Multiple
neuromodulators act in concert to shape the properties of neural circuits. Different
neuromodulators usually activate distinct receptors but can have overlapping targets. Therefore, circuit output depends on
neuromodulator interactions at shared targets, a poorly understood process. We explored quantitative rules of co-modulation of two principal targets of neuromodulation: synapses and voltage-gated ionic currents. In the stomatogastric
ganglion of the male crab
Cancer borealis, the
neuropeptides proctolin (Proc) and the
crustacean cardioactive peptide (CCAP) modulate synapses of the pyloric circuit and activate a voltage-gated current (IMI) in multiple neurons. We examined the validity of a simple dose-dependent quantitative rule, that co-modulation by Proc and CCAP is predicted by the linear sum of the individual effects of each modulator up to saturation. We found that this rule is valid for co-modulation of synapses, but not for the activation of IMI, in which co-modulation was sublinear. The predictions for the co-modulation of IMI activation were greatly improved if we assumed that the intracellular pathways activated by two
peptide receptors inhibit one another. These findings suggest that the pathways activated by two
neuromodulators could have distinct interactions, leading to distinct co-modulation rules for different targets even in the same neuron. Given the evolutionary conservation of
neuromodulator receptors and signaling pathways, such distinct rules for co-modulation of different targets are likely to be common across neuronal circuits.SIGNIFICANCE STATEMENT We examine the quantitative rules of co-modulation at multiple shared targets, the first such characterization to our knowledge. Our results show that dose-dependent co-modulation of distinct targets in the same cells by the same two
neuromodulators follows different rules: co-modulation of synaptic currents is linearly additive up to saturation, whereas co-modulation of the voltage-gated ionic current targeted in a single neuron is nonlinear, a mechanism that is likely generalizable. Given that all neural systems are multiply modulated and
neuromodulators often act on shared targets, these findings and the methodology could guide studies to examine dynamic actions of
neuromodulators at the biophysical and systems level in sensory and motor functions, sleep/wake regulation, and cognition.