High-throughput identification and characterization of conserved regulators of drug-induced plasticity using single-neuron resolution atlases of the complete Caenorhabditis elegans nervous system - Project Summary/Abstract Chronic exposure to psychostimulants leads to maladaptive long-lasting molecular and functional changes in the brain of vulnerable individuals that may contribute to susceptibility to Substance Use Disorder (SUD). Despite significant advances in understanding genetic and epigenetic factors that may underlie SUD, few effective treatment options exist. In order to advance our knowledge to therapeutic avenues, we need to overcome some of the existing technical and practical limitations of existing models, including the inability to characterize drug-induced changes nervous-system- wide with cellular resolution and the lack of in vivo high-throughput screening platforms for putative regulators and therapeutic compounds. The nematode Caenorhabditis elegans is a simple and well-characterized model organism that has led to many fundamental discoveries in conserved biological mechanisms. The genetic amenability and the compact nervous system allow us to conduct high-throughput screens and to analyze the entire nervous system with single neuron resolution, respectively. Combining advanced genetic, genomics, microscopy, and behavioral approaches, we will generate comprehensive molecular (transcriptome and chromatin landscape), behavioral, and neuronal activity atlases in response to acute vs. chronic exposure to cocaine. Leveraging these atlases, we will use high-throughput screening approaches in C. elegans to identify genetic regulators that underlie nervous-system-wide molecular and functional changes as a result of drug exposure. Finally, the genetic amenability of the C. elegans model allows us to causally examine the mechanistic roles of these regulators in drug-induced plasticity with unprecedented locus and cellular specificity. By establishing these approaches and platforms in the C. elegans model with cocaine, we can investigate other classes of drugs in the future, and open up new avenues for disease mechanism investigation and therapeutic identification for SUD.
