Effects of adolescent cannabinoid exposure on cortical development

青少年接触大麻素对皮质发育的影响

基本信息

批准号：
9755791
负责人：
SIERRA STRINGFIELD
金额：
$ 6.61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9755791
关键词：
Address Adolescence Adolescent Adult Affect Agonist Animals Area Autoradiography Behavior Behavioral Brain CNR1 gene Cannabinoids Cells Chronic Cognitive Communities Complex Control Groups Data Data Set Development Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dose Drug Exposure Drug usage Ensure Exposure to Glutamates Health Human Image Individual Infusion procedures Knowledge Learning Longitudinal Studies Marijuana Measures Medial Memory Memory impairment Modeling Molecular Neurobiology Neurons Neurotransmitters Pattern Performance Pharmaceutical Preparations Politics Population Prefrontal Cortex Primates Process Rattus Reporting Research Research Personnel Research Training Rodent Sampling Self Administration Short-Term Memory Signal Transduction Statistical Data Interpretation Sucrose Synapses System THC exposure Task Performances Techniques Testing Tetrahydrocannabinol Therapeutic Uses Time Training Universities Volition base cannabinoid receptor career cognitive function cognitive performance cognitive task controlled release critical period drug of abuse experimental study faculty mentor gamma-Aminobutyric Acid hippocampal pyramidal neuron implantation improved in vivo in vivo calcium imaging innovation insight interest lens marijuana use neuroadaptation neurodevelopment neuron development neuronal excitability neuronal patterning non-drug preclinical study protein expression receptor receptor expression response rimonabant skills synthetic cannabinoid

项目摘要

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.

项目摘要 /摘要青春期是神经元发展的关键时期，在TIS期间暴露于滥用药物脆弱性会改变非发育的过程，从而导致变化持续到成年。最初暴露于大麻素（例如-9-四氢大麻酚（THC））发生在青春期期间这种暴露会改变神经元和分子水平的发育。表明在青春期重复接触THC可以产生学习学习和人为缺陷。这些研究是使用实验者管理的THC进行的，作为啮齿动物的自我管理 THC很难实现。动物的剂量可以选择随着时间的推移接受多少药物可能与经验管理的剂量。在学习和记忆方面，其他范式证明了这一差距。支撑研究将测试青少年THC自我管理对行为的长期影响，受体表达和成年中的神经元活性。在整个青春期，一旦成年，它们将接受测试在某些老鼠中，我们将最多的多巴胺能和大麻素受体随着受体的表达在青春期发育，可能会被慢性激活是由于高厚的暴露。工作记忆任务以测量神经元活动，跟踪单个PFC神经元并测量动态我们学习过程中的活动波动。将在皮质多巴胺能和大麻素信号中引起剂量依赖性神经适应，从而导致绩效要求行为的神经元活动的改变培训计划Willow我将在细胞和分子技术方面发展新的和必要的技能复杂神经元数据集的统计分析。匹兹堡大学和卡内基·梅隆大学的导师和合作者，无论是什么成功完成我的研究培训计划。促进我们对青少年暴露的神经生物学效应的了解支撑实验将提供单个前额叶进度的详细表征在吸毒和药物暴露的动物中，在学习复杂任务的过程中，神经元和合奏。鉴于对大麻素对娱乐活动的影响最近与政治和健康有关的兴趣治疗用途，应用程序内部提出的研究为科学提供了有用的知识社区，以及我在作为独立研究员的生产生涯中充满活力的生活。