Neuromodulation and homeostasis: complementary mechanisms for robust neural function

TL;DR

It is demonstrated that controlled neuromodulation preserves neuronal firing patterns while maintaining intracellular calcium levels, and suggested that targeting neuromodulation pathways-rather than ion channels directly-may offer safer pharmacological strategies to manage neuronal dysfunctions.

Abstract

Neurons depend on two interdependent mechanisms-homeostasis and neuromodulation-to maintain robust and adaptable functionality. Homeostasis stabilizes neuronal activity by adjusting ionic conductances, whereas neuromodulation dynamically modifies ionic properties in response to external signals. Combining these mechanisms in conductance-based models often produces unreliable outcomes, particularly when sharp neuromodulation interferes with homeostatic tuning. This study explores how a biologically inspired neuromodulation controller can harmonize with 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 maintaining 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 central pattern generators in crustaceans. These findings suggest that targeting neuromodulation pathways-rather than ion channels directly-may offer safer pharmacological strategies to manage neuronal dysfunctions. This study highlights the complementary roles of homeostasis and neuromodulation, proposing a unified control framework for maintaining robust and adaptive neural activity under physiological and pathological conditions.

Figures (6)

• Figure 1: Interference between homeostasis and sharp neuromodulation leads to pathological outcomes. Time evolution of all conductances in the STG model, displayed on a logarithmic scale, during homeostasis with sharp neuromodulation (instantaneous changes in $\bar{g}_\mathrm{CaS}$ and $\bar{g}_\mathrm{A}$ starting at the dashed blue line) for a degenerate population of 200 models (top). The corresponding mean intracellular calcium concentration over time (bottom) shows the target value (red dash-dotted line) is maintained both before and after sharp neuromodulation.
• Figure 2: Controlled neuromodulation and homeostasis naturally lead to robust and modulable neuronal function. A. Schematic representation of neuromodulation (left) and homeostasis (right) cascades. Neuromodulators bind to G-protein receptors, triggering complex signaling pathways that selectively affect subsets of ion channels. In contrast, homeostasis senses intracellular calcium levels and regulates them by adjusting all conductances uniformly. B. Time evolution of all conductances in the STG model, displayed on a logarithmic scale, during homeostasis with controlled neuromodulation (controlled changes in $\bar{g}_\mathrm{CaS}$ and $\bar{g}_\mathrm{A}$) for a degenerate population of 200 models (left). The corresponding mean intracellular calcium concentration over time (right) shows the target value (red dash-dotted line) is maintained both before and after controlled neuromodulation.
• Figure 3: Controlled neuromodulation tunes the direction of homeostasis-driven changes in conductance values to ensure stable neuromodulated function during homeostatic regulation. A. Trajectories of the STG population from Fig \ref{['fig:fig1']} in the modulated conductance space during homogeneous scaling in tonic spiking only. As expected from homeostasis, all neurons move in the same direction. White circles represent the initial conditions at the start of the step, and the green triangle marks the final conditions. B. Same as panel A, but during the brief period when neuromodulation is active. All trajectories are parallel to one another. C. Same as panels A and B, but during the homeostasis phase following neuromodulation. The outcome depends on the type of neuromodulation: sharp (left) or controlled (right). Sharp neuromodulation results in non-robust outcomes, whereas controlled neuromodulation preserves robust neural function.
• Figure 4: Schematic explanation of why controlled neuromodulation integrates better with homeostasis compared to sharp neuromodulation. A. Schematic of the modulated conductance space for homeostasis combined with sharp neuromodulation. Initially (white circles), the neuron spikes at the target calcium level, located at the intersection of the firing pattern isocline (dashed blue lines) and the calcium level isocline (dashed green lines). Following sharp neuromodulation to a new firing pattern (red diamond), calcium levels sharply increase. Homeostasis reduces calcium (solid red arrow) by moving along the same direction as before neuromodulation (dashed red arrow), causing the neuron to deviate from the neuromodulated firing pattern isocline. B. Same as panel A, but with controlled neuromodulation. The initial steps are identical, but after neuromodulation, as homeostasis acts to reduce calcium, controlled neuromodulation simultaneously adjusts to keep the neuron on the neuromodulated firing pattern isocline (sawtooth red arrow). Because controlled neuromodulation operates on a much faster timescale than homeostasis, the neuron remains on the neuromodulated firing pattern isocline throughout.
• Figure 5: Controlled neuromodulation and homeostasis ensure the preservation of function under physiologically recoverable disturbances. A. Time evolution of all conductances in the STG model, displayed on a logarithmic scale, during homeostasis with controlled neuromodulation (controlled changes in $\bar{g}_\mathrm{CaS}$ and $\bar{g}_\mathrm{A}$ starting at the dashed blue line) for a degenerate population of 200 models with H-type ion channel blockade (left). The corresponding distribution of behaviors before the blockade, immediately after the blockade, and following compensation (right) demonstrates the effect of the blockade. In this case, no neurons lose bursting due to the channel blockade or compensation. B. Same as panel A, but with a CaT channel blockade. The blockade causes half of the neurons to lose bursting; however, all neurons recover bursting with compensation. C. Same as panel A, but with a KCa channel blockade. The blockade causes more than half of the neurons to lose bursting, but nearly all recover bursting with compensation. D. Same as panel A, but with a Na channel blockade. The blockade causes all neurons to lose bursting, and compensation does not restore bursting due to the non-degenerate essential role of Na channels.