Studies of Cannabidiol in Neurodevelopment

大麻二酚在神经发育中的研究

• 批准号: 10366030
• 负责人: Cecilia J Hillard
• 金额: $ 19.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366030
• 关键词: Address; Adult; Affect; Age; Apoptosis; Attitude; Axon; Behavior; Behavioral; Biogenic Amines; Biological Models; Brain; California; Cannabidiol; Cannabinoids; Cannabis; Cellular Morphology; Cerebellum; Child Health; Communities; Consumption; Cytoplasmic Granules; Data; Dendrites; Dependence; Development; Dose; Elderly; Equilibrium; Exhibits; Exposure to; Female; Fetus; Food Additives; G-Protein-Coupled Receptors; GPR55 receptor; GTP-Binding Protein alpha Subunits, Gs; Genetic; Goals; Growth Cones; Hemp; Human Milk; Impairment; In Vitro; Inflammation; Ingestion; Knowledge; Laboratories; Lactation; Lead; Legal; Literature; Mainstreaming; Measures; Mediating; Methods; Morphology; Movement; Mus; Nervous system structure; Neurites; Neurons; Newborn Infant; Pain; Perception; Performance; Perinatal; Perinatal Exposure; Phase; Phosphorylation; Phosphotransferases; Plants; Pregnancy; Pregnant Women; Process; Publishing; Rattus; Retinal Ganglion Cells; Risk; Role; Rotarod Performance Test; Safety; Signal Transduction; Site; Sleep Disorders; Terpenes; Tetrahydrocannabinol; Toxic effect; Transcriptional Regulation; Woman; Zebrafish; antagonist; antagonist G; anxiety treatment; axon growth; behavioral phenotyping; epidemiology study; evidence base; glycogen synthase kinase 3 beta; in vivo; male; marijuana use; neonate; nerve supply; neurodevelopment; neuron development; neuronal circuitry; neurotoxic; offspring; preclinical study; pregnant; prenatal exposure; pup; transcriptome sequencing; trend; virtual

Cannabidiol (CBD) is a terpenoid constituent of the cannabis plant that is currently enjoying popularity as an herbal and food additive with purported beneficial effects in the treatment of anxiety, sleep disorders, inflammation and pain. Epidemiological studies indicate that use of CBD-containing products is increasing, including among pregnant and lactating women. In spite of these trends, we know very little about the effects of CBD on the developing brain. The purpose of the studies in this exploratory project is to examine the consequences of CBD exposure during development on the functioning of the cerebellum in later life. The overall hypothesis of these studies is that exposure of developing neurons to CBD results in increased apoptosis and dysregulated outgrowth of axons and dendrites. The specific goals of this project are to explore this hypothesis in the cerebellum of mice. The premise of this project is supported by a few studies in the literature and by preliminary data from our laboratory demonstrating that CBD exposure in utero results in significant reductions in performance on the rotarod assay, indicative of loss of balance and coordination. In addition, we have found that direct exposure of cerebellar granule neurons (CGNs) in culture to CBD results in apoptosis and, at lower concentrations, inappropriate activation of glycogen synthase kinase 3ß (GSK3ß). GSK3ß regulates activity-dependent dendritic arborization in CGNs and its over-activation has been associated with loss of appropriate cell morphology and connections to targets. Thus, our preliminary data support the hypothesis that CBD can be neurotoxic to developing neurons in the cerebellum. A second goal of these studies is to explore the hypothesis that GPR55, a G protein coupled receptor that is antagonized by CBD, is the site of action for CBD to affect neuronal development. In the first aim, we will examine the effects of perinatal CBD exposure on several cerebellar-dependent behaviors and cerebellar morphology at several ages. We will study the hypothesis that GPR55 is the site of action of CBD to alter cerebellar function and determine whether GSK3ß phosphorylation is altered by in vivo exposure to CBD. We utilize a voluntary consumption method for the administration of CBD to pregnant mice and will measure the concentrations of CBD that result in the dam and pups using this approach. In the second aim, we will examine the mechanism by which CBD affects GSK3ß activity in cultured CGNs, focusing on the role of GPR55, and determine the effects of CBD on activity-dependent neuritic outgrowth in these neurons. Successful completion of these studies will provide important information regarding the role of CBD in neuronal maturation and will begin to address an important gap in our knowledge regarding the effects of perinatal CBD exposure on brain development.

大麻二酚（CBD）是大麻植物的萜类成分，其目前作为一种抗氧化剂而受到欢迎。 本发明涉及一种草药和食品添加剂，其据称在治疗焦虑、睡眠障碍 炎症和疼痛。流行病学研究表明，含CBD产品的使用正在增加， 包括孕妇和哺乳期妇女。尽管有这些趋势，我们对这些影响知之甚少。 CBD对大脑发育的影响这项探索性项目的研究目的是审查 CBD暴露在发展过程中对小脑功能的影响。的 这些研究的总体假设是，发育中的神经元暴露于CBD会导致 细胞凋亡和轴突和树突生长失调。本项目的具体目标是探索 这一假设在小鼠的小脑中得到证实。该项目的前提得到了一些研究的支持， 文献和我们实验室的初步数据表明，子宫内的CBD暴露导致 在转棒试验中表现显著降低，表明失去平衡和协调。在 此外，我们发现，直接暴露于CBD培养的小脑颗粒神经元（CGN）， 细胞凋亡，以及在较低浓度下，糖原合成酶激酶3 β（GSK 3 β）的不适当激活。 GSK3 β调节CGN中的活性依赖性树突状分支，其过度活化已被证实是一种重要的机制。 与丧失适当的细胞形态和与靶的连接有关。因此，我们的初步数据 支持CBD对小脑中发育中的神经元具有神经毒性的假设。第二个目标是 这些研究是为了探索GPR55的假说，GPR55是一种G蛋白偶联受体， CBD是CBD影响神经元发育的作用部位。在第一个目标中，我们将研究 围产期CBD暴露对几种小脑依赖行为和小脑形态的影响 年龄我们将研究GPR55是CBD改变小脑功能的作用位点的假设， 确定体内暴露于CBD是否改变了GSK3 β磷酸化。我们利用自愿 消费方法的CBD管理怀孕的小鼠，并将测量浓度 CBD导致使用这种方法的大坝和幼崽。在第二个目标中，我们将研究机制 CBD影响培养CGNs中GSK3 β活性的方法，重点关注GPR55的作用，并确定 CBD对这些神经元中活性依赖性神经炎生长的影响。成功完成这些 研究将提供关于CBD在神经元成熟中的作用的重要信息，并将开始 解决我们关于围产期CBD暴露对大脑影响的知识中的一个重要空白 发展