Elucidating the neurochemical basis of LTP induction and maintenance in vivo

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PROJECT SUMMARY Norepinephrine (NE)-containing neuronal cells in the locus coeruleus (LC) are thought to co-release dopamine (DA) from many of its projections, including into the hippocampus. Through DA and NE release, the LC is thought to play a major role in modulating hippocampal memory encoding through the maintenance of long-term potentiation (LTP), an integral mechanism for memory consolidation. Understanding the mechanisms by which the LC modulates memory is of fundamental importance to investigations into hippocampal memory circuitry and dynamics. However, because of their structural similarity, it has been difficult to ascertain the precise roles that DA and NE each have on LTP maintenance. In vivo microdialysis has been traditionally used in the past to measure tonic extracellular concentrations of molecules in the brain, but damage to tissue because of the size of the sampling probe and low spatiotemporal resolution make real-time tracking of tonic neurotransmitter concentrations, and their biological functions, problematic. Our lab has developed state- of-the-art voltammetric techniques capable of measuring tonic concentrations of neurotransmitters in real-time with very high spatial resolution. We hypothesize that by altering the voltammetric waveform applied in vivo and by developing a novel artificial intelligence based post-processing pipeline, very similar analytes such as DA and NE can be reliably resolved. Through accurate neurotransmitter identification and pharmacologic manipulation, we aim to ascertain the specific effects NE and DA have on hippocampal LTP. Additionally, we hypothesize that electrical stimulation of the LC will lead to increased hippocampal DA and NE release and enhanced LTP induction compared to no stimulation. The ability to resolve individual analytes based on their voltammetric signals has been an unsolved problem in electrochemistry and will enable tracking of their relative real-time contributions to LTP induction and maintenance in the hippocampus with high accuracy. A greater understanding of LTP induction and maintenance mechanisms is of vital importance to garnering an increased understanding of memory circuitry and physiology.