ICAL: Impact of Cannabinoids Across Lifespan: Behavioral Project

ICAL：大麻素对整个生命周期的影响：行为项目

• 批准号: 10188480
• 负责人: Stephen Vincent Mahler
• 金额: $ 33.65万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188480
• 关键词: AM 251; Adolescence; Adolescent; Adult; Age; Agonist; Animals; Behavior; Behavioral; Behavioral Assay; Biochemical; Brain; Brain region; CB1 receptor antagonist; CNR1 gene; Cannabinoids; Cannabis; Cognition; Cognitive; Data; Dependence; Development; Dose; Drug Kinetics; Emotional; Emotions; Endocannabinoids; Epigenetic Process; Etiology; Evaluation; Exposure to; FOS gene; Female; Gene Expression; Hippocampus (Brain); Human; Ice; Individual; Literature; Longevity; Maintenance; Measures; Medial; Memory; Methodology; Microinjections; Molecular; Motivation; Mus; Nature; Nucleus Accumbens; Pathway interactions; Pharmacodynamics; Pharmacology; Phenotype; Prefrontal Cortex; Process; Protocols documentation; Proxy; Rattus; Reporting; Research Personnel; Rewards; Rodent; Standardization; Synapses; THC exposure; Teenagers; Testing; Tissue Banks; United States National Institutes of Health; Variant; Viral Vector; base; behavior test; behavioral phenotyping; cannabinoid receptor; endocannabinoid signaling; endogenous cannabinoid system; immunoreactivity; longitudinal human study; male; marijuana use; mature animal; motivated behavior; neurodevelopmental effect; pre-clinical; prospective; relating to nervous system; sex; targeted agent

PROJECT SUMMARY: BEHAVIORAL PROJECT ICAL’s core hypothesis is that non-physiological activation of the endocannabinoid (ECB) system by cannabis exposure during adolescence permanently alters ECB signaling, ultimately causing persistent alterations in cognition and motivated behavior. In this project, we propose a comprehensive behavioral evaluation of rodents exposed in adolescence to THC. Using a well-validated set of behavioral tasks and standardized protocols congruent with other Projects, we will characterize male and female, rat and mouse behavior across carefully selected measures of reward, memory, cognition and emotion to determine the scope of persistent THC behavioral effects, and how alterations in ECB signaling within hippocampal and mesocorticolimbic circuits underlie such effects. We have two Aims. Aim 1: To characterize behavioral phenotypes caused by adolescent THC exposure. We will phenotype the effects of prolonged THC administration in adolescent mice and rats of both sexes (PND 30-43), a proxy for daily cannabis use in human teenagers. The animals will be tested in adulthood (PND 70+) on standardized behavioral assays within the domains of reward, memory, cognition, and emotion. Additional groups will compare THC effects in adult animals to determine whether adolescent exposure effects are developmental in nature, and will examine behavioral effects that may emerge as animals age (PND 300+). Following behavioral testing, brains will be processed for behavior-related c-Fos immunoreactivity to determine changes in behavior-related neural activity. Aim 2: To identify mechanisms of induction and maintenance of adolescent THC effects on behavior. We hypothesize that THC, via stimulation of cannabinoid CB1 receptors (CB1R) in adolescence, changes ECB signaling and plasticity mechanisms within hippocampal and mesocorticolimbic circuits, resulting in the persistent behavioral effects identified in Aim 1. In Aim 2.1 we will determine the CB1R-dependence of persistent adolescent THC effects. In Aim 2.2 we will investigate the behavioral functions served by adolescent THC-induced ECB dysregulation, using microinjections of selective pharmacological agents or silencing/enhancing of gene expression via targeted viral vectors. In Aim 2.3 we will utilize chemogenetic manipulations to characterize and correct adolescent THC-induced circuit activity changes. These studies will provide the first comprehensive examination of the behavioral and circuit-level mechanisms of adolescent THC effects under a standardized, validated protocol in rodents. In addition, they will provide a mechanistic framework in which to interpret the results of NIH’s prospective ABCD consortium, and will help reveal the true neurodevelopmental effects of teen cannabis use.

项目摘要：行为项目 ICAL 的核心假设是大麻对内源性大麻素 (ECB) 系统的非生理激活 青春期暴露会永久改变 ECB 信号传导，最终导致持续改变 认知和动机行为。在这个项目中，我们提出了一个全面的行为评估 啮齿动物在青春期接触 THC。使用一组经过充分验证和标准化的行为任务 协议与其他项目一致，我们将描述男性和女性、大鼠和小鼠的行为 精心选择奖励、记忆、认知和情感的衡量标准，以确定持久性的范围 THC 行为影响，以及海马和中皮质边缘内 ECB 信号传导的改变 电路是造成这种效应的原因。我们有两个目标。目标 1：表征由以下因素引起的行为表型： 青少年 THC 暴露。我们将研究长期 THC 给药对青春期小鼠的影响 以及男女大鼠（PND 30-43），这是人类青少年每日使用大麻的代表。动物们将是 在成年期 (PND 70+) 在奖励、记忆、 认知、情感。其他小组将比较 THC 对成年动物的影响，以确定是否 青少年暴露影响本质上是发展性的，并将检查可能出现的行为影响 随着动物年龄的增长（PND 300+）。行为测试后，大脑将被处理以获取与行为相关的 c-Fos 免疫反应性以确定行为相关神经活动的变化。目标 2：确定机制 诱导和维持青少年 THC 对行为的影响。我们假设 THC 通过刺激 青春期的大麻素 CB1 受体 (CB1R) 改变海马内的 ECB 信号传导和可塑性机制 和中皮质边缘回路，导致目标 1 中确定的持续行为效应。在目标 2.1 中，我们将 确定青少年持续性 THC 效应的 CB1R 依赖性。在目标 2.2 中，我们将调查行为 使用选择性药理显微注射，研究青少年 THC 诱导的 ECB 失调所发挥的功能 通过靶向病毒载体来沉默/增强基因表达。在目标 2.3 中，我们将利用化学遗传学 描述和纠正青少年 THC 引起的回路活动变化的操作。这些研究将提供 首次全面检查青少年 THC 效应的行为和回路水平机制 根据啮齿类动物的标准化、经过验证的方案。此外，他们还将提供一个机制框架 解读 NIH 未来 ABCD 联盟的结果，有助于揭示真实情况 青少年使用大麻对神经发育的影响。