The Unexplored Territory of Neural Models: Potential Guides for Exploring the Function of Metabotropic Neuromodulation

•Neural network models fail to incorporate many dimensions of physiological function regulated by metabotropic receptors.•Enumeration of the dimensions of metabotropic regulation of physiological function reveals unexplored areas of model space.•Not enough models address metabotropic regulation of adaptation, persistent and rebound spiking, and presynaptic inhibition.•Underexplored properties include metabotropic regulation of nonlinear dendritic interactions and synaptic plasticity. The space of possible neural models is enormous and under-explored. Single cell computational neuroscience models account for a range of dynamical properties of membrane potential, but typically do not address network function. In contrast, most models focused on network function address the dimensions of excitatory weight matrices and firing thresholds without addressing the complexities of metabotropic receptor effects on intrinsic properties. There are many under-explored dimensions of neural parameter space, and the field needs a framework for representing what has been explored and what has not. Possible frameworks include maps of parameter spaces, or efforts to categorize the fundamental elements and molecules of neural circuit function. Here we review dimensions that are under-explored in network models that include the metabotropic modulation of synaptic plasticity and presynaptic inhibition, spike frequency adaptation due to calcium-dependent potassium currents, and afterdepolarization due to calcium-sensitive non-specific cation currents and hyperpolarization activated cation currents. Neuroscience research should more effectively explore possible functional models incorporating under-explored dimensions of neural function.