UC San Diego

Methamphetamine (METH) and tetrahydrocannabinol (THC) are drugs that a segment of pregnant women may be exposed to, however, their effect on the development of the fetal brain is not completely understood. Research has been done on the effects of these drugs, but these studies are typically done in mice models which may not be completely representative of the human brain. Analyzing the effects of these drugs through the human cerebral organoid model can provide valuable insights into the human fetal brain and the factors that affect its development. We use single-cell RNA-sequencing analysis of human cerebral brain organoids to study the changes in gene expression caused by these drugs and to determine their effects on the developing brain. Exposure of human cerebral organoids to METH led to the upregulation of genes associated with stress and inflammation suggesting that METH leads to neuroinflammation. Furthermore, genes associated with neural development were downregulated suggesting that METH hinders the development of the brain. The upregulated and downregulated pathways as a result of METH exposure indicate that there is likely a negative effect on fetal brain development and that METH exposure may lead to neuroinflammation. Analysis of THC organoids suggests that THC exposure may be altering glutamatergic neurons with enhanced expression of CNR1 and leading to preferential differentiation toward glutamatergic fate via NEUROD6. These results indicate that human cerebral organoids may provide valuable insights into the effects of drugs on the development and gene expression in the human fetal brain.