Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function

项目概要/摘要 大麻使用在青少年中仍然居高不下，在年轻人中也在增加。这是一个重大 公共卫生问题，因为在此期间大量使用大麻与发展中国家的风险增加有关。 情感性、成瘾性或精神性障碍。青春期和成年早期也是 在执行功能和工作记忆中起关键作用的前额叶皮层（PFC）正在成熟。 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。这表明青少年使用大麻会破坏PFC 这可能会导致大脑发育成熟，损害工作记忆/执行功能，并增加日后患精神疾病的风险。 这一假设得到了对在吸毒期间大量使用大麻的个人的功能成像研究的支持。 青少年已经确定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电路的错误布线，增加精神疾病的风险。 为了更好地了解青少年和早期使用大麻的后果和机制， 成年后，我们通过青少年给予Δ-9-四氢大麻酚（THC）在啮齿动物中模拟了这一过程， 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， 在青少年THC之后介导的行为，如果向成人给予类似剂量的THC， 强调一个特定的脆弱窗口。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，青少年THC治疗减少了预测 从内侧背丘脑到内侧PFC（mPFC）。第二，青少年THC治疗 导致神经炎症，包括增加IL-6和激活小胶质细胞。第三是共同治疗， 大麻二酚可预防青少年THC的行为和神经炎症效应。拟议 我们将研究这些发现背后的机制，并评估基于机制的潜力。 治疗，以扭转青少年THC引起的行为和认知异常。 我们建议通过以下方式对青少年使用大麻的后果形成一种机械的理解： 结合分子、解剖学、电生理学和行为学方法来完成三个目标： 目标1。测试CB 1受体对青少年的有害影响所需的假设 THC对工作记忆的影响，并评估扭转这些缺陷的潜在疗法。 目标二。检验青少年THC暴露降低MD丘脑/mPFC连接的假设， 削弱工作记忆 目标3。测试青少年THC激活小胶质细胞过度修剪mPFC输入的假设 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.