The Neurometabolome of a Sensory Neuronal Network

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DESCRIPTION (provided by applicant): Understanding the healthy and the diseased brain requires knowledge of the biochemistry occurring within the neurons and supporting cells that make up our brain. It is well known that individual cells in the nervous system have distinct protein complements, but the consequences of this heterogeneity on the cellular metabolome are much less well understood. While neurotransmitters used in a network vary neuron-by-neuron, what are the cell-to-cell variations of the metabolome in the mammalian nervous system? For most metabolites, the answer is unknown. Using a suite of analytical technologies based on small-volume sampling, capillary electrophoresis with laser- induced fluorescence detection, single cell mass spectrometry, and capillary separations coupled to Fourier-transform mass spectrometry, the neurometabolome of a network of dorsal root ganglion (DRG) sensory neurons will be studied with unmatched chemical detail. DRG neurons are involved in the mechanisms of pain - one of most devastating side effects of many disorders. The neurotransmitters and metabolites in individual neurons and their functional neuronal compartments such as dendrites, axons, and cell bodies, will be characterized. The first stage of this work is to compile information on the metabolome of the DRG neurons, and examine this for unusual molecules. Next, using the DRG and its neurometabolome as the model, several specific questions are addressed: (1) Does the neurometabolome of functionally distinct neuronal compartments differ? (2) What subset of the small-molecule complement is released upon electrical or chemical stimulation, and thus may participate in cell-to-cell communication? (3) How does inflammation- induced pain change the neurometabolome of the DRG neurons? These efforts fit within the scope of the metabolomics roadmap initiative by developing innovative methodologies to investigate neurotransmitter and other small molecule compartmentalization on the function of a model sensory neuron network.