Activity-dependent neuromodulation and calcium homeostasis cooperate to produce robust and modulable neuronal function.

Neurons rely on two interdependent mechanisms - homeostasis and neuromodulation - to maintain robust and adaptable functionality. Calcium homeostasis stabilizes neuronal activity by adjusting ionic conductances, whereas neuromodulation dynamically modifies ionic properties in response to external signals carried by neuromodulators. Combining these mechanisms in conductance-based models often produces unreliable outcomes, particularly when sharp neuromodulation interferes with calcium-homeostatic tuning. This study explores how a biologically inspired neuromodulation controller can harmonize with calcium homeostasis to ensure reliable neuronal function. Using computational models of stomatogastric ganglion and dopaminergic neurons, we demonstrate that controlled neuromodulation preserves neuronal firing patterns while calcium homeostasis simultaneously maintains target intracellular calcium levels. Unlike sharp neuromodulation, the neuromodulation controller integrates activity-dependent feedback through mechanisms mimicking G-protein-coupled receptor cascades. The interaction between these controllers critically depends on the existence of an intersection in conductance space, representing a balance between target calcium levels and neuromodulated firing patterns. Maximizing neuronal degeneracy enhances the likelihood of such intersections, enabling robust modulation and compensation for channel blockades. We further show that this controller pairing extends to network-level activity, reliably modulating the rhythmic activity of central pattern generators. This study highlights the complementary roles of calcium homeostasis and neuromodulation, proposing a unified control framework for maintaining robust and adaptive neural activity under physiological and pathological conditions.