An Integrated Five-Discipline Computational Framework for Modeling Neurochemical Dysfunction in Symptomatic Rabies: A Rigorous Theoretical Protocol Combining Computational Neuroscience, Mathematical Virology, Systems Biology, Bayesian Inference, and Neuropharmacology

Background: Rabies virus (RABV) infection causes near-universal mortality (>99.9%) once clinical symptoms manifest, primarily through functional disruption of neurotransmitter systems and brainstem autonomic centers rather than gross neuronal destruction. Current therapeutic approaches, including the Milwaukee Protocol, have failed to demonstrate reproducible efficacy in rigorous evaluation.Methods: We present a mathematically rigorous theoretical framework integrating five disciplines: (1) Computational Neuroscience for modeling neurotransmitter receptor kinetics and synaptic transmission dynamics; (2) Mathematical Virology for characterizing within-host viral population dynamics with spatial compartmentalization; (3) Systems Biology for network-level analysis of perturbed neurochemical pathways; (4) Bayesian Inference for parameter estimation under epistemic uncertainty with formal identifiability analysis; and (5) Neuropharmacology for in silico evaluation of targeted intervention strategies. We develop coupled nonlinear ordinary differential equation (ODE) systems with proven existence and uniqueness properties, implement Hamiltonian Monte Carlo (HMC) with convergence diagnostics, and perform global sensitivity analysis using variance-based Sobol' indices with polynomial chaos expansion for uncertainty propagation.Results: Our model quantitatively characterizes the disruption of acetylcholine (ACh) and serotonin (5-HT) signaling pathways, predicting critical bifurcation thresholds for intervention efficacy. Bayesian parameter estimation with weakly informative priors reveals substantial epistemic uncertainty in key kinetic parameters (posterior coefficient of variation: 45--89%). Global sensitivity analysis identifies viral receptor binding affinity (γ_V) as the most influential parameter for brainstem dysfunction outcomes (total-effect Sobol' index: S_T = 0.87 ± 0.06). Formal falsifiability criteria are established through testable predictions regarding neurotransmitter recovery dynamics.Conclusions: This theoretical framework provides a quantitative, reproducible foundation for understanding rabies pathophysiology at the systems level and identifies potential mechanistic intervention points. However, given the documented near-universal fatality of symptomatic rabies and the failure of previous therapeutic attempts in controlled evaluation, this framework remains strictly hypothetical. We emphasize that no validated treatment exists for symptomatic rabies, and prevention through vaccination and post-exposure prophylaxis remains the only evidence-based approach. This work is intended solely to guide future preclinical research under appropriate ethical oversight.