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

生命早期阿片类药物暴露对隔膜细胞类型分子和功能轨迹的影响

基本信息

批准号：
10775154
负责人：
COREY C HARWELL
金额：
$ 79.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10775154
关键词：
Address Adult Affect Animal Model Atlases Aversive Stimulus Behavior Behavioral Brain Calcium Catalogs Cell Nucleus Cells Child Cognitive Cognitive deficits Complex Data Desire for food Development Electrophysiology (science)Embryo Exposure to Genetic Transcription Image Infant Knowledge Lateral Life Link Measures Mediating Molecular Mus Neonatal Abstinence Syndrome Neuroglia Neurologic Neurons Opiate Addiction Opioid Pattern Perinatal Perinatal Exposure Pharmaceutical Preparations Play Pregnancy loss Pregnant Women Property Puberty Rewards Risk Role Slice Stress Structure Subgroup Synaptic Transmission Testing Time Transgenic Mice Work addiction cell type course development data integration drug reward drug seeking behavior experimental study fentanyl abuse fentanyl exposure fetal opioid exposure gliogenesis in vivo insight mature animal mouse model multimodal data neural neural circuit neuroadaptation neurodevelopment neurogenesis neurophysiology opioid exposure opioid withdrawal postnatal development programs stillbirth synaptogenesis transcriptomics two-photon

项目摘要

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.

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胎的风险，并可能导致新生儿阿片类药物戒断综合征（NOWS），导致儿童和成人的认知和行为风险。然而，这些缺陷是不被理解的。动物模型表明，产前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引起的，但这些暴露的细胞和分子基础赤字在很大程度上是未知的。中隔复合体在成瘾、寻求药物和压力中起着关键作用相关的行为，但目前还不清楚具体的隔神经细胞类型如何有助于阿片类药物诱导的神经适应神经发育是否是一个敏感时期，药物诱导的变化是否可以影响神经发育，成为永久性的或什么样的细胞类型和分子程序是由阿片类药物暴露和成瘾诱导在发育和成人大脑中的状态。使用可扩展的互补细胞和分子方法，这项研究将描述隔复合体中神经细胞类型的发育轨迹和适应性在早期阿片类药物暴露和戒断的小鼠模型中，以解决这些知识空白。我们的研究将提供一个全面的目录的细胞，电路和分子的适应，发生在在芬太尼暴露后形成隔复合体，并确定介导回路的关键隔细胞类型以及早期阿片类药物暴露时发生的行为适应。