Spatial multiomic insights into acute cocaine exposure

Despite extensive research on the subject, a comprehensive understanding of the molecular events occurring within the reward system following acute and chronic cocaine use has been lacking. In this study, we propose to employ a novel analytical workflow that combines high-resolution mass spectrometry imaging of the brain with region-specific microscale proteomics to reveal the molecular consequences of cocaine exposure on the principal areas of the reward system. We will employ a unique molecular imaging system, recently established at the Hebrew University, called Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI), to spatially map hundreds of metabolites, neurotransmitters and lipids in the reward system. This will be coupled with newly developed region-specific microscale proteomics enabling analysis of minuscule tissue samples — less than 20 µg. Our preliminary results show that taken together these two unique methods provide a holistic overview of the intricate interplay between metabolites and proteins within the reward circuitry regions in vivo following cocaine exposure. Our findings include distinct region-specific alterations in the tricarboxylic acid cycle and lipid synthesis in mice 24 hours post-cocaine injections. Additionally, we link widespread reductions in key neurotransmitters across the reward system and calcium level modifications to changes in synaptic plasticity and mitochondria dysfunction.