Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function

项目概要/摘要 青少年中大麻的使用率仍然很高，而且年轻人中的大麻使用率也在增加。这是一个意义重大的 公共卫生问题，因为在此期间大量使用大麻与罹患疾病的风险增加有关 晚年出现情感、成瘾或精神障碍。青春期和成年早期也是 在执行功能和工作记忆中发挥关键作用的前额皮质（PFC）正在日趋成熟。 有趣的是，早期使用大麻后出现的精神疾病通常涉及 PFC 和 执行功能在这些疾病中很常见。这表明青少年吸食大麻会扰乱 PFC 成熟，损害工作记忆/执行功能并增加日后精神疾病的风险。 这一假设得到了对在怀孕期间大量使用大麻的个体进行的功能成像研究的支持。 已发现 PFC 和几个大脑区域之间的功能连接缺陷。 因此，使用大麻可能会导致 PFC 电路错误接线，增加精神疾病的风险。 为了更好地了解青春期和早期吸食大麻的后果和机制 成年后，我们通过青少年服用 Δ-9-四氢大麻酚（THC）来模拟啮齿类动物的这一过程， 大麻的主要致醉成分。这些研究有力地证明了 PFC 的持久缺陷 青少年服用 THC 后的介导行为，如果成人服用相似剂量的 THC，则不会出现这种行为， 强调特定的漏洞窗口。我们调查潜在机制的初步数据 确定了三个可能相互关联的过程。首先是青少年 THC 治疗会降低预测 从内侧丘脑到内侧前额皮质（mPFC）。第二个是青少年 THC 治疗 引起神经炎症，包括 IL-6 增加和小胶质细胞激活。三是协同治疗。 大麻二酚可防止青少年 THC 的行为和神经炎症影响。在提议的 研究中我们将调查这些发现背后的机制并评估基于机制的潜力 逆转青少年 THC 引起的行为和认知异常的疗法。 我们建议对青少年吸食大麻的后果有一个机械性的理解 结合分子、解剖学、电生理学和行为方法来完成三个目标： 目标 1. 检验以下假设：CB1 受体对于青少年的有害影响是必需的 THC 对工作记忆的影响并评估扭转这些缺陷的潜在疗法。 目标 2. 检验青少年 THC 暴露会降低 MD 丘脑/mPFC 连接性的假设 损害工作记忆。 目标 3. 检验青少年 THC 激活小胶质细胞过度修剪 mPFC 输入的假设 来自MD丘脑的损害工作记忆。

PROJECT SUMMARY / ABSTRACT Cannabis use continues to be high among adolescents and is increasing in young adults. This is a significant public health issue as heavy cannabis use during this period is linked to an increased risk for developing affective, addictive, or psychotic disorders later in life. Adolescence and early adulthood are also when the prefrontal cortex (PFC), which plays a key role in executive function and working memory, is maturing. Interestingly, psychiatric disorders seen following early cannabis use often involve the PFC and deficits in executive function are common in these disorders. This suggests that adolescent cannabis use disrupts PFC maturation, impairing working memory/executive function and increasing risk for later psychiatric disorders. This hypothesis is supported by functional imaging studies of individuals who heavily used cannabis during adolescence that have identified defects in functional connectivity between PFC and several brain regions. Thus, cannabis use may cause miswiring of PFC circuits, increasing the risk for psychiatric disorders. To better understand the consequences and mechanisms of cannabis use during adolescence and early adulthood, we model this process in rodents by adolescent administration of Δ-9-tetrahydrocannabinol (THC), the primary intoxicating component of cannabis. These studies robustly demonstrate enduring deficits in PFC- mediated behaviors following adolescent THC that are lacking if similar doses of THC are given to adults, emphasizing a specific window of vulnerability. Our preliminary data investigating potential mechanisms have identified three, likely-interrelated processes. The first is that adolescent THC treatment decreases projections from the mediodorsal thalamus to the medial PFC (mPFC). The second is that adolescent THC treatment causes neuroinflammation, including increased IL-6 and activated microglia. The third is that co-treatment with cannabidiol prevents the behavioral and neuroinflammatory effects of adolescent THC. In the proposed studies we will investigate the mechanisms underlying these findings and evaluate mechanism-based potential therapies to reverse the behavioral and cognitive abnormalities caused by adolescent THC. We propose to develop a mechanistic understanding of the consequences of adolescent cannabis use by combining molecular, anatomical, electrophysiological, and behavioral approaches to complete three aims: Aim 1. Test the hypothesis that CB1 receptors are required for the detrimental effects of adolescent THC on working memory and evaluate potential therapies to reverse these deficits. Aim 2. Test the hypothesis that adolescent THC exposure reduces MD thalamus/mPFC connectivity to impair working memory. Aim 3. Test the hypothesis that adolescent THC activates microglia to excessively prune mPFC inputs from the MD thalamus to impair working memory.