Cholinergic Modulation of Proteinoid Microsphere Networks as Prebiotic Depression Models

Abstract

The molecular origins of mood disorders remain obscured by the overwhelming complexity of biological neural networks. Proteinoid microspheres are cell-like structures composed of amino acids, formed through heat-driven polymerization. Spontaneous electrical activity is observed in these microspheres and is modulated by nicotine, a potent cholinergic agonist associated with depression. Electrochemical characterization using impedance spectroscopy and cyclic voltammetry, combined with long-duration monitoring (over 75 h), demonstrates that nicotine induces a “depressive” state in prebiotic networks, defined here as a suppression of coherent, high-amplitude spiking activity. Crucially, this suppression is not a reduction in total activity: nicotine induces hyperactive but low-fidelity dynamics, in which increased firing frequency is accompanied by degraded signal organization and reduced informational content. This state is not defined by reduced activity, but rather by degraded signal quality. A 52% increase in firing frequency is accompanied by reduced amplitude precision, as deterministic dynamics collapse into stochastic noise. In parallel, phase-space volume expands by 1500-fold, indicating a major breakdown in homeostatic regulation. Equivalent circuit modeling shows that nicotine decreases membrane charge-transfer resistance by up to 90%, while capacitance increases 3-fold and exhibits chaotic fluctuations. These effects are consistent with membrane permeabilization and “shunting inhibition,” which suppress threshold depolarization. The transition is marked by a shift from self-organized criticality (fractal dimension D ≈ 5.0) to low-dimensional stochasticity (D ≈ 1.5). Shannon entropy increases by 1.67 bits, quantifying the thermodynamic cost of the depressed state as information leakage. These results indicate that cholinergic modulation of excitability is not solely a biological phenomenon dependent on evolved receptors, but rather a fundamental physicochemical interaction that may have influenced the emergence of nervous systems. It is proposed that depression reflects a breakdown in thermodynamic self-organization, in which an information-processing system shifts from ordered dynamics to chaotic disorder. These results point toward a physicochemical precursor to this principle, potentially extending its origins back to the prebiotic era─long before the evolutionary emergence of the first synapse.