Lasting Neurological Effects of Perinatal Opioids

围产期阿片类药物的持久神经系统影响

基本信息

批准号：
10708784
负责人：
Seth Abrams Ament
金额：
$ 71.86万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
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/10708784
关键词：
Adolescence Adolescent Adult Affect Age Animals Anxiety Behavior Behavioral Brain Candidate Disease Gene 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 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 Synapses Testing Time Uterus Vertebral column Weaning Woman addiction anxiety-like behavior behavioral outcome cell type child bearing density emotional behavior epigenome editing fentanyl exposure 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 single nucleus RNA-sequencing tool transcriptome virtual

项目摘要

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.

项目概要近年来，阿片类药物的使用、依赖和成瘾已达到流行病的程度，导致巨大的财政和社会健康负担。超过 20% 的孕妇参加了医疗补助计划处方阿片类药物；近年来，孕妇自行怀孕的比例增加了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生率增加了 >400% 2000 年至 2012 年间。这些新生儿经常接受阿片类药物治疗，进一步增加了他们接触阿片类药物的机会这些物质。子宫内接触阿片类药物的婴儿神经发育障碍的风险增加问题或不良的感觉、认知、精神运动和行为结果，持续的负面结果贯穿整个童年，甚至可能贯穿一生。目前，几乎没有关于神经回路的信息生命早期接触阿片类药物时发生的适应。我们开发了一种小鼠模型，其中动物在相应的时间内接受芬太尼治疗人类妊娠。这些小鼠表现出与性别相关的情绪行为的持久改变。暴露于围产期芬太尼的青春期男性表现出增强的焦虑样行为，而青少年男性则表现出增强的焦虑样行为。女性表现出动力减弱。我们的研究将调查内侧前额皮质 (mPFC) 的变化已知伏隔核（NAc）电路参与这些情绪行为。我们将调查围产期接触芬太尼的 mPFC 和 NAc 细胞亚型的细胞、可塑性和分子适应断奶后早期直至青春期的小鼠。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干扰中的作用接触。我们的研究将首次揭示细胞、回路和分子适应发生在围产期接触芬太尼并确定介导长期持续神经生物学异常的回路围产期阿片类药物暴露时发生的情况。