Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol (THC) microdose on old mice

Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti- aging effects of THC microdose treatment in old mice. Experiments were performed on old (24 months old) female and young (2 months old) male mice of the Institute of Cancer Research. Each age-group was treated with a THC microdose (0.002mg/kg), or vehicle solution. Hippocampal samples were obtained from old and young mice 5 weeks after administration, an extra group of treated old mice were sampled 5 days after treatment. RNA was extracted from the samples and sequenced.

Delta-9-四氢大麻酚（Delta-9-tetrahydrocannabinol，简称THC）是大麻植物的主要精神活性成分，同时也是内源性大麻素系统（endocannabinoid system）的外源性配体。在既往研究中，我们证实单次给予THC微剂量（0.002mg/kg，相较于啮齿类动物标准剂量低3~4个数量级），可对遭受急性神经损伤的模型小鼠产生显著且长期的神经保护作用。当给予老年健康小鼠该THC微剂量时，可诱导出持久（长达数周）的多维度认知功能改善，同时伴随显著的大脑形态学与生化改变。为阐明这些效应背后的分子机制，我们对模型小鼠的海马组织样本进行了基因表达分析。给药后5天采集的样本显示，与神经发生（neurogenesis）及脑发育相关的基因存在显著差异表达。给药后5周采集的样本，其转录特征（transcriptional signature）则转向与神经元分化（neuronal differentiation）及神经元存活（neuronal survival）相关的特征。本研究证实，通过海马转录组分析（hippocampal transcriptome profiling），可揭示老年小鼠接受THC微剂量治疗后所产生的非典型抗衰老效应的分子基础。本实验使用的实验动物为24月龄雌性与2月龄雄性的ICR（Institute of Cancer Research）小鼠。各年龄组小鼠分别接受THC微剂量（0.002mg/kg）处理或溶剂对照（vehicle solution）处理。分别于给药后5周采集老年与年轻小鼠的海马组织样本；另有一组经处理的老年小鼠于给药后5天被采集样本。从样本中提取RNA并进行测序。