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Critical Mechanisms Underlying THC Neurotoxicity in Developing CNS

THC 对中枢神经系统发育的神经毒性的关键机制

基本信息

批准号：
9222525
负责人：
MARIETA B HEATON
金额：
$ 22.88万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222525
关键词：
Adult Affect Age Animals Apoptosis Apoptotic Attenuated BAX gene Behavioral Blood - brain barrier anatomy Brain CASP3 gene CNR1 gene Cannabinoids Cannabis Cell Death Cells Cerebellum Chronic Clinical Cognitive Cognitive deficits DNA Fragmentation Data Development Europe Exposure to Female Functional disorder Gene Deletion Genetic Genetically Engineered Mouse Genotype Hippocampus (Brain)Human Human Milk In Vitro Individual Lead Learning Link MAPK8 gene Marijuana Mediating Memory Mitochondria Modification Molecular Motor Mus Neonatal Neuraxis Neurobiology Neurocognitive Neurons Nuclear Performance Pharmaceutical Preparations Physical condensation Population Prefrontal Cortex Pregnancy Process Protein p53 Purkinje Cells Pyramidal Cells Rattus Reporting Series Short-Term Memory Staining method Stains THC exposure Technology Testing Tetrahydrocannabinol Tumor Suppressor Proteins United States Wild Type Mouse annexin A5 behavior test child bearing critical period cytochrome c improved in vivo male marijuana use morris water maze motor deficit neonatal exposure neurobehavioral neuron loss neurotoxicity postnatal prenatal prenatal exposure receptor young adult

项目摘要

The psychotropic substance, cannabis (marijuana), is becoming increasingly accepted, for both medicinal and recreational purposes. Cannabis is used predominantly by young adults of childbearing ages and since warnings against its use during pregnancy have not been forthcoming, it is frequently used/abused during these critical periods. It has in fact been estimated that more than 10% of pregnancies in the United States and Europe are affected by maternal cannabis use. Although both human clinical observations and animal studies have demonstrated that prenatal and/or neonatal exposure to cannabis produces a range of neurocognitive and neurobehavioral deficits, relatively little is known of the molecular mechanisms involved, and the extent of the central nervous system (CNS) damage produced. The proposed studies will combine behavioral and neuroanatomical analyses of the neurobiological consequences of prenatal and early postnatal cannabis (CB) exposure, to test the global hypothesis that a critical mechanism underlying cannabis neurotoxicity to the developing CNS is the cannabis receptor-mediated triggering of the intrinsic apoptosis pathway, leading to cell death within CNS regions corresponding to many of the previously demonstrated cannabis-related behavioral/cognitive/motor deficits, i.e., prefrontal cortex, hippocampus, and cerebellum. For these studies, 9-tetrahydrocannabinol (9THC), the primary psychoactive component of marijuana, will be administered during gestation or in the early neonatal period, to wild-type mice, and to genetically engineered mice, lacking the pro-apoptotic bax gene. We will then conduct behavioral tests chosen to reveal functional deficits specific to these CNS regions, and will determine whether loss of Bax attenuates these deficits. We will then perform stereological counts of neurons in prefrontal cortex, hippocampus, and cerebellum, regions critical to the behavioral tasks chosen, to determine whether 9THC-induced neuronal loss contributes to the behavioral deficits, and whether loss of Bax mitigates this loss. Individual identities will be retained so that behavioral and neuroanatomical data may be correlated. We hypothesize that loss of this primary apoptosis effector will significantly improve performance in behavioral/cognitive/motor tasks, accompanied by blocking or blunting 9THC-mediated neuronal death. This project will be the first to investigate apoptotic neuronal loss as a consequence of developmental THC exposure, and as an antecedent to THC-mediated behavioral/cognitive deficits; and will also be the first to use gene-deletion technologies to define critical mechanisms underlying the harmful effects of 9THC on the developing brain.

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