Most neuromodulators signal, at least in part, by volume transmission. That is, the signaling molecules are released at sites where there is no synapse, and/or they escape from synapses to diffuse through the tissue more widely. This diffusion through the extracellular space (ECS), away from sites of release is not well understood. Furthermore, it complicates using pre-synaptic activity in modulatory axons as a measure of modulatory signaling.
To address this complexity, we collaborate with computational and theoretical neuroscientists to develop models of ECS diffusion and modulator concentration, and then test those models using methods from neurochemistry.
In this branch of the lab, we currently make use of the following methods:
- Fast scan cyclic voltammetry and constant potential amperometry to measure levels of individual modulatory molecules in the ECS.
- Microdialysis to sample the ECS
- Liquid chromatography combined with electrochemical detection or mass spectrometry to quantify levels of multiple modulators from single samples
This is also the branch of the lab in which we currently do most of our new methods development. We are working on:
- Improved electrochemical electrodes for use in vivo
- Applying methods from proteomics and metabolomics to the study of neuromodulation
- Detecting neuropeptides
- Optical sensors
- Improving viral methods for cell access
Identifying which modulatory molecules are active in a circuit is an essential first step in understanding flexible processing by that circuit.
Strikingly, even for V1 - arguably one of the best-described model circuits in the mammalian brain - the list of locally-active modulators is not known. This is a crucial knowledge gap that we seek to fill.
Some of the key unknowns in this domain are:
- What is the endogenous ligand for dopamine receptors for V1?
- Which neuropeptides are active in the V1 circuit? Which neurons are releasing them? Which cells express peptide receptors