During adolescence, cannabis experimentation is common, and its association with interindividual variations in brain maturation well studied. Cellular and molecular underpinnings of these system-level relationships are, however, unclear. We thus conducted a three-step study. First, we exposed adolescent male mice to -9-tetrahydrocannabinol (THC) or a synthetic cannabinoid WIN 55,212-2 (WIN) and assessed differentially expressed genes (DEGs), spine numbers, and dendritic complexity in their frontal cortex. Second, in human (male) adolescents, we examined group differences in cortical thickness in 34 brain regions, using magnetic resonance imaging, between those who experimented with cannabis before age 16 (n = 140) and those who did not (n = 327). Finally, we correlated spatially these group differences with gene expression of human homologs of mouse-identified DEGs. The spatial expression of 13 THC-related human homologs of DEGs correlated with cannabis-related variations in cortical thickness, and virtual histology revealed coexpression patterns of these 13 genes with cell-specific markers of astrocytes, microglia, and a type of pyramidal cells enriched in dendrite-regulating genes. Similarly, the spatial expression of 18 WIN-related human homologs of DEGs correlated with group differences in cortical thickness and showed coexpression patterns with the same three cell types. Gene ontology analysis indicated that 37 THC-related human homologs are enriched in neuron projection development, while 33 WIN-related homologs are enriched in processes associated with learning and memory. In mice, we observed spine loss and lower dendritic complexity in pyramidal cells of THC-exposed animals (vs controls). Experimentation with cannabis during adolescence may influence cortical thickness by impacting glutamatergic synapses and dendritic arborization.

在青春期，大麻实验很常见，其与大脑成熟个体间差异的关系得到了很好的研究。然而，这些系统级关系的细胞和分子基础尚不清楚。因此，我们进行了一项三步研究。首先，我们将青春期雄性小鼠暴露于 -9-四氢大麻酚 （THC） 或合成大麻素 WIN 55,212-2 （WIN），并评估了其额叶皮层的差异表达基因 （DEG）、脊柱数量和树突复杂性。其次，在人类（男性）青少年中，我们使用磁共振成像检查了 16 岁之前尝试大麻的人 （n = 140） 和没有尝试过大麻的人 （n = 327） 之间 34 个大脑区域皮质厚度的组别差异。最后，我们在空间上将这些组差异与小鼠鉴定的 DEGs 的人类同源物的基因表达相关联。DEGs 的 13 种 THC 相关人类同源物的空间表达与大麻相关的皮层厚度变化相关，虚拟组织学揭示了这 13 个基因与星形胶质细胞、小胶质细胞和一种富含树突调节基因的锥体细胞的细胞特异性标志物的共表达模式。同样，DEGs 的 18 个 WIN 相关人类同源物的空间表达与皮质厚度的组差异相关，并显示出与相同三种细胞类型的共表达模式。基因本体分析表明，37 个 THC 相关的人类同源物在神经元投射发育中富集，而 33 个 WIN 相关同源物在与学习和记忆相关的过程中富集。在小鼠中，我们观察到 THC 暴露动物 （与对照组相比） 的锥体细胞的脊柱缺失和树突复杂性降低。 在青春期使用大麻的实验可能通过影响谷氨酸能突触和树突状树枝形成来影响皮质厚度。