Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function

青少年植物大麻素前额皮质功能损伤的机制和治疗

• 批准号: 10391869
• 负责人: HUI-CHEN LU
• 金额: $ 48.9万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391869
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Adult; Adverse effects; Age; Anatomy; Behavior; Behavioral; Brain; Brain region; CNR1 gene; Cannabidiol; Cannabis; Chronic; Cognitive; Cognitive deficits; Data; Defect; Development; Disease; Dose; Electrophysiology (science); Endocannabinoids; Female; Functional Imaging; Genetic; Goals; Human; Impairment; Individual; Interleukin-6; Life; Link; Medial; Mediating; Memory impairment; Mental disorders; Microglia; Modeling; Molecular; Mood Disorders; Mus; Outcome; Pathway interactions; Pharmacology; Play; Prefrontal Cortex; Process; Psychotic Disorders; Public Health; Research; Risk; Rodent; Role; Short-Term Memory; Synapses; THC exposure; Testing; Tetrahydrocannabinol; Thalamic structure; Therapeutic; Time; Treatment Efficacy; addiction; attenuation; base; behavioral impairment; cognitive function; designer receptors exclusively activated by designer drugs; effective therapy; emerging adult; executive function; experimental study; imaging study; insight; male; marijuana use; neural circuit; neuroinflammation; novel; phytocannabinoid; prevent; public health relevance; sex; synaptic pruning; vulnerable adolescent; young adult; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Adverse effects; Age; Anatomy; Behavior; Behavioral; Brain; Brain region; CNR1 gene; Cannabidiol; Cannabis; Chronic; Cognitive; Cognitive deficits; Data; Defect; Development; Disease; Dose; Electrophysiology (science); Endocannabinoids; Female; Functional Imaging; Genetic; Goals; Human; Impairment; Individual; Interleukin-6; Life; Link; Medial; Mediating; Memory impairment; Mental disorders; Microglia; Modeling; Molecular; Mood Disorders; Mus; Outcome; Pathway interactions; Pharmacology; Play; Prefrontal Cortex; Process; Psychotic Disorders; Public Health; Research; Risk; Rodent; Role; Short-Term Memory; Synapses; THC exposure; Testing; Tetrahydrocannabinol; Thalamic structure; Therapeutic; Time; Treatment Efficacy; addiction; attenuation; base; behavioral impairment; cognitive function; designer receptors exclusively activated by designer drugs; effective therapy; emerging adult; executive function; experimental study; imaging study; insight; male; marijuana use; neural circuit; neuroinflammation; novel; phytocannabinoid; prevent; public health relevance; sex; synaptic pruning; vulnerable adolescent; young adult

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.

项目摘要 /摘要 在青少年中，大麻的使用量仍然很高，并且年轻人的使用量越来越高。这是重要的 公共卫生问题作为此期间大麻使用的大麻使用与发展的风险增加有关 情感，加性或精神病患者以后的生活。青少年和成年早期也是 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，精神疾病会看到以下大麻使用以下通常涉及PFC，并定义 执行功能在这些疾病中很常见。这表明青少年大麻使用中断PFC 成熟，损害工作记忆/执行功能以及增加后来精神疾病的风险。 该假设得到了对在 已经确定了PFC和几个大脑区域功能连通性缺陷的青少年。 这是大麻使用可能会导致对PFC电路的失误，从而增加了精神疾病的风险。 更好地了解青少年和早期大麻使用的后果和机制 成年，我们通过青少年给药δ-9-四氢大麻醇（THC），在啮齿动物中对此过程进行建模 大麻的主要陶醉成分。这些研究强烈地证明了PFC-的持久防御能力 如果给人类似剂量的成年人，青春期thc之后的介导的行为，则缺乏介导的行为， 强调特定的脆弱性窗口。我们的初步数据研究潜在机制具有 确定了三个可能间接的过程。首先是青春期的THC治疗逐渐下降 从培养基丘脑到内侧PFC（MPFC）。第二个是青少年的THC治疗 引起神经炎症，包括增加IL-6和活化的小胶质细胞。第三是与 大麻二醇可防止青少年THC的行为和神经炎症作用。在提议中 研究我们将研究这些发现的基础机制，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。 我们建议对青少年大麻使用的后果进行机械理解 结合分子，解剖学，电生理和行为方法，以完成三个目标： AIM 1。检验以下假设：青少年有害影响需要CB1受体 THC在工作记忆方面并评估潜在疗法以扭转这些缺陷。 AIM 2。检验以下假设：青少年THC暴露将MD Thalamus/MPFC连接降低到 损害工作记忆。 AIM 3。测试青少年THC激活小胶质细胞的假设以极度修剪MPFC输入 从MD Thalamus到损害工作记忆。