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. Overall design: 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.