Cerebellar biobehavioral markers in cannabis users

大麻的使用代表着一个重大的和日益增长的公共卫生问题，因为社会接受 伴随着这种药物的合法化用于医疗和娱乐目的。这些因素使得 了解大麻(CB)的健康后果是迫切和关键的。例如，最近的一项研究 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，39%的人曾使用过 最后一年。流行的观点认为，氯苯是一个重要的公共健康风险因素，因为(1)使用与 随着健康和事故风险的增加，(2)青少年使用药物可能会干扰关键的大脑成熟 过程；(3)长期使用与认知障碍有关；(4)使用CB的人处于 增加精神病和情绪障碍的风险。然而，对大麻相关风险的评估是 目前不完整且模棱两可。这项拟议的研究强烈主张，理解风险 (或缺乏)关键依赖于神经回路知情的方法来测试大脑的完整性 已知的系统具有丰富的CB相关受体，这些受体会因CB暴露而改变。 CB的主要精神活性成分是三角洲-9-四氢大麻酚(THC)，它是 在人脑中广泛分布的CB1受体。小脑的CB1R密度是 大脑。尽管小脑功能的测量可以为神经行为的影响提供灵敏的探针 对于CB的使用，很少在CB使用者身上进行测试，也没有明确地将它们与行为缺陷联系起来。 具体目标1将测量小脑各亚区之间的静息功能连接(RsFC) 建立皮层静息状态脑网络(RSNs)。特定目标2将测试：a)小脑fMRI CB使用者在小脑依赖延迟眨眼条件反射(DEBC)期间的激活减少；以及b) 基于任务的小脑激活是否产生不同模式的RSN连接(使用10个RSN 来自AIM 1)对CB使用具有不同敏感性的。《特定目标3》将测试一套 小脑依赖行为任务对CB的使用。这项拟议研究的结果可能会确定 当前CB使用者中受影响最大的小脑范例和测量方法。如果有强大的基础 预测得到证实，这套措施随后可以用于广泛的研究，包括1) 对高危人群和CB使用者的纵向研究，这对未来的研究项目至关重要，2) 在人体内直接给药大麻化合物，3)动物模型中可比措施的研究 关于大麻使用和后果的研究，4)遗传知情的家族和双胞胎研究以及5)关于 大麻中毒。此外，这些协议在分析小脑回路时可能会提供大量信息 它们与广泛的成瘾行为有关。

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.