yang ◽

Wei Pan ◽

...

Keyword(s):

Physical Activity ◽

Family History ◽

Early Life ◽

Central Obesity ◽

Abdominal Fat ◽

Family History Of Diabetes ◽

Fat Accumulation ◽

Early Life Exposure ◽

History Of ◽

And Function

Abstract The present study aimed to investigate the association of early-life exposure to famine with abdominal fat accumulation and function and further evaluate the influence of first-degree family history of diabetes and physical activity on this association. The present work analysed parts of the REACTION study. A total of 3033 women were enrolled. Central obesity was defined as waist circumferences (W) ≥ 85 cm. Chinese visceral adiposity index (CVAI) was used to evaluate visceral adipose distribution and function. Partial correlation analysis showed BMI, W, glycated Hb and CVAI were associated with early-life exposure to famine (both P < 0·05). Logistic regression showed that the risks of overall overweight/obesity and central obesity in fetal, early-childhood, mid-childhood and late-childhood exposed subgroups were increased significantly (all P < 0·05). Compared with the non-exposed group, the BMI, W and CVAI of fetal, early- to late-childhood exposed subgroups were significantly increased both in those with or without first-degree family history of diabetes and in those classified as physically active or inactive, respectively (all P < 0·05). The associations of BMI, W and CVAI with early-life exposure to famine were independent of their associations with first-degree family history of diabetes (all P < 0·01) or physical activity status (all P < 0·001). Early-life exposure to famine contributed to abdominal fat accumulation and dysfunction, which was independent of the influence of genetic background and exercise habits. Physical activity could serve as a supplementary intervention for women with high risk of central obesity.

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Atypical Spatial Working Memory and Task-General Brain Activity in Adolescents with a Family History of Alcoholism

Alcoholism Clinical and Experimental Research ◽

10.1111/j.1530-0277.2012.01948.x ◽

2012 ◽

Vol 37 (3) ◽

pp. 390-398 ◽

Cited By ~ 18

Author(s):

Kristen L. Mackiewicz Seghete ◽

Anita Cservenka ◽

Megan M. Herting ◽

Bonnie J. Nagel

Keyword(s):

Working Memory ◽

Family History ◽

Spatial Working Memory ◽

Brain Activity ◽

History Of ◽

And Task

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Evidence for an Interaction Between NEDD4 and Childhood Trauma on Clinical Characters of Schizophrenia With Family History of Psychosis

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.608231 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiao-Jiao Bi ◽

Lei Hu ◽

Dong-Dong Qiao ◽

Chao Han ◽

Meng-Meng Sun ◽

...

Keyword(s):

Working Memory ◽

Social Cognition ◽

Family History ◽

Learning And Memory ◽

Childhood Trauma ◽

Visual Learning ◽

Environment Interaction ◽

Memory Score ◽

History Of ◽

Physical Neglect

Background: Neural precursor cell-expressed developmentally downregulated 4 (NEDD4) polymorphisms and childhood trauma (CT) are associated with schizophrenia. However, whether NEDD4 interacts with CT on symptoms of schizophrenia remains unknown. This study aimed to investigate the gene–environment interaction effect.Methods: We recruited 289 schizophrenia patients and 487 controls and genotyped rs2303579, rs3088077, rs7162435, rs11550869, and rs62043855 in their NEDD4 gene.Results: We found significant differences in the rs2303579 and rs3088077 between the two groups. Patients with the rs2303579 CC genotype had higher scores compared with other genotype (P = 0.026) in the test of positive schizophrenia syndrome scores, whereas patients with the rs3088077 TT (P = 0.037) and rs7162435 CC genotypes (P = 0.009) had higher scores compared with the other genotypes in the test of excitement factor. Patients with a family history of psychosis (FH+) reported higher negative scores (P = 0.012) than those without. Patients exposed to physical abuse (PA) reported a lower language learning and memory score (P = 0.017) and working memory score (P = 0.047) than those not. Patients exposed to sexual abuse (SA) reported a lower reasoning and problem-solving skills score (P = 0.025); those exposed to emotional neglect (EN) reported a lower social cognition score (P = 0.044); and those exposed to physical neglect reported a lower social cognition score (P = 0.036) but higher visual learning and memory score (P = 0.032). Rs3088077 could interact with EN to increase risk for schizophrenia. Optimal model rs62043855 × EA, rs3088077 × rs7162435 × rs11550869 × SA × EN and rs2303579 × rs7162435 × rs11550869 × rs62043855 × EA × PA could explain positive symptom, excitement symptom and working memory, respectively, in FH+ group.Conclusion: The study highlighted that the combined interaction of NEDD4 and CT may be associated with symptoms of schizophrenia especially for those with FH+.

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Phenotypic characterisation of early COPD: a prospective case–control study

ERJ Open Research ◽

10.1183/23120541.00047-2020 ◽

2020 ◽

Vol 6 (4) ◽

pp. 00047-2020

Author(s):

Borja G. Cosío ◽

Sergi Pascual-Guardia ◽

Alicia Borras-Santos ◽

Germán Peces-Barba ◽

Salud Santos ◽

...

Keyword(s):

Family History ◽

Early Life ◽

Respiratory Diseases ◽

Case Control Study ◽

Case Control ◽

Airflow Limitation ◽

Chronic Obstructive ◽

Phenotypic Characterisation ◽

History Of ◽

Control Study

The phenotypic characteristics of chronic obstructive pulmonary disease (COPD) in individuals younger than 50 years of age (early COPD) are not well defined. This prospective, multicentre, case–control study sought to describe these characteristics and compare them with those of smokers (≥10 pack-years) of similar age with normal spirometry (controls).We studied 92 cases (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7) and 197 controls. Results were contrasted with participants with similar inclusion criteria recruited into the ECLIPSE and COPDGene cohorts.Cases had moderate airflow limitation (FEV1 71.3±20.8%) but were often symptomatic, used healthcare resources frequently, had air trapping (residual volume 150.6±55.5% ref.), had reduced diffusing capacity (84.2±20.7% ref.) and had frequent evidence of computed tomography (CT) emphysema (61%). Of note, less than half of cases (46%) had been previously diagnosed with COPD. Interestingly, they also often reported a family history of respiratory diseases and had been hospitalised because of respiratory problems before the age of 5 years more frequently than controls (12% versus 3%, p=0.009). By and large, these observations were reproduced when available in the ECLIPSE and COPDGene cohorts.These results show that early COPD is associated with substantial health impact and significant structural and functional abnormalities, albeit it is often not diagnosed (hence, treated). The fact that a sizeable proportion of patients with early COPD report a family history of respiratory diseases and/or early-life events (including hospitalisations before the age of 5 years) renders further support to the possibility of early-life origin of COPD.

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