Enabling New Insights into the Living Brain Metabolome using LC-MS/MS and Untargeted Chemometrics

Central to advancing neuroscience is characterizing and monitoring the chemical composition of the brain extracellular space. The extracellular space is a complex microdomain between brain cells with a chemical composition that reflects several physiological functions occurring simultaneously on different spatiotemporal scales. Elucidating the role that these compounds play in normal and diseased brains can improve our understanding of neurological disorders. This work aims to define the living brain metabolome and reveal neurochemical differences underlying addiction vulnerability. Using in vivo microdialysis and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we are able to routinely monitor hundreds of compounds in the nucleus accumbens, a brain region associated with reward and motivation. Application of untargeted chemometrics can now allow us to dig deeper into these chromatograms and discover metabolites associated with differences in brain function. We show that the in vivo chemical composition of the nucleus accumbens undergoes significant alterations due to acute drug exposure. Ultimately, this work broadens our neurochemical understanding of addiction by implicating additional metabolic pathways involved in stress, neuroinflammation, and non-dopaminergic neurotransmission.