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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要 2010年，美国估计有600万人滥用处方止痛药，触发当前的阿片类药物流行。此外，估计美国的妇女中有10-20％的妇女分别获得处方怀孕期间阿片类药物（例如羟考酮（氧））的一年。总的来说，这导致了五倍在过去的十年中，准妈妈的处方药使用增加，还有一个婴儿出生每15分钟的阿片类药物戒断，称为新生儿节制综合征（NAS）。尽管迅速增长患有NAS的个体的人口，基础研究对产前暴露阿片类药物的影响大脑发育以及终身行为影响的定义很差。更好地识别关于神经回路和行为的发展，产前氧气暴露将允许将来进行研究进入基本机制。长期目标是发展新颖和创新的策略减轻终身影响和当前对Oxy的关注是基于由于其FDA批准的状态。在子宫内暴露于Oxy的成年小鼠中进行的大量行为测试表明这种发育侮辱会产生与冲动控制和响应有关的行为定义与特定于性别作用的绿o虫类药物与接触的儿童可获得的有限数据一致子宫里阿片类药物。媒体前额叶皮层（MPFC）是控制这些的神经电路的核心成员行为，通常与纹状体和杏仁核的性驱动相关。那是总体假设是，产前氧改变了前额叶皮层的远程输入的发展，从而改变在行为失调中。为了开始解决这个问题，在 GAD2-CRE小鼠在所有直接的，长期输入的男性中创建全脑图神经元。与低核心的可能性一致，该分析揭示了一个明显的选择性雌性的基本杏仁核（BLA）的结构连通性与MPFC中间神经元（INS）的高程暴露于产前氧气。这导致了这里的工作假设，该假设是产前氧暴露会产生BLA介导的MPFC抑制作用，从而导致行为失调。完成提出的两个目标有望产生以下内容：（1）单突触的无偏整个大脑图兴奋性和抑制性（PV，SST和VIP+）MPFC神经元的远程输入氧气暴露，以确定这些输入的来源和平衡。（2）确定BLA的影响在产前氧气暴露后的MPFC上，就功能连通性而言，使用高密度硅使用化学遗传学的光遗传刺激和行为问题。拟议的研究有望为未来的机械研究提供框架，旨在进一步定义功能子电路，以及如何最好地减轻母体阿片类药物使用的后果，并评估当前NAS干预措施的影响在NICUS中使用，由产后阿片类药物替代疗法组成。