Effects of adolescent cannabinoid exposure on cortical development

项目总结/摘要 青春期是神经元发育的关键时期，在这一时期暴露于滥用药物， 脆弱性可以改变正常的神经发育过程，造成持续到成年的变化。 初次接触大麻素，如Δ-9-四氢大麻酚（THC），通常发生在青春期 这种暴露可以在神经元和分子水平上改变发育。先前的临床前研究 研究表明，在青春期反复接触THC会导致学习和记忆障碍。 这些研究使用实验者施用剂量的THC进行，作为啮齿动物自我施用THC。 众所周知，THC很难实现。因此，大麻素暴露在自我管理的影响， 动物可以选择随时间接受多少药物的THC剂量可能不同于 实验者施用的剂量。此外，以这种方式施用的THC可能导致交替效应。 在学习和记忆上的作用要比其他范例所证明的要大。为了弥补这一知识差距， 拟议的研究将测试青少年THC自我给药对行为的长期影响， 受体表达和成年期的神经元活动。大鼠将获得低或高剂量的THC 在整个青春期，一旦他们成年，他们将接受延迟匹配样本的测试， 工作记忆任务在一些大鼠中，我们将测量多巴胺能和大麻素的表达， 受体，因为这些受体的表达是在青春期发展，并可能被破坏， 由于高浓度四氢大麻酚暴露而导致的慢性激活此外，我们将在体内使用钙成像， 工作记忆任务来测量神经元活动，跟踪单个PFC神经元并测量动态 学习过程中的波动。我们的核心假设是，青春期长期接触THC 将在皮质多巴胺能和大麻素信号传导中引起剂量依赖性神经适应， 影响认知需求行为表现的神经元活动的改变。拟议 培训计划将使我能够发展细胞和分子技术方面的新的和必要的技能，以及 复杂神经元数据集的统计分析。我将能够利用强大的教师的专业知识 匹兹堡大学和卡内基梅隆大学的导师和合作者，以确保 顺利完成我的研究培训计划。这些创新的纵向研究将大大 推进我们对青少年暴露于THC的长期神经生物学影响的认识。的 拟议的实验将提供一个详细的表征进展活动的个人前额叶 在药物和非药物暴露的动物中，在复杂任务的学习过程中，神经元和合奏。 考虑到最近对大麻素用于娱乐和保健的影响的政治和健康相关的兴趣， 治疗用途，本申请中提出的研究将为科学研究提供有用的知识。 社区，以及不可或缺的，因为我开始了一个富有成效的职业生涯作为一个独立的调查员。

Project Summary / Abstract Adolescence is a critical period for neuronal development, and exposure to drugs of abuse during this period of vulnerability can alter the course of normal neurodevelopment causing changes that persist into adulthood. Initial exposure to cannabinoids, such as Δ-9-tetrahydrocannabinol (THC), often occurs during adolescence and this exposure can alter development on a neuronal and molecular level. Previous preclinical studies have indicated that repeated exposure to THC during adolescence can produce learning and memory deficits. These studies were performed using experimenter-administered doses of THC, as rodent self-administration of THC has been notoriously hard to achieve. Thus, the effects of cannabinoid exposure at self-administered doses of THC where the animal can choose how much drug to receive over time may differ from the effects of experimenter-administered doses. Additionally, THC administered in this manner may result in alternate effects on learning and memory than have been demonstrated by other paradigms. To address this gap in knowledge, the proposed studies will test the prolonged effects of adolescent THC self-administration on behavior, receptor expression, and neuronal activity in adulthood. Rats will be given access to low or high dose THC throughout adolescence, and once they reach adulthood, they will be tested on a delayed-match-to-sample working memory task. In some rats, we will then measure the expression of dopaminergic and cannabinoid receptors as the expression of these receptors is developing during adolescence and may be disrupted by chronic activation due to high THC exposure. Additionally, we will use in vivo calcium imaging during the working memory task to measure neuronal activity, tracking individual PFC neurons and measuring dynamic fluctuations in activity during learning. Our central hypothesis is that chronic THC exposure during adolescence will cause dose-dependent neuroadaptations in cortical dopaminergic and cannabinoid signaling, leading to alterations in neuronal activity that impact the performance of a cognitively demanding behavior. The proposed training plan will allow me to develop new and necessary skills in cell and molecular techniques, as well as in the statistical analysis of complex neuronal datasets. I will be able to draw on the expertise of strong faculty mentors and collaborators at the University of Pittsburgh and Carnegie Mellon University to ensure the successful completion of my research training plan. These innovative longitudinal studies will significantly advance our knowledge of the protracted neurobiological effects of adolescent exposure to THC. The proposed experiments will provide a detailed characterization of the progression activity in individual prefrontal neurons and ensembles during the learning of a complex task, in both drug and non-drug exposed animals. Given the recent political and health-related interest in the effects of cannabinoids for recreational and therapeutic use, the research proposed within this application will provide useful knowledge to the scientific community, as well as being indispensable as I embark on a productive career as an independent investigator.