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）是大麻植物的萜类化合物，目前正在流行作为一种 草药和食物上瘾，在动画，睡眠障碍治疗中具有有益的有益作用， 炎症和疼痛。流行病学研究表明，使用含CBD的产品的使用正在增加， 包括怀孕和哺乳期妇女。尽管存在这些趋势，但我们对效果知之甚少 在发育中的大脑上的CBD。该探索性项目中研究的目的是检查 开发过程中CBD暴露在后来的小脑功能中的后果。这 这些研究的总体假设是，发育神经元暴露于CBD会导致增加 轴突和树突的凋亡和失调的生长。该项目的具体目标是探索 在小鼠小脑中的这一假设。该项目的前提得到了一些研究的支持 文献和通过我们实验室的初步数据表明，子宫内的CBD暴露会导致 Rotarod测定法的性能显着降低，表明平衡和协调的丧失。在 此外，我们发现培养物中小脑颗粒神经元（CGN）直接暴露于CBD导致 细胞凋亡，在较低浓度下，糖原合酶激酶3ß（GSK3ß）的不适当激活。 GSK3ß调节CGN中依赖活性的树突状树皮及其过度激活一直是 与丧失适当的细胞形态和与靶标的连接有关。那，我们的初步数据 支持CBD可以在小脑中发展神经元具有神经毒性的假设。第二个目标 这些研究是为了探讨以下假设：GPR55是G蛋白偶联受体，它被拮抗 CBD是CBD影响神经元发展的作用部位。在第一个目标中，我们将检查效果 几种小脑依赖性行为和小脑形态的围产期CBD暴露于几种 年龄。我们将研究以下假设：GPR55是CBD改变小脑功能和 确定GSK3ß磷酸化是否会因体内暴露于CBD而改变。我们使用自愿 将CBD施用到怀孕小鼠的消耗方法，将测量的浓度 CBD使用这种方法导致大坝和幼崽。在第二个目标中，我们将检查机制 CBD会影响培养的CGN中GSK3ß活性，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质产生的影响。这些成功完成 研究将提供有关CBD在神经元成熟中的作用的重要信息，并将开始 解决有关围产期CBD暴露对大脑影响的知识的重要差距 发展。