ICAL: Impact of Cannabinoids Across Lifespan: Cellular Project

ICAL：大麻素对整个生命周期的影响：细胞项目

• 批准号: 10188479
• 负责人: Christine M Gall
• 金额: $ 38.06万
• 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/10188479
• 关键词: 2-arachidonylglycerol; Address; Adolescence; Adolescent; Adolescent and Young Adult; Adolescent marijuana use; Adult; Affect; Axon; Back; Biochemical; Biological; Brain; CNR1 gene; Cannabinoids; Cannabis; Cells; Cognition; Cognitive; Complement; Complex; Controlled Study; Defect; Dendrites; Dose; Electrophysiology (science); Elements; Endocannabinoids; Epigenetic Process; Episodic memory; Exhibits; Exposure to; Female; Frequencies; Generations; Genomics; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Investigation; Lateral; Learning; Legal; Life Experience; Long-Term Depression; Long-Term Potentiation; Longevity; Measures; Medial; Memory; Mental disorders; Molecular; Mus; Neurobiology; Neurons; Outcome Measure; Pathway interactions; Perforant Pathway; Physiological; Physiology; Population; Prefrontal Cortex; Prevalence; Process; Production; Research; Risk; Rodent; Semantics; Signal Transduction; Site; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; System; THC exposure; Techniques; Testing; Tetrahydrocannabinol; Therapeutic; Training; Vertebral column; Work; behavior measurement; behavioral study; cognitive function; design; dosage; early adolescence; endocannabinoid signaling; endogenous cannabinoid system; epidemiology study; experimental study; frontal lobe; information processing; insight; male; marijuana use; memory encoding; middle age; optogenetics; postnatal; postsynaptic; presynaptic; quantitative imaging; ranpirnase; response; sex; signal processing; social; synaptic function; targeted treatment; transmission process; young adult

Project 2 Summary The incidence of cannabis use in the US population has been on the rise over the last decade and with legalization is likely to increase even further in coming years. This includes increases in the prevalence of use in adolescence both as a therapeutic and in social settings. Adolescent use presents special risks as brain networks are still developing and malleable. In this context, evidence that cannibis disturbs cognitive function and can impair learning and memory is a particular concern. Controlled studies with defined doses and outcome measures are clearly needed to understand these cognitive disturbances, and neurobiological processes underlying then. Studies in rodent have shown that exposure to cannabinoids (either Δ9- tetrahydrocannabinol (THC), the psychoactive ingredient in cannabis, or a synthetic mimic) alters brain levels of components of the endocannabinoid (ECB) system and impairs specific forms of learning and memory. Less effort has been devoted to analysis of specific forms of synaptic plasticity thought to form the neurobiological substrate for memory or to projection-specific effects. Project 2 will evaluate both of these issues. Aim 1 will use electrophysiological (brain slice) techniques to determine if daily THC treatment of adolescent (ado) and young adult mice (both sexes) influences, and specifically impairs, synaptic transmission and activity-induced long-term potentiation (LTP) for three systems involved in memory encoding: (1) the lateral perforant path (LPP) afferents to hippocampus which we have found exhibits an ECB-dependent form of LTP, (2) Schaffer- commissural afferents to hippocampal field CA1 for which LTP is very well characterized and does not depend on ECB function, and (3) excitatory afferents to medial/prelimbic frontal cortex. Preliminary results indicate that THC effects are indeed projection specific: in male mice, daily ado-THC treatment eliminates the ECB- dependent form of LTP in the LPP. The same THC treatments impair, but do not eliminate non-ECB dependent field CA1-LTP but disturb processing of gamma-frequency afferent input to this region. Aim 1 studies will further determine if ado-THC effects on synaptic transmission persist into middle age, and are greater than effects of similar THC treatments applied to young adults. Aim 2 then will focus on hippocampal systems to test specific hypotheses as to the neurobiological processes underlying disturbances in synaptic plasticity and memory with ado-THC exposure: three sets of studies will test if changes in plasticity are associated with compartment-specific changes CB1R expression and CB1R signaling and if manipulation of ECB levels can offset impairments in synaptic function otherwise induced by ado-THC exposure. These studies have been designed to complement activities in other components of ICAL to provide an extensive vertical analysis of disturbances in substrates that underlie effects of THC on behavioral measures to be assessed in Project 3. Together this work will determine if mnemonic systems in the adolescent brain are particularly vulnerable to THC exposure and if levels of use in real world settings have enduring effects on higher cognitive function. !

项目2总结 过去十年来，美国人口吸食大麻的比例一直在上升，而且 未来几年合法化可能会进一步增加，其中包括使用普及率的增加。 在青春期，无论是作为治疗还是在社交场合使用，都会给大脑带来特殊的风险。 在这种情况下，网络仍在发展和可塑性中，有证据表明大麻会扰乱认知功能。 并且会损害学习和记忆是一个特别令人关注的问题。 显然需要结果测量来理解这些认知障碍和神经生物学 对啮齿动物的研究表明，接触大麻素（Δ9-） 四氢大麻酚（THC），大麻中的精神活性成分，或合成模拟物）会改变大脑水平 内源性大麻素 (ECB) 系统的组成部分，并损害特定形式的学习和记忆。 人们一直致力于分析突触可塑性的具体形式，这些突触可塑性被认为形成了神经生物学 项目 2 将评估这两个问题。 使用电生理学（脑切片）技术来确定青少年 (ado) 和 年轻成年小鼠（两性）影响，特别是损害，突触传递和活动诱导 参与记忆编码的三个系统的长时程增强（LTP）：（1）侧向穿通路径 我们发现海马的 (LPP) 传入神经表现出 ECB 依赖性形式的 LTP，(2) Schaffer- 海马区 CA1 的连合传入，LTP 已被很好地表征并且不依赖于 ECB 功能，以及 (3) 内侧/前额叶皮质的兴奋性传入。 THC 效应确实具有预测特异性：在雄性小鼠中，每日 ado-THC 治疗消除了 ECB- LPP 中 LTP 的依赖形式相同的 THC 治疗会损害但不能消除非 ECB 依赖。 场 CA1-LTP 但干扰该区域的伽马频率传入输入的处理，目标 1 研究将。 进一步确定 ado-THC 对突触传递的影响是否持续到中年，并且大于 然后，类似的 THC 治疗对年轻人的影响将集中在海马系统上。 测试关于突触可塑性和突触可塑性紊乱的神经生物学过程的具体假设 ado-THC 暴露引起的记忆：三组研究将测试可塑性的变化是否与以下因素相关： 隔室特异性改变 CB1R 表达和 CB1R 信号传导，以及 ECB 水平的操纵是否可以 抵消 ado-THC 暴露引起的突触功能损伤。 旨在补充 ICAL 其他组成部分的活动，以提供广泛的垂直分析 THC 对项目 3 中要评估的行为测量产生影响的基质干扰。 这项工作将共同确定青少年大脑中的记忆系统是否特别容易受到影响 THC 暴露以及在现实世界中的使用水平是否会对高级认知功能产生持久影响。 ！