Effects of adolescent cannabinoid exposure on cortical development

项目摘要/摘要 青春期是神经元发育的关键时期，而在这一时期接触滥用药物 脆弱性可以改变正常神经发育的进程，导致持续到成年的变化。 初次接触大麻素，如Δ-9-四氢大麻酚，通常发生在青春期。 这种暴露可以改变神经元和分子水平的发育。之前的临床前研究已经 研究表明，青春期反复接触THC会导致学习和记忆障碍。 这些研究是使用实验者给药剂量的THC进行的，作为啮齿动物自身给药 众所周知，THC很难实现。因此，自我给药时暴露于大麻素的影响 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-给药剂量。此外，以这种方式给药可能会产生交替的效果 对学习和记忆的影响超过了其他范式所证明的。为了解决这一知识差距， 这项拟议的研究将测试青少年自我管理对行为的长期影响， 成年期的受体表达和神经元活性。将允许大鼠获得低剂量或高剂量的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。然后，我们将在一些大鼠身上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育的，并可能被 由于高THC暴露而导致的慢性激活。此外，我们将在体内使用钙质成像。 工作记忆任务，测量神经元活动，跟踪单个PFC神经元并测量动态 学习过程中活动的波动。我们的中心假设是青春期长期接触THC 将导致皮质多巴胺能和大麻素信号的剂量依赖性神经适应，导致 影响认知要求行为表现的神经元活动的改变。建议数 培训计划将使我在细胞和分子技术方面以及在 复杂神经元数据集的统计分析。我将能够利用强大教职员工的专业知识 匹兹堡大学和卡内基梅隆大学的导师和合作者确保 圆满完成了我的科研培训计划。这些创新的纵向研究将显著 促进我们对青少年接触THC的长期神经生物学影响的了解。这个 拟议的实验将提供个体前额叶进展活动的详细特征 在药物和非药物暴露的动物中，学习复杂任务过程中的神经元和群体。 鉴于最近与政治和健康有关的对大麻素对娱乐和健康的影响的兴趣 治疗用途，这项申请中提出的研究将为科学工作者提供有用的知识 在我作为一名独立调查员开始富有成效的职业生涯时，也是不可或缺的。

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.