Learning Hybrid Biophysical Neuron Models with Neural ODEs
Authors: Jonas Beck, Michael Deistler, Dóra Viktória Molnár, Jakob H. Macke, Philipp Berens
Organizations: Hertie Institute for AI in Brain Health, Tübingen, Germany · Tübingen AI Center, University of Tübingen, Tübingen, Germany · Machine Learning in Science, Excellence Cluster Machine Learning, University of Tübingen, Tübingen, Germany · Max Planck Institute for Biological Intelligence, München, Germany · Department Empirical Inference, Max Planck Institute for Intelligent Systems, Tübingen, Germany
Abstract
Biophysical neuron models link measurements of neural activity to underlying cellular mechanisms. Yet, a central challenge is that the kinetics of many ion channels are poorly characterized, and practical simplifications -- omitting channels or reducing morphological detail -- introduce systematic gaps between model and biology. Bridging these gaps requires approaches that can flexibly discover unmodeled dynamics while preserving mechanistic interpretability. Here, we introduce a hybrid modeling framework that embeds neural ordinary differential equations into conductance-based biophysical models to capture unknown currents or mis-specified channel kinetics. By parameterizing the neural ODE in terms of voltage-dependent steady-state and time-constant functions, we recover interpretable gating dynamics directly from voltage recordings without assuming a functional form. We show that the hybrid model fits the gating kinetics of 2400 ion channel models and recovers unknown gating dynamics from single current-clamp recordings, generalizing to out-of-distribution stimulus regimes under realistic inputs and parameter misspecification. We also use our method to reduce a multicompartment model of a cortical neuron into a single-compartment hybrid model with a learned axial current, yielding up to an order of magnitude lower computational cost. Together, our results establish a plug-and-play framework for selectively replacing unknown components of conductance-based models with neural ODEs while preserving their mechanistic structure.
Ordinary differential equation models of biochemical reactions are often formulated as stoichiometric systems in which the dynamics arise from a collection of interacting processes. A central challenge is that the functional form of each process is rarely known a priori and may be difficult to infer from data. We propose biochemically informed neural ordinary differential equations (BINODEs), a neural-ODE framework that retains the stoichiometric structure of mechanistic models while representing individual processes by neural networks. In BINODEs, the outputs of neural network processes (NNPs) are mapped to state derivatives through a linear layer analogous to a stoichiometric matrix. This architecture allows biological side information, such as process-specific inputs, sign constraints, and monotonicity assumptions, to be built directly into the model. We characterize the approximation properties of NNPs for several standard biochemical rate laws and show that the proposed framework recovers both trajectories and process-level structure in Monod, Lotka--Volterra, pharmacokinetic, and ultradian endocrine models. These results suggest that BINODEs offer a useful compromise between mechanistic interpretability and data-driven flexibility for modeling partially known biochemical or biological dynamical systems.
Luis L. Fonseca, Reinhard C. Laubenbacher, Lucas Böttcher
We introduce \emph{Dynamical Physics-Modeled Neural Networks} (DynPMNNs), a continuous-time deep learning architecture in which each hidden layer is defined as the solution of an ordinary differential equation. Unlike classical feed-forward networks, this approach replaces static activation functions with time-evolving dynamical systems, providing a biologically inspired interpretation of hidden-layer behavior and enabling the integration of physically meaningful models. The framework is rigorously grounded in Reproducing Kernel Banach Spaces (RKBSs), allowing DynPMNNs to be characterized as finite-dimensional solutions of an abstract training problem and revealing structural connections with standard neural networks. We present a concrete implementation based on the FitzHugh--Nagumo model for neuronal activation, where numerical ODE solvers are embedded into the computational graph via Euler-type schemes. Both network weights and dynamical parameters are trained jointly. Through experiments on the California Housing dataset, we compare DynPMNNs with Neural ODEs (NODEs) and Closed-form Continuous-Time Networks (CfCs). Despite using fewer trainable parameters, DynPMNNs achieve competitive performance. These results position DynPMNNs as a principled bridge between dynamical systems and deep learning, with promising directions for further research in expressivity, stability, and physics-based modeling.
Raul Felipe-Sosa, Angel Martin del Rey, Maria Flores Ceballos
Ordinary differential equations (ODEs) are widely used to model dynamical systems in physics, biology, neuroscience, and physiology, but in many applications some equations of the dynamics are unknown and only a subset of the state variables are measured. We propose a hybrid neural--physics framework in which the known components of the ODE are kept explicit and the missing components are represented by a neural network. The proposed method consists of two stages where we alternate between state and parameter estimation and iterate until a predetermined criterion is met. Specifically, in the first step, we treat the model parameters as being known and we infer the latent states from the available measurements using a Rauch--Tung--Striebel (RTS) smoother. In the second stage, we treat the smoothed trajectories as being known and use them to estimate the neural networks' parameters through backpropagation. We evaluate the method on benchmark systems spanning linear, nonlinear, and stiff dynamics under partial state observation. Across these settings, the proposed method learns missing ODE components from incomplete measurements while exploiting and retaining interpretable mechanistic structure and improving latent-state reconstruction and long-horizon prediction.
Ahmet Demirkaya, Georgios Stratis, Tales Imbiriba +2