Lasting Neurological Effects of Perinatal Opioids

围产期阿片类药物的持久神经系统影响

• 批准号: 10462821
• 负责人: Seth Abrams Ament
• 金额: $ 73.32万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462821
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Animals; Anxiety; Behavior; Behavioral; Brain; Candidate Disease Gene; Cell Nucleus; Cells; Childhood; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Data; Dependence; Diagnosis; Dopamine Receptor; Electrophysiology (science); Emotional; Enrollment; Epidemic; Exposure to; Female Adolescents; Fentanyl; Functional disorder; Gene Expression; Genes; Goals; Health; Human; Immunohistochemistry; Impairment; Incidence; Infant; Lead; Life; Male Adolescents; Medial; Mediating; Medicaid; Mental disorders; Messenger RNA; Molecular; Molecular Abnormality; Mothers; Motivation; Mus; Neurobiology; Neurodevelopmental Problem; Neurologic Effect; Neurons; Newborn Infant; Nucleus Accumbens; Opioid; Outcome; Patient Self-Report; Perinatal; Perinatal Exposure; Physiological; Population; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevalence; Prevention; Process; Property; Regulation; Risk; Role; Sensory; Small Nuclear RNA; Synapses; Testing; Time; Uterus; Vertebral column; Weaning; Woman; addiction; anxiety-like behavior; behavioral outcome; cell type; child bearing; density; emotional behavior; epigenome editing; mouse model; nano-string; nervous system disorder; neural circuit; neurobiological mechanism; offspring; opioid abuse; opioid exposure; opioid misuse; opioid use; prescription opioid; reward circuitry; sex; tool; transcriptome; transcriptome sequencing; virtual

Project Summary Opioid use, dependence, and addiction have increased to epidemic proportions in recent years, leading to substantial financial and societal health burdens. More than 20% of pregnant women enrolled in Medicaid are prescribed opioids; In recent years there was a 14-fold increase in the proportion of pregnant women self- reporting opioid abuse. As a result, the incidence of infants born to opioid-using mothers has increased >400% between 2000 and 2012. These newborns are often treated with opioids, further increasing their exposure to these substances. Infants with intrauterine exposure to opioids have an increased risk for neurodevelopmental problems or adverse sensory, cognitive, psychomotor, and behavioral outcomes, negative outcomes that last through childhood, and likely throughout life. Currently, there is virtually no information regarding neural-circuit adaptations occurring in with opioid exposure during early life. We developed a mouse model in which animals are treated with fentanyl during a period corresponding to human gestation. These mice display lasting alterations in emotional behaviors that are specific to sex. Adolescent males exposed to perinatal fentanyl show enhanced anxiety-like behavior, while adolescent females show reduced motivation. Our studies will investigate alterations in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) circuitry known to be involved in these emotional behaviors. We will investigate cellular, plasticity, and molecular adaptations in mPFC and NAc cell subtypes in perinatal fentanyl exposed mice at early post weaning until adolescence. We will target identified molecular adaptations in distinct cell subtypes to determine their role in circuit and emotional behavioral disruptions occurring with perinatal fentanyl exposure. Our studies will, for the first time, uncover cellular, circuit, and molecular adaptations occurring after perinatal exposure to fentanyl and determine the circuitry mediating the long lasting neurobiological anomalies that occur with perinatal opioid exposure.

项目摘要 近年来，阿片类药物的使用、依赖和成瘾已增加到流行病的程度， 沉重的财政和社会健康负担。超过20%参加医疗补助的孕妇是 处方阿片类药物;近年来，孕妇自我治疗的比例增加了14倍， 报告阿片类药物滥用因此，使用阿片类药物的母亲所生婴儿的发病率增加了>400% 在2000年到2012年之间。这些新生儿经常接受阿片类药物治疗，进一步增加了他们对阿片类药物的接触。 这些物质。宫内暴露于阿片类药物的婴儿神经发育风险增加 问题或不良的感觉，认知，心理和行为结果，持续的负面结果， 整个童年，甚至一生。目前，几乎没有关于神经回路的信息 适应发生在生命早期的阿片类药物暴露。 我们开发了一种小鼠模型，其中动物在对应于以下时间段内用芬太尼治疗： 人类妊娠这些老鼠表现出持久的情感行为变化，这是特定的性别。 暴露于围产期芬太尼的青少年男性表现出增强的焦虑样行为，而青少年 女性的积极性降低。我们的研究将探讨内侧前额叶皮层（mPFC）的变化 以及已知参与这些情绪行为的神经核（NAc）回路。我们将调查 围产期芬太尼暴露者mPFC和NAc细胞亚型的细胞、可塑性和分子适应 小鼠在断奶后早期直至青春期。我们将针对不同细胞中已识别的分子适应性， 亚型，以确定其在围产期芬太尼发生的回路和情绪行为中断中的作用 exposure.我们的研究将首次揭示细胞，电路和分子适应后发生的变化。 围产期暴露于芬太尼，并确定介导长期神经生物学异常的回路 这是由于围产期阿片类药物暴露引起的。