Cerebellar biobehavioral markers in cannabis users

大麻使用者的小脑生物行为标记

基本信息

批准号：
10116984
负责人：
WILLIAM P HETRICK
金额：
$ 54.32万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116984
关键词：
Accidents Addictive Behavior Adolescence Adolescent Adult Advocate Affect Age Age of Onset Agonist Anatomy Animal Model Anterior Behavior Behavioral Brain Brain region CNR1 gene Cannabis Cerebellum Cerebrum Chronic Cognitive Cognitive deficits Data Equipment and supply inventories Exposure to Failure Functional Magnetic Resonance Imaging Functional disorder Future Health Human Impairment Intoxication Knowledge Legal Life Ligands Link Lobular Lobule Longitudinal Studies Marijuana Measures Meta-Analysis Methods Michigan Monitor Motor Nature Neurobiology Neurologic Pattern Performance Peripheral Pharmaceutical Preparations Population Posture Process Protocols documentation Psychotic Mood Disorders Public Health Research Research Project Grants Rest Risk Risk Assessment Risk Factors Seeds Sensory Signal Transduction Son Spinal Structure System Testing Tetrahydrocannabinol Twin Studies United States base behavior measurement biobehavior emerging adult experimental study eyeblink conditioning field study high risk population marijuana use marijuana user mental function neural circuit neurobehavioral neuroimaging receptor receptor density relating to nervous system response social trend university student young adult

项目摘要

Cannabis use represents a significant and increasing public health concern as social acceptance accompanies legalization of this drug for medicinal and recreational purposes. These factors make understanding the health consequences of cannabis (CB) urgent and critical. For example, a recent study found university students age 19-22 had the highest rate of CB use in the last 30 years, with 39% having used in the last year. The prevailing view is that CB is a significant public health risk factor because (1) use is associated with increased risk for health and accidents, (2) adolescent use likely disturbs crucial brain maturation processes; (3) chronic use has been associated with cognitive deficits and (4) people who use CB are at increased risk for psychotic and mood disorders. However, the assessment of risks associated with cannabis is currently incomplete and equivocal. The proposed research strongly advocates that understanding the risks (or lack thereof) depends critically on a neural circuit-informed approach to testing the integrity of brain systems known to be richly endowed with CB-relevant receptors that are altered in response to CB exposure. The principal psychoactive ingredient of CB is delta-9-tetrahydrocannabinol (THC), which acts as a ligand for widely distributed CB1 receptors in the human brain. CB1R density in cerebellum is one of the highest in the brain. Although measures of cerebellar function could provide sensitive probes for the neurobehavioral effects of CB use, they have rarely been tested in CB users, nor have they been explicitly linked to behavioral deficits. Specific Aim 1 will measure resting state functional connectivity (rsFC) between cerebellum sub-regions and established cortical resting state brain networks (RSNs). Specific Aim 2 will test: a) whether cerebellar fMRI activation during cerebellar-dependent delay eyeblink conditioning (dEBC) is reduced in CB users; and b) whether task-based cerebellar activations produce different patterns of RSN connectivity (using the 10 RSNs from Aim 1) that are differentially sensitive to CB use. Specific Aim 3 will test the sensitivity of a set of cerebellar-dependent behavioral tasks to CB use. Findings from the proposed research will likely identify the cerebellar paradigms and measures which are most affected in current CB users. If the strongly founded predictions are borne out, this set of measures could then be utilized in a wide range of studies, including 1) longitudinal studies of high risk groups and CB users which would be critical for future research projects, 2) direct administration of cannabis compounds in humans, 3) studies of comparable measures in animal models of cannabis use and consequences, 4) genetically informed familial and twin studies and 5) field studies of cannabis intoxication. Additionally, these protocols could be highly informative in parsing cerebellar circuits which have been implicated in a broad range of addictive behaviors.

随着社会接受度的提高，大麻的使用代表了一个重要且日益增长的公共卫生问题伴随着这种药物用于医疗和娱乐目的的合法化。这些因素使得了解大麻 (CB) 对健康的影响刻不容缓。例如，最近的一项研究发现 19-22 岁的大学生在过去 30 年中使用 CB 的比例最高，其中 39% 的人曾在去年。普遍的观点是，CB 是一个重要的公共卫生风险因素，因为 (1) 使用与随着健康和事故风险的增加，(2) 青少年使用可能会干扰重要的大脑成熟流程； (3) 长期使用 CB 与认知缺陷有关，并且 (4) 使用 CB 的人处于精神病和情绪障碍的风险增加。然而，对大麻相关风险的评估是目前不完整且模棱两可。拟议的研究强烈主张了解风险（或缺乏）主要取决于神经回路知情的方法来测试大脑的完整性已知具有丰富的CB相关受体的系统，这些受体会随着CB暴露而改变。 CB 的主要精神活性成分是 δ-9-四氢大麻酚 (THC)，它是 CB1受体广泛分布于人脑中。小脑中的 CB1R 密度是大脑中最高的之一脑。尽管小脑功能的测量可以为神经行为效应提供敏感的探针尽管关于 CB 使用的研究很少，但它们很少在 CB 用户中进行过测试，也没有与行为缺陷明确相关。具体目标 1 将测量小脑子区域和小脑子区域之间的静息状态功能连接 (rsFC) 建立了皮质静息态大脑网络（RSN）。具体目标 2 将测试：a) 是否小脑功能磁共振成像 CB使用者的小脑依赖性延迟眨眼调节（dEBC）期间的激活减少；和 b) 基于任务的小脑激活是否会产生不同的 RSN 连接模式（使用 10 个 RSN）来自目标 1) 对 CB 使用有不同的敏感度。具体目标 3 将测试一组的敏感性 CB 使用的小脑依赖性行为任务。拟议研究的结果可能会确定当前 CB 用户受影响最大的小脑范例和测量。如果有坚实的基础如果预测得到证实，这组措施可以用于广泛的研究，包括 1) 高风险群体和 CB 用户的纵向研究对于未来的研究项目至关重要，2) 直接对人类施用大麻化合物，3）动物模型中可比措施的研究大麻使用及其后果，4）遗传信息家族和双胞胎研究以及 5）实地研究大麻中毒。此外，这些协议在解析小脑回路方面可能提供大量信息这与广泛的成瘾行为有关。