Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function

项目摘要/摘要 大麻在青少年中的使用率仍然很高，在年轻人中也在增加。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增加患病风险有关 精神错乱晚年的情绪性、成瘾性或精神错乱青春期和成年期早期也是 在执行功能和工作记忆中起关键作用的前额叶皮质(PFC)正在走向成熟。 有趣的是，早期使用大麻后出现的精神障碍通常涉及PFC和 执行功能在这些障碍中很常见。这表明青少年大麻的使用扰乱了PFC 成熟，损害工作记忆/执行功能，并增加后来患精神疾病的风险。 这一假说得到了对大量吸食大麻的人的功能成像研究的支持 青春期发现PFC和几个大脑区域之间的功能连接存在缺陷。 因此，使用大麻可能会导致PFC电路接线错误，增加精神障碍的风险。 更好地了解在青春期和早期使用大麻的后果和机制 成年后，我们通过青春期给予Δ-9-四氢大麻酚(THC)在啮齿动物身上模拟这一过程， 大麻的主要令人陶醉的成分。这些研究有力地证明了PFC的持久缺陷- 如果给成年人服用类似剂量的THC，青少年THC后的中介行为是缺乏的， 强调一个特定的脆弱性窗口。我们调查潜在机制的初步数据显示 确定了三个可能相互关联的过程。第一个是青少年THC治疗降低了预测 从丘脑内侧至中脑内侧核(MPFC)。二是青少年THC治疗 导致神经炎症，包括IL-6升高和激活的小胶质细胞。三是联合治疗， 大麻二醇可预防青少年THC的行为和神经炎性反应。在建议的 研究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治疗。 我们建议通过以下方式发展对青少年吸食大麻后果的机械性理解 结合分子、解剖学、电生理学和行为学方法来完成三个目标： 目的1.验证CB1受体对青少年的有害影响是必需的假设 对工作记忆的影响，并评估扭转这些缺陷的潜在治疗方法。 目的2.验证青少年接触THC降低MD丘脑/mPFC连接的假设 损害工作记忆。 目的3.验证青春期THC激活小胶质细胞过度修剪mPFC输入的假设 从MD丘脑中分离出来，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.