From cellular cognition to psychopathology: a three-level framework of biological decision-making

Nole Guerrero G.L. · Medical Hypotheses (2026) · DOI: 10.1016/j.mehy.2026.111914

Resumen

This article proposes a three-level framework for understanding biological decision-making. At Level 1, the cellular living system perceives its environment through metabolic signals and selects adaptive states within gene regulatory networks. At Level 2, the neuron—as an evolved living system—amplifies these capacities through adaptive dendritic processing; we propose that nervous system evolution follows a hierarchical principle where newer structures acquire regulatory control over older ones. At Level 3, neuronal groups operate as collective selection units whose behavior depends on the balance between subcortical driver circuits and cortical inhibitory circuits. The central contribution is a framework with falsifiable predictions. Cortical inhibitory control may critically depend on two energetically demanding neuronal populations: fast-spiking parvalbumin-positive interneurons (PV + ) and prefrontal pyramidal neurons (PrN). We propose that these populations share convergent vulnerability. PV + interneurons require maintenance of ionic gradients and sustained high-frequency firing. Prefrontal pyramidal neurons appear to have evolved with a specialization toward lipid metabolism, consistent with TKTL1-linked findings; they also exhibit higher energy costs due to partial myelination, depend on external lipid supply whose relevance has been highlighted by brain lipidomics studies, and show preferential enrichment of the MCT2 transporter, which could be compatible with preferential use of monocarboxylates as physiological substrate. Critically, the type of energy substrate—not just its quantity—may determine neuronal firing stability. Metabolic studies suggest that β-hydroxybutyrate is an efficient substrate for GABA synthesis in cultured GABAergic neurons, and that ketones may favor inhibitory firing patterns while glucose may favor excitatory patterns. When the living system cannot sustain inhibitory tone, subcortical circuits such as the nucleus accumbens may assume behavioral control, restricting behavior outside conscious control and generating self-maintained pathological patterns: hyperphagia, depressive rumination, compulsion, craving.