Maternal adversity, inflammation, and neurodevelopment: How intergenerational processes perpetuate disadvantage in a low-resource setting

母亲的逆境、炎症和神经发育：代际过程如何在资源匮乏的环境中延续劣势

• 批准号: 10369780
• 负责人: Cristiane S. Duarte
• 金额: $ 5.25万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369780
• 关键词: Attention deficit hyperactivity disorder; Brain; Brazil; C-reactive protein; Child; Development; Disadvantaged; Disease; Enrollment; Exposure to; Functional disorder; Funding; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Risk; Grant; Hair; Home environment; Hydrocortisone; Impulsivity; Infant; Inflammation; Inflammatory; Interleukin-6; Knowledge; Life; Magnetic Resonance Imaging; Measures; Modeling; Moods; Odds Ratio; Pathway interactions; Patient Self-Report; Perinatal; Pregnancy; Pregnant Women; Prevention; Process; Proxy; Recording of previous events; Resources; Risk; Role; Sexually Transmitted Diseases; Site; Substance Use Disorder; TNF gene; Testing; Third Pregnancy Trimester; Time; Universities; Work; adverse childhood events; base; brain behavior; childhood adversity; cognitive control; fetal; genome wide association study; high risk sexual behavior; hypothalamic-pituitary-adrenal axis; inflammatory marker; intergenerational; neural circuit; neurodevelopment; neurodevelopmental effect; offspring; perceived stress; poor communities; pre-clinical research; prenatal

SUMMARY OR ABSTRACT OF THE FUNDED GRANT OR PROJECT Over 50% of US children are exposed to at least one Adverse Childhood Experience (ACE); in Brazil — our site for the proposed work — this rate is even higher. Children with greater ACEs are at significantly in- creased risk for ADHD/externalizing disorders [Odds ratio (OR) 1.5-6.8], as well as substance use disorders (OR2.3 - 7.7), risky sexual behaviors and sexually transmitted diseases (OR 1.7-8.1). Moreover, ACEs in one generation have been shown to confer risk for psychiatric dysfunction onto the next. However, the mechanisms underlying ACE-related intergenerational effects are unclear, significantly limiting prevention efforts. This project will study maternal ACEs in relation to child brain-behavior development focusing on cogni- tive control and related neural circuits implicated in externalizing and impulsivity-related conditions. We will test the role of maternal prenatal inflammation as a key understudied pathway for these intergenerational effects. Infants exposed to high maternal interleukin-6 (IL-6) and C-reactive protein (CRP) show atypical connectivity within prefrontal temporoparietal, and insular cortices related to cognitive control. Preclinical research suggests that maternal ACEs and related inflammation confer these neurodevelopment effects by altering expression of pro-inflammatory genes (e.g. II-6, II-1β, TNF-α). Our proposal is a collaborative effort based on a fruitful partnership between CUIMC/NYSPI and the Federal University of São Paulo (UNIFESP) focused on impoverished communities highly exposed to ACEs with elevated rates of externalizing and impulsivity-related disorders. In our recently completed pilot infant MRI study in São Paulo (n=44; 2-4 week old infants) we found associations between maternal ACEs, increased prenatal maternal inflammation (CRP), and diminished functional connectivity within cognitive control sub- strates in infants. Here, we aim to build on these findings and test a mechanistic model hypothesizing that (i) ACEs give rise to increased maternal inflammatory markers and (ii) during gestation, maternal inflammation alters placental gene regulation and, consequently, infant brain development. To identify neurodevelopment effects specific to prenatal inflammation, we will measure and adjust for other perinatal influences on fetal/in- fant neurodevelopment including maternal mood, perceived stress (self-report), third trimester maternal hypo- thalamic-pituitary-adrenal axis activity (hair cortisol levels), home environment, and offspring genetic liability (poly-genetic risk from GWAS-ADHD, a proxy for diminished cognitive control). We will enroll 580 pregnant women [n=290 with low ACEs (0 or 1); n=290 with high ACEs (2 or more)] and follow their offspring for 24 months. Substantiating intergenerational effects of ACEs will dramatically impact current knowledge of the eti- ologies of impulsivity and disorders related to poor cognitive control, broaden the time frame for curtailing risk- inducing factors, and identify new avenues for prevention — especially relevant to low-resourced settings.

基金资助或项目的摘要或摘要