Neuromodulation Of Neuronal Oscillations

Neuromodulators provide flexibility for neural circuit operation and behavior. Yet, at any given time, neuralcircuits are subject to modulation by multiple neurotransmitters and neurohormones. Each modulator elicits itsown specific activity pattern, and presumably, co-modulation by multiple substances increases the degree ofcircuit flexibility. Despite the multitude of possible combinations and relative concentrations, the output of anyneural circuit has low variability across individuals under baseline conditions. Even under identical modulatoryconditions this would not be obvious, given that the expression levels of the molecular targets of modulators,for example ion channels, can vary substantially across the population. Numerous studies show that multiplemodulators can target the same voltage-gated ion channel type or the same synapse. We propose, somewhatcounterintuitively, that the presence of multiple convergent neuromodulators at low concentrations in factreduces population variability of circuit activity, a hypothesis that is supported by preliminary data. We furtherpropose that consistent circuit activity can occur in the presence of different sets of convergent modulators.We examine these hypotheses in the oscillatory pyloric circuit of the crab stomatogastric ganglion (STG), oneof the premier systems for the study of neuromodulation. We propose to combine detailed quantitativemeasurements of circuit output, as well as underlying synaptic and voltage-gated ionic currents, at differentconcentrations of 5 neuropeptide modulators and a muscarinic agonist. The modulators of interest are knownto target the same fast low-threshold voltage-gated inward current, which increases excitability of STGneurons. A subset of the peptide modulators are known to enhance the same synaptic connections, whileothers have unknown actions on the synapses, which we plan to explore. Electrical coupling conductancesalso appear to be modulated by the peptides, potentially with nonlinear interactions. We propose experimentsto examine the interactions of modulators at these component levels, with a detailed focus on two well studiedneuropeptide modulators, proctolin and the crustacean cardioactive peptide.We will use evolutionary algorithm optimization techniques to produce populations of computational models ofthe pyloric neurons and synapses, based on these data, where each single model produces the sameresponses, but different models in the population have different levels of ionic conductances, as observed inthe biological system. Component models will be used to build circuit models that produce appropriate activityand correct (co-)modulatory responses. These models would allow us to explore how circuit-level populationvariability may be changed by co-modulation and by component variability. Additionally, the models will enableus to predict how modulation of components gives rise to circuit patterns of activity specific to that modulator.This work would provide a basic framework for understanding the interactions between different convergentneuromodulators, which can help elucidate drug interaction mechanisms in pharmaceutical therapies.