Sex-specific Impact of Prenatal Opioids on Brain Reward Signaling and Neonatal Feeding Regulation

产前阿片类药物对大脑奖赏信号和新生儿喂养调节的性别特异性影响

• 批准号: 10506345
• 负责人: Elizabeth Yen
• 金额: $ 19.12万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506345
• 关键词: 1 year old; Acute; Address; Adverse effects; Age; Behavior; Behavioral; Binding; Biological; Biological Markers; Birth; Body mass index; Brain; CCL2 gene; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Child; Clinical; DRD2 gene; Data; Development; Diagnosis; Dopamine; Dopamine Receptor; Energy Intake; Female; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; Head circumference; Health; High Density Lipoprotein Cholesterol; Hospitalization; Hospitals; Hyperphagia; IL6 gene; Immune; Infant; Inflammation; Inflammatory; Interdisciplinary Study; Knowledge; Laboratories; Length; Life; Lipids; Measures; Medical; Mentored Clinical Scientist Development Program; Metabolic; Metabolic Diseases; Microglia; Molecular; Molecular Analysis; Monitor; Multicenter Trials; Nature; Neonatal; Neonatal Abstinence Syndrome; Nutritional; Opiate Addiction; Opioid; Outcome; Pathway interactions; Pharmacotherapy; Phenotype; Pilot Projects; Population; Prevention strategy; Regulation; Research; Rewards; Risk; Saliva; Salivary; Serum; Sex Distribution; Signal Transduction; TLR4 gene; Techniques; Testing; Translating; Up-Regulation; Visit; Weight; Withdrawal; Women' s Health; animal data; cardiometabolic risk; career; cost; diagnostic assay; differential expression; drug withdrawal; excessive weight gain; feeding; fetal opioid exposure; immunoregulation; improved; inflammatory modulation; low density lipoprotein triglyceride; male; neonatal brain; neonate; neurogenesis; novel diagnostics; opioid exposure; personalized care; personalized medicine; personalized strategies; precision medicine; preclinical study; prenatal; public health priorities; recruit; risk stratification; saliva sample; salivary gene; sex; sexual dimorphism; tool; transcriptomics; treatment strategy

Project Summary/Abstract: Although Neonatal Abstinence Syndrome (NAS) is an urgent public health priority, the diagnosis and management of NAS remains challenging. This is primarily due to the multifactorial nature of NAS and the highly subjective measures to assess this condition. Males and females with NAS have distinct risk profiles, yet within the current paradigm they are managed uniformly. The limited understanding of long-term outcomes further compounds the problem and predisposes this population to a myriad of health issues. To address these knowledge gaps, the current proposal expands upon the molecular and behavioral data from our K12-funded pilot study to better understand the impact of prenatal opioid exposure. An early sign of withdrawal in opioid- exposed neonates is difficulty feeding followed by hyperphagia, which often precedes severe NAS and the need for pharmacotherapy. Using saliva collected immediately after birth, we showed higher expression of a key reward gene (DRD2) in opioid-exposed males compared to females. The expression of DRD2 also correlated with the caloric intake in opioid-exposed males who later developed severe NAS and required pharmacotherapy. These transcriptomic-behavioral data indicate that prenatal opioid exposure dysregulates brain reward signaling in a sex-specific manner, resulting in hyperphagia as a reward-seeking behavior that offsets the acute loss of opioids. Furthermore, opioid-exposed neonates have heightened expression of inflammatory genes (IL6, MCP1) that correlate with the expression of DRD2, particularly in females. Expanding on these preliminary results, the current proposal will examine if prenatal opioids dysregulate brain reward signaling and modulate pro-inflammatory pathways with increased sex-specific risks for hyperphagia and associated long-term cardiometabolic disorders. Our overarching goal is to understand changes in sex-specific reward and inflammatory gene expression in opioid-exposed neonates throughout the first year of life. The hypothesis will be tested in two aims: 1) Identify sex-specific effects of prenatal opioids on reward signaling and inflammation, 2) Evaluate effects of prenatal opioids on risk for subsequent cardiometabolic disorders. We will collect serial saliva samples from 56 opioid-exposed and 56 sex- and age-matched non-exposed neonates during the initial hospitalization and then in a subset of infants post hospital discharge up to 1 year of age to evaluate the expression of reward and inflammation genes. Early cardiometabolic risk will be assessed using serum lipid panels at 1 year of age, along with growth and nutritional data. Results will be analyzed by sex. The impact of this proposed project lies in the potential to advance the field with a more comprehensive understanding of the sex-specific impact of prenatal opioid exposure on the developing brain through non- invasive molecular analyses, enabling personalized medicine and longitudinal health monitoring.

项目概要/摘要： 虽然新生儿禁欲综合征（NAS）是一个紧迫的公共卫生优先事项，诊断和 NAS的管理仍然具有挑战性。这主要是由于NAS的多因素性质， 非常主观的方法来评估这种情况。患有NAS的男性和女性有不同的风险特征，然而， 在目前的范例中，它们是统一管理的。对长期结果的理解有限 这进一步加剧了问题，并使这一人群容易出现各种健康问题。解决这些 知识差距，目前的建议扩大了我们的K12资助的分子和行为数据， 试点研究，以更好地了解产前阿片类药物暴露的影响。阿片类药物戒断的早期迹象- 暴露的新生儿是喂养困难，其次是摄食过度，这往往是严重的NAS和 需要药物治疗。使用出生后立即收集的唾液，我们发现a 关键奖励基因（DRD 2）在阿片类药物暴露的男性相比，女性。DRD 2的表达也 与阿片类药物暴露男性的热量摄入相关，这些男性后来发展为严重的NAS， 药物治疗.这些转录组行为数据表明，产前阿片类药物暴露失调， 大脑奖励信号以性别特异性的方式，导致暴食作为一种寻求奖励的行为， 抵消阿片类药物的急性流失。此外，暴露于阿片类药物的新生儿具有高表达的 炎症基因（IL 6，MCP 1）与DRD 2的表达相关，特别是在女性中。扩大 根据这些初步结果，目前的建议将研究产前阿片类药物是否会使大脑奖赏功能失调 信号传导和调节促炎途径，增加性别特异性摄食过多的风险， 相关的长期心脏代谢疾病。我们的首要目标是了解性别特异性 阿片类药物暴露的新生儿在生命的第一年中的奖励和炎症基因表达。的 我们将从两个方面来检验这一假设：1）确定产前阿片类药物对奖赏信号的性别特异性影响 和炎症，2）评估产前阿片类药物对随后心脏代谢疾病风险的影响。我们 将从56名阿片类药物暴露的新生儿和56名性别和年龄匹配的非暴露新生儿中收集一系列唾液样本 在最初住院期间，然后在出院后1岁以下的婴儿亚组中， 评估奖赏和炎症基因的表达。将使用以下指标评估早期心脏代谢风险： 1岁时的血脂检查，沿着生长和营养数据。将按性别分析结果。的 这一拟议项目的影响在于有可能以更全面的方式推进该领域 了解产前阿片类药物暴露对发育中大脑的性别特异性影响， 侵入性分子分析，实现个性化医疗和纵向健康监测。