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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.

项目概要/摘要大麻（Cannabis sativa）是美国使用最广泛的非法药物，在青少年中使用很常见。青春期早期吸食大麻与暂时性认知障碍有关，但长期影响术语“神经生物学后果”尚未得到很好的理解。此外，大麻素的药用用途儿童和青少年可能需要治疗某些癫痫相关疾病；因此，一个有必要进一步了解青少年接触大麻素的成本与收益正在制定规范大麻合法使用的政策。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对照实验，并消除人类研究的潜在混淆，例如先前存在的条件和接触其他滥用药物的情况。在除了确定接触大麻的长期行为后果外，也很重要确定对神经回路活动的影响，这可能会对功能结果产生更微妙的影响。当前的技术限制了我们对特定细胞类型的神经活动进行纵向记录的能力跨越青少年发展的方式，特别是在动物自我注射静脉注射滥用药物中并执行复杂的认知任务。一种解决方案是对整体神经活动进行体内成像使用基因编码钙指示剂（GECI）。体内 Ca2+ 成像可以解析细胞活动使用集成的头戴式梯度折射率研究清醒行为动物的深层大脑结构 (GRIN) 透镜和小型落射荧光显微镜（显微内窥镜）。目前，该技术已主要限于对成年小鼠的研究。然而，表达该基因的转基因大鼠的开发最新一代 GECI，GCaMP6f，将允许对青少年时期的皮质活动进行成像开发并使得可以比较自我管理的啮齿类动物的神经回路发育相对于对照组，静脉注射滥用药物，如大麻素。因此，在这个为期两年的项目中，我们建议开发在神经元启动子控制下表达 GCaMP6f 的转基因大鼠。我们将评估神经负责工作记忆和认知表现的前额皮质区域的活动模式在青春期自我施用大麻素的老鼠。青少年自我给药组将进行比较接受过类似培训的成年人和食品自我管理控制。我们将评估工作记忆表现以及这些大鼠在整个发育过程中以及禁欲一段时间后的成年期的相关皮质活动。这些研究的结果将阐明青少年大麻素自我使用的急性后果与长期后果对工作记忆表现进行管理，并确定任务的发展是否适合神经活动模式受到正在进行或之前的大麻素自我给药的影响。此外，GCaMP6f 转基因大鼠将公开供神经科学界广泛使用。