Imaging cannabinoid effects on developing cortical circuits

成像大麻素对皮质回路发育的影响

基本信息

批准号：
9308931
负责人：
Susanne Elizabeth Ahmari
金额：
$ 19.44万
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：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308931
关键词：
Abstinence Acute Address Adolescence Adolescent Adolescent Development Adult Affect Age Agonist Alcohol or Other Drugs use Alpha Cell Animals Attitude Behavior Behavior assessment Behavioral Brain CNR1 gene Calcium Cannabinoids Cannabis Cannabis sativa plant Catheters Cells Child Clinical Clinical Research Cognition Communities Complex Data Designer Drugs Development Disease Drug usage Endocannabinoids Evolution Exposure to Food Future Generations Head Human Image Immunohistochemistry Impaired cognition Impairment Implant Incidence Infusion procedures Intravenous Intravenous Drug Abuse K2/Spice Laboratories Link Literature Marijuana Mediating Methods Microscope Microscopy Modeling Mus Neurobiology Neurons Neurosciences Pattern Performance Pharmaceutical Preparations Phase Policy Developments Population Positioning Attribute Prefrontal Cortex Process Psychotropic Drugs Rattus Regulation Reporting Research Resolution Response Elements Rodent Rodent Model Seizures Self Administration Self-Administered Short-Term Memory Specificity Structure Techniques Technology Testing Tetracyclines Time Tissues Training Trans-Activators Transgenic Mice Transgenic Organisms Viral adolescent brain development age related awake base calcium indicator cannabinoid receptor cell type cognitive function cognitive performance cognitive task cost critical period development policy drug of abuse early adolescence experience experimental study functional outcomes illicit drug use in vivo in vivo imaging indexing interest lens marijuana legalization marijuana use microendoscope miniaturize mouse model neural circuit postnatal preclinical study promoter relating to nervous system sensor success synthetic cannabinoid tool

项目摘要

Project Summary/Abstract Marijuana (Cannabis sativa) is the most widely used illicit drug in the U.S. and use in adolescence is common. Onset of cannabis use in early adolescence is associated with temporary cognitive impairments, but the long- term neurobiological consequences are not well understood. In addition, medicinal use of cannabinoids in children and adolescents may be warranted for treating certain seizure-related disorders; therefore, an increased understanding of the costs vs. benefits of adolescent cannabinoid exposure are warranted to inform the ongoing development of policies regulating legal marijuana use. Rodent models provide the opportunity to perform controlled experiments on the timing, duration, and amount of cannabinoid exposure and eliminate potential confounds of human studies, such as pre-existing conditions and exposure to other drugs of abuse. In addition to determining the long-term behavioral consequences of cannabis exposure, it is also important to determine the effects on neural circuit activity that may produce more subtle effects on functional outcomes. Current technologies limit our ability to perform longitudinal recordings of neural activity in a cell-type specific manner across adolescent development, particularly in animals self-administering intravenous drugs of abuse and performing complex cognitive tasks. One solution is to perform in vivo imaging of ensemble neural activity using genetically-encoded calcium indicators (GECIs). In vivo Ca2+ imaging can resolve cellular activity in deep brain structures in awake behaving animals using integrated, head-mounted gradient refraction index (GRIN) lenses and miniaturized epifluorescent microscopes (microendoscopes). Currently, this technique has been primarily restricted to studies in adult mice. However, development of a transgenic rat expressing the latest generation GECI, GCaMP6f, will permit imaging of cortical activity over the course of adolescent development and make it feasible to compare neural circuit development in rodents that self-administer intravenous drugs of abuse, like cannabinoids, relative to controls. Thus, in this two-year project we propose to develop transgenic rats expressing GCaMP6f under the control of a neuronal promoter. We will assess neural activity patterns in prefrontal cortical regions responsible for working memory and cognitive performance, in rats that self-administer cannabinoids in adolescence. Adolescent self-administration groups will be compared to similarly trained adults and to food self-administering controls. We will assess working memory performance and associated cortical activity in these rats across development and in adulthood after a period of abstinence. The results of these studies will clarify the acute vs. long-term consequences of adolescent cannabinoid self- administration on working memory performance, and determine if the development of task appropriate neural activity patterns are affected by ongoing or prior cannabinoid self-administration. In addition, the GCaMP6f transgenic rat will be publicly available for broad use by the neuroscience community.

项目摘要/摘要大麻（Cannabis sativa）是美国使用最广泛的非法药物，在青春期使用很常见。青春期早期使用大麻的发作与暂时的认知障碍有关，但长期术语神经生物学后果尚不清楚。另外，大麻素在儿童和青少年可能有必要治疗某些与癫痫发作有关的疾病；因此，一个有必要提高对成本与青少年大麻素暴露的收益的了解。持续制定规范合法大麻使用的政策。啮齿动物模型提供了机会对大麻素暴露的时间，持续时间和数量进行受控实验并消除人类研究的潜在混淆，例如先前存在的疾病和接触其他滥用药物。在除了确定大麻暴露的长期行为后果外，对于确定对神经回路活性的影响，可能会对功能结果产生更细微的影响。当前技术限制了我们在细胞类型中执行神经活动纵向记录的能力跨青少年发展的方式，特别是在动物中自我管理滥用药物并执行复杂的认知任务。一种解决方案是进行整体神经活动的体内成像使用遗传编码的钙指标（GECIS）。体内Ca2+成像可以解决细胞活性使用集成的头部安装梯度折射指数的清醒行为动物中的深脑结构（笑）镜片和微型落荧光散发显微镜（微型镜检查）。目前，这项技术有主要仅限于成年小鼠的研究。但是，发育的转基因大鼠表达最新一代GECI GCAMP6F将允许在青少年过程中对皮质活动进行成像开发并使比较自我管理的啮齿动物中的神经回路发育是可行的相对于对照组，诸如大麻素的静脉滥用药物。因此，在这个为期两年的项目中，我们建议在神经元启动子的控制下发展出表达GCAMP6F的转基因大鼠。我们将评估神经前额叶皮质区域的活动模式，负责工作记忆和认知表现，在青春期中自我辅助大麻素的大鼠。将比较青少年的自我管理组对类似训练的成年人和食物自我管理对照。我们将评估工作记忆表现在戒酒时期，这些大鼠跨发育和成年后，这些大鼠的皮质活性相关。这些研究的结果将阐明青少年大麻素自我的急性与长期后果在工作记忆表现上管理，并确定任务的发展是否适当活动模式受到持续或先前的大麻素自我管理的影响。此外，GCAMP6F 神经科学界将公开使用转基因老鼠。