Mechanistic bridges from receptors to whole-brain dynamics: mean-field reductions, validity domains, and computational trade-offs

Abstract

Many pharmacological and pathological perturbations arise at molecular, synaptic, or cellular scales, but are observed through population and whole-brain signals. Cross-scale reductions must preserve relevant mechanisms while remaining tractable. This review asks which microscopic mechanisms remain explicit, interpretable, and testable after reduction, and what claims these models support. Using receptor-aware adaptive mean fields from the master-equation lineage as a worked case, we trace finite-size population statistics and semi-analytical transfer functions into conductance-based adaptive nodes coupled through the connectome. We compare this strategy with phenomenological neural masses, low-dimensional and population-density reductions, large-scale spiking models, and learned or hybrid surrogates, including computational work and memory traffic. Receptor-dependent synaptic kinetics, conductance state, and spike-frequency adaptation can remain manipulable across scales, enabling interpretable interventions and testable mesoscopic and macroscopic consequences. However, this relies on coarse-grained Markovianity, population homogeneity, quasi-stationary transfer functions, moment closure, regional uniformity, and measurement-specific observation models. First-order implementations discard covariance dynamics, while macroscopic agreement cannot identify a unique molecular cause. Node-local biological detail mainly changes prefactors, whereas dense global covariances change the scaling class. Cross-scale models should therefore be judged by the interventions and observables they preserve, validity domain, identifiability, empirical adequacy, and computational burden. Receptor-aware mean fields are not universal, but offer a transparent, tractable strategy for selected mechanistic questions when each reduction step is independently validated.