The impact of early life opioid exposure on the molecular and functional trajectories of septal cell types

项目摘要 近年来，孕妇使用阿片类药物的情况有所增加，特别是在美国滥用芬太尼。 阿片类药物会增加流产和死产的风险，并可能导致新生儿阿片类药物戒断综合征 (现在)在婴儿中，导致儿童和成年人的认知和行为风险。然而，大脑的神经基础 这些赤字是不被理解的。动物模型表明，产前造成的行为和认知缺陷 阿片类药物暴露是由持续的阿片类药物暴露直接造成的，但其细胞和分子基础 赤字在很大程度上是未知的。隔复合体在成瘾、寻求毒品和应激中起着关键作用。 相关行为，但尚不清楚特定的隔神经细胞类型如何参与阿片类药物诱导 神经适应。神经发育是否是药物引起的变化的敏感期也是未知的。 成为永久性的，或阿片类药物暴露和成瘾诱导的细胞类型和分子程序 在发育中的大脑和成年大脑中处于不同状态。使用可扩展的互补细胞和分子方法 研究将描述隔区复合体中神经细胞类型的发育轨迹和适应 在小鼠的早期生命模型中，阿片类药物的暴露和戒断解决了这些知识上的差距。我们的研究 将提供发生在细胞、电路和分子适应的全面目录 芬太尼暴露后出现间隔复合体，并确定介导回路的关键间隔细胞类型 以及早期生活中接触阿片类药物时发生的行为适应。

Project Summary The use of opioids by pregnant women has increased in recent years, especially the abuse of fentanyl in the US. Opioids increase the risk of pregnancy loss and stillbirth and can cause neonatal opioid withdrawal syndrome (NOWS) in infants, leading to cognitive and behavioral risks in children and adults. However, the neural basis of these deficits is not understood. Animal models suggest that behavioral and cognitive deficits from prenatal opioid exposure are directly caused by persistent opioid exposure, but the cellular and molecular basis of these deficits are largely unknown. The septal complex plays a critical role in addiction, drug-seeking, and stress related behaviors, but it is unclear how specific septal neural cell types contribute to opioid-induced neuroadaptations. It is also unknown if neurodevelopment is a sensitive period where drug-induced changes can become permanent or what cell types and molecular programs are induced by opioid exposure and addictive states in the developing and adult brain. Using scalable complementary cellular and molecular approaches our study will characterize the developmental trajectories and adaptations of neural cell types in the septal complex in a mouse model of early life opioid exposure and withdrawal to address these gaps in knowledge. Our studies will provide a comprehensive catalogue of the cellular, circuit and molecular adaptations that occur in the developing septal complex after fentanyl exposure and determine the key septal cell types that mediate circuit and behavioral adaptations that occur with early life opioid exposure.