Impact of prenatal opioid exposure on long-range brain circuit connectivity and behavior

产前阿片类药物暴露对长程脑回路连接和行为的影响

• 批准号: 10163154
• 负责人: Courtney A Miller
• 金额: $ 23.13万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163154
• 关键词: Address; Adult; Aggressive behavior; American; Amygdaloid structure; Animals; Area; Attention deficit hyperactivity disorder; Basic Science; Behavior; Behavioral; Brain; Child; Corpus striatum structure; Data; Development; Diagnosis; Drug Prescriptions; Drug usage; Environmental Risk Factor; Equilibrium; Exposure to; FDA approved; Female; Functional disorder; Future; Goals; Health; Hour; Human; Hyperactivity; Impulse Control Disorders; Impulsivity; Individual; Interneurons; Intervention; Investigation; Link; Maps; Medial; Mediating; Morphine; Mothers; Mus; Neonatal Abstinence Syndrome; Neurons; Opioid; Opioid replacement therapy; Oxycodone; Pharmaceutical Preparations; Population; Prefrontal Cortex; Pregnancy; Pregnant Women; Presynaptic Terminals; Provider; Public Health; Rabies virus; Reporting; Research; Risk; Safety; Silicon; Source; Specificity; Structure; Substance Use Disorder; Synapses; Testing; Translating; United States; Withdrawal; Withdrawal Symptom; Woman; aged; base; behavior change; behavior influence; behavior test; brain circuitry; cell type; density; design; excitatory neuron; externalizing behavior; fetal opioid exposure; follow up assessment; illicit opioid; in utero; inhibitory neuron; innovation; male; maternal drug abuse; maternal opioid abuse; maternal opioid use; member; neural circuit; neurodevelopment; novel; offspring; opioid epidemic; opioid withdrawal; optogenetics; postnatal; prenatal; prenatal exposure; prescription opioid; prescription pain reliever; response; sex; social

PROJECT SUMMARY In 2010, an estimated 6 million individuals in the United States abused prescription pain relievers, triggering the current opioid epidemic. Further, an estimated 10-20% of women in the U.S. receive a prescription each year for an opioid, such as oxycodone (OXY), during pregnancy. Collectively, this has resulted in a five-fold increase in prescription drug use among expectant mothers over the last decade, as well as one baby born every 15 minutes in opioid withdrawal, termed neonatal abstinence syndrome (NAS). Despite a rapidly growing population of individuals born with NAS, basic research efforts on the effects of prenatal exposure to opioids on brain development, as well as the lifelong behavior impacts, are poorly defined. Better identifying the effects of prenatal OXY exposure on the development of neural circuits and behavior will allow for future investigations into the underlying mechanisms. The long-term goal is development of novel and innovative strategies to mitigate the lifelong impact and the current focus on OXY specifically is based on the perceived safety due to its FDA-approved status. A broad battery of behavioral tests performed in adult mice exposed to OXY in utero indicates this developmental insult produces behavioral deficits related to impulse control and response to opioids, with sex-specific effects, that are consistent with the limited data available on children exposed to opioids in utero. The medial prefrontal cortex (mPFC) is a core member of the neural circuitry governing these behaviors, often with a link to hypofrontality driven by the striatum and amygdala. Thus, the overarching hypothesis is that prenatal OXY alters the development of long-range inputs to the prefrontal cortex, resulting in behavioral dysregulation. To begin addressing this, unbiased monosynaptic circuit tracing was performed in GAD2-Cre mice to create whole brain maps in both sexes of all direct, long-range inputs to mPFC inhibitory neurons. Consistent with the possibility of hypofrontality, this analysis revealed a marked and selective elevation in structural connectivity to mPFC interneurons (INs) from the basolateral amygdala (BLA) in females exposed to prenatal OXY. This led to the working hypothesis to be addressed here, that prenatal OXY exposure produces BLA-mediated inhibition of the mPFC, resulting in behavioral dysregulation. Completion of the two proposed Aims is expected to produce the following: (1) Unbiased whole brain maps of monosynaptic long-range inputs to excitatory and inhibitory (PV, SST and VIP+) mPFC neurons in the context of prenatal OXY exposure, to determine the source and balance of these inputs. (2) Determination of the BLA’s influence over the mPFC following prenatal OXY exposure, in terms of functional connectivity, using high density silicon probes with optogenetic stimulation and behavior, using chemogenetics. The proposed research is expected to provide a framework for future mechanistic studies aimed at further defining the functional subcircuits, how to best mitigate the consequences of maternal opioid use and assessing the impact of current NAS interventions employed in NICUs, which consists of postnatal opioid replacement therapies.

项目概要 2010 年，美国估计有 600 万人滥用处方止痛药，引发了 此外，据估计，美国有 10-20% 的女性服用阿片类药物。 怀孕期间使用阿片类药物（例如羟考酮 (OXY)）的一年，总共导致了五倍的死亡。 过去十年来，准妈妈和一名婴儿出生时处方药的使用量有所增加 每 15 分钟发生一次阿片类药物戒断，称为新生儿戒断综合征 (NAS)，尽管这种情况增长迅速。 出生时患有 NAS 的人群，关于产前接触阿片类药物对胎儿的影响的基础研究工作 大脑发育以及终生行为影响尚不清楚。 产前氧气暴露对神经回路和行为发育的影响将为未来的研究提供依据 长期目标是制定新颖和创新的战略 减轻终生影响，目前对 OXY 的关注具体是基于由于以下原因而感知到的安全性： 其已获得 FDA 批准，对子宫内暴露于 OXY 的成年小鼠进行了一系列广泛的行为测试。 表明这种发育损伤会产生与冲动控制和反应相关的行为缺陷 阿片类药物具有特定性别的影响，这与接触阿片类药物的儿童的有限数据一致 子宫内的阿片类药物（mPFC）是控制这些药物的神经回路的核心成员。 行为，通常与纹状体和杏仁核驱动的额叶下垂有关。 假设是产前 OXY 改变了前额皮质长程输入的发展，从而导致 为了开始解决这个问题，进行了无偏单突触回路追踪。 GAD2-Cre 小鼠将创建两性所有直接、远程 mPFC 抑制输入的全脑图 与额叶功能减退的可能性一致，该分析揭示了显着且选择性的神经元。 女性基底外侧杏仁核 (BLA) 与 mPFC 中间神经元 (IN) 的结构连接性升高 暴露于产前 OXY 这导致了这里要讨论的工作假设，即产前 OXY。 暴露会产生 BLA 介导的 mPFC 抑制，导致行为失调。 这两个拟议的目标预计将产生以下成果：（1）单突触的无偏全脑图 产前对兴奋性和抑制性（PV、SST 和 VIP+）mPFC 神经元的远程输入 (2) BLA影响力的判定 在产前 OXY 暴露后的 mPFC 上，在功能连接方面，使用高密度硅 拟议的研究预计将利用化学遗传学来进行光遗传学刺激和行为的探针。 为未来的机制研究提供一个框架，旨在进一步定义功能子电路，如何 最好地减轻母亲使用阿片类药物的后果并评估当前 NAS 干预措施的影响 在 NICU 中使用，其中包括产后阿片类药物替代疗法。