Critical Mechanisms Underlying THC Neurotoxicity in Developing CNS

精神药物，大麻（大麻），正变得越来越被接受，无论是药用还是 娱乐用途。大麻主要由育龄青年使用， 没有关于在怀孕期间使用避孕药的警告，但在怀孕期间经常使用/滥用避孕药。 这些关键时期。事实上，据估计，在美国， 欧洲受到产妇使用大麻的影响。尽管人类临床观察和动物研究 已经证明，产前和/或新生儿接触大麻会产生一系列神经认知功能障碍， 和神经行为缺陷，所涉及的分子机制知之甚少， 中枢神经系统（CNS）损伤。拟议的研究将结合联合收割机的行为和 产前和产后早期大麻（CB）神经生物学后果的神经解剖学分析 暴露，以检验全球假设，大麻神经毒性的关键机制， 发展中的CNS是大麻受体介导的内在凋亡途径的触发，导致细胞凋亡。 CNS区域内的死亡对应于许多先前证明的大麻相关的 行为/认知/运动缺陷，即，前额叶皮层海马体和小脑对于这些研究， 将给予大麻的主要精神活性成分--四氢大麻酚（THC） 在妊娠期间或新生儿早期，野生型小鼠和基因工程小鼠，缺乏 促凋亡bax基因。然后我们将进行行为测试，以揭示特定的功能缺陷 这些中枢神经系统区域，并将确定是否Bax的损失减弱这些赤字。然后我们将表演 前额叶皮层、海马和小脑中神经元的体视学计数，这些区域对神经元的功能至关重要。 选择的行为任务，以确定是否109 THC诱导的神经元损失有助于行为 赤字，以及Bax的损失是否减轻了这种损失。个人身份将被保留，以便行为和 神经解剖学数据可以是相关的。我们假设，这种主要凋亡效应物的丢失将导致 显著改善行为/认知/运动任务的表现，伴有阻滞或迟钝 9 THC介导的神经元死亡。该项目将是第一个研究凋亡神经元丢失作为一种 THC暴露的发展结果，并作为THC介导的行为/认知的前因 缺陷;也将是第一个使用基因删除技术来定义关键机制的基础上， 9 THC对大脑发育的有害影响。

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.