Cerebellar biobehavioral markers in cannabis users

大麻的使用是一个日益严重的公共卫生问题， 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）的健康后果是紧迫和关键的。例如，最近的一项研究 研究发现，在过去30年中，19-22岁的大学生使用CB的比例最高，39%的人在 最后一年普遍的观点是，氯苯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）青少年使用可能会扰乱关键的大脑成熟 （3）长期使用与认知缺陷有关，（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 目前不完整和模棱两可。这项拟议中的研究强烈主张， (or缺乏）严重依赖于神经回路知情的方法来测试大脑的完整性 已知系统富含CB相关受体，这些受体在CB暴露后发生改变。 CB的主要精神活性成分是δ-9-四氢大麻酚（THC），其充当以下物质的配体： CB 1受体在人脑中广泛分布。小脑的CB 1 R密度是所有脑区中最高的。 个脑袋虽然小脑功能的测量可以为神经行为效应提供敏感的探针， 在CB使用中，它们很少在CB使用者中进行测试，也没有明确与行为缺陷有关。 具体目标1将测量小脑子区域之间的静息状态功能连接（rsFC）， 建立了皮质静息态脑网络（RSN）。具体目标2将测试：a）小脑fMRI是否 在CB使用者中小脑依赖性延迟眨眼条件反射（dEBC）期间的激活减少;和B） 基于任务的小脑激活是否产生不同的RSN连接模式（使用10个RSN 目标1），对CB使用的敏感性不同。具体目标3将测试一组 小脑依赖行为任务到CB使用。拟议研究的结果可能会确定 小脑范式和措施，其中最受影响的当前CB用户。如果有充分的根据 预测得到证实，这套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，这对未来的研究项目至关重要，2） 大麻化合物对人体的直接给药，3）在动物模型中进行的可比措施研究 大麻使用和后果，4）遗传知情的家庭和双胞胎研究和5）现场研究， 大麻中毒此外，这些协议在解析小脑回路时可以提供大量信息 这与一系列的成瘾行为有关。

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.