ICAL: Impact of Cannabinoids Across Lifespan: Cellular Project

项目2摘要 美国人口中使用大麻的发生率在过去十年中一直在上升， 在未来几年，合法化可能会进一步增加。这包括使用流行率的增加 在青少年时期，无论是作为治疗还是在社会环境中。青少年使用会带来特殊风险， 网络仍在发展和可塑性。在这种情况下，有证据表明，食人鱼扰乱认知功能， 并且可能损害学习和记忆是一个特别的问题。确定剂量的对照研究， 显然需要结果测量来理解这些认知障碍， 在此基础上的过程。在啮齿动物中的研究表明，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）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。少 人们一直致力于分析突触可塑性的特殊形式，这些形式被认为是形成神经生物学的基础。 用于存储器或投影特定效果的衬底。项目2将评估这两个问题。目标1将 使用电生理（脑切片）技术，以确定是否每天THC治疗青少年（ado）和 年轻的成年小鼠（两种性别）的影响，特别是损害，突触传递和活动诱导 长时程增强（LTP）涉及三个系统的记忆编码：（1）横向穿孔路径 (LPP)我们发现海马的传入神经表现出依赖于ECB的LTP形式，（2）Schaffer- 海马CA 1区的连合传入，LTP非常好地表征，并且不依赖于 对ECB功能的影响;（3）对内侧/前边缘额叶皮层的兴奋性传入。初步结果表明 THC的作用确实是投射特异性的：在雄性小鼠中，每日ado-THC治疗消除了ECB- LPP中的LTP依赖形式。同样的THC治疗损害，但不消除非欧洲央行依赖 场CA 1-LTP，但干扰γ频率传入输入到这个区域的处理。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 类似的THC治疗对年轻人的影响。Aim 2将重点关注海马系统， 测试关于突触可塑性障碍的神经生物学过程的特定假设， 记忆与ado-THC暴露：三组研究将测试可塑性的变化是否与 隔室特异性改变CB 1 R表达和CB 1 R信号传导，如果操纵ECB水平可以 抵消突触功能的损伤，否则由ado-THC暴露诱导。这些研究 旨在补充国际比较标准化组织其他组成部分的活动， 四氢大麻酚对行为指标影响的基质干扰，将在项目3中进行评估。 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 THC暴露以及在真实的世界环境中的使用水平是否对更高的认知功能产生持久影响。 !

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. !