R. Grashow, T. Brookings, and E. Marder, Reliable neuromodulation from circuits with variable underlying structure, Proc Natl Acad Sci U S A, vol. 106, no. 28, pp. 11742–11746, Jul. 2009.

Recent work argues that similar network performance can result from highly variable sets of network parameters, raising the question of whether neuromodulation can be reliable across individuals with networks with different sets of synaptic strengths and intrinsic membrane conductances. To address this question, we used the dynamic clamp to construct 2-cell reciprocally inhibitory networks from gastric mill (GM) neurons of the crab stomatogastric ganglion. When the strength of the artificial inhibitory synapses (g(syn)) and the conductance of an artificial I(h) (g(h)) were varied with the dynamic clamp, a variety of network behaviors resulted, including regions of stable alternating bursting. Maps of network output as a function of g(syn) and g(h) were constructed in normal saline and again in the presence of serotonin or oxotremorine. Both serotonin and oxotremorine depolarize and excite isolated individual GM neurons, but by different cellular mechanisms. Serotonin and oxotremorine each increased the size of the parameter regions that supported alternating bursting, and, on average, increased burst frequency. Nonetheless, in both cases some parameter sets within the sample space deviated from the mean population response and decreased in frequency. These data provide insight into why pharmacological treatments that work in most individuals can generate anomalous actions in a few individuals, and they have implications for understanding the evolution of nervous systems.