Neurodevelopmental impact of prenatal exposure to prescription pain medication

描述(申请人提供)：2010年，美国估计有600万人滥用处方止痛药。这导致在过去十年中，孕妇滥用处方药的人数增加了五倍，每小时就有超过一个新生儿对羟考酮等处方药上瘾。这些婴儿一出生就会患上新生儿禁欲综合症(NAS)。尽管出生时患有NAS的人数迅速增加，但关于产前接触处方止痛药的影响的基础研究工作有限。确定孕期羟考酮暴露对大脑回路发育的影响，将有助于未来对潜在机制的研究。长期目标是开发新的和创新的战略，以减轻终身影响。成年小鼠的行为数据表明，出生前 接触羟考酮会导致一种类似焦虑的表型，这种表型被解释为冲动和冒险。前额叶皮质，特别是前扣带回和眶前叶皮质，杏仁核和纹状体是与冲动控制障碍有关的神经回路的核心成员，包括ADHD，这是产前接触阿片类药物的儿童的常见诊断。因此，我们的中心假设是，产前接触羟考酮会改变参与情绪行为调节的远程和局部神经回路的发育。这个项目的目标是确定这种神经发育障碍对远程和局部皮质连接的影响。这项提案详细介绍了一种创新的方法，通过在啮齿动物模型中进行单突触、逆行电路追踪，将行为分析与输入前额叶皮质和杏仁核的全脑图相结合。初步数据表明，这些方法可以用来揭示行为缺陷小鼠连接能力的细微变化。在识别出因产前羟考酮暴露而改变的特定投射(S)后，该回路将通过识别参与大脑混乱的细胞类型而得到更充分的表征。这将提供实质性的功能见解，将在未来的项目中进一步研究。总体而言，这一项目有望完成。 得出几个关键发现：(1)旨在减轻产前羟考酮暴露的神经发育后果的未来机械学研究的框架。(2)通过产前接触处方止痛药而形成的关键结构和连接性的地图， 对鸦片类药物有更广泛的适用性。(3)由于使用了高度敏感的追踪方法，在野生动物中发现以前未知的大脑连接的可能性。

DESCRIPTION (provided by applicant): In 2010, an estimated 6 million individuals in the United States abused prescription pain relievers. This has led to a five-fold increase in prescription drug abuse among expectant mothers over the last decade, giving rise to more than one baby born every hour addicted to prescription pain medications, such as oxycodone. Upon birth, these babies suffer from neonatal abstinence syndrome (NAS). Despite a rapidly growing population of individuals born with NAS, basic research efforts on the effects of prenatal exposure to prescription pain medication are limited. Identifying the effects of prenatal oxycodone exposure on the development of brain circuits 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. Behavioral data from adult mice indicates that prenatal exposure to oxycodone results in an anxiolytic-like phenotype that is interpreted as impulsivity and risk-taking. The prefrontal cortex, particularly the anterior cingulate and orbitofrontal cortices, amygdala and striatum are core members of the neural circuit implicated in Impulse Control Disorders, including ADHD, a common diag- nosis in children exposed to opiates prenatally. Thus, our central hypothesis is that prenatal exposure to oxycodone alters the development of both long-range and local neural circuitry involved in the regulation of emotional behaviors. The goal of this project is to determine the impact of this neurodevelopmental insult on long-range and local cortical connectivity. This proposal details an innovative approach that combines behavioral analyses with whole brain mapping of inputs to the prefrontal cortex and amygdala through monosynaptic, retrograde circuit tracing in a rodent model. Preliminary data demonstrates that these methods can be used to uncover subtle alterations in connectivity in mice with behavioral deficits. Upon identification of specific projection(s) that are changed by prenatal oxycodone exposure, the circuit will be more fully characterized by identifying the cell types involved in the brain's disorganization. This will provide substantive functional in- sight that will be further studied in future projects. As a whole, completion of this project is expected to result in several key findings: (1) a framework for future mechanistic studies aimed at mitigating the neurodevelopmental consequences of prenatal oxycodone exposure. (2) A map of critical structures and connectivity shaped by prenatal exposure to prescription pain relievers, with broader applicability to the opiate class of drugs. (3) The potential for discovery of previously unknown brain connectivity in wildtype animals due to the highly sensitive tracing methodology being used.