Cholinergic Modulation of Proteinoid Microsphere Networks as Prebiotic Depression Models.

Overview

1. Unconventional Computing Laboratory, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, U.K

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• zenodo:20540303, at Zenodo; found in “Data Availability Statement”

Data Availability Statement

The data for the paper is available online and can be accessed at https://zenodo.org/records/20540303.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 5 keywords, 1 funder, 57 references.

Cite

This paper

Mougkogiannis, P., & Adamatzky, A. (2026). Cholinergic Modulation of Proteinoid Microsphere Networks as Prebiotic Depression Models. ACS physical chemistry Au, 6(4), 901-928. https://doi.org/10.1021/acsphyschemau.6c00066

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1162/imag.a.1319 [code]

When the inner clock fades: Interoceptive decline and consolidation of phase resetting in cortical rhythms by cardiac events underlie healthy lifespan aging.

Journal: Imaging neuroscience (Cambridge, Mass.)

In common: 2 references

[2] doi:10.2147/jpr.s604974

Normative Modeling of EEG Complexity Reveals Cortical Rigidity Associated with Pain Severity in Chronic Pain.

Journal: Journal of pain research

In common: 2 references

[3] doi:10.1080/26941899.2026.2619222

Neurodatascience: Past, Present, and Future.

Journal: Data science in science

In common: 2 references

[4] doi:10.64898/2026.06.21.26356048

Changes in hierarchical brain dynamics of rumination following mindfulness-based cognitive therapy for depression

Journal: medRxiv (preprint)

In common: depression, 1 reference

[5] doi:10.1371/journal.pdig.0001665

Inflammation is associated with altered functional connectivity of the cingulate cortex in individuals with subthreshold depression.

Journal: PLOS digital health

In common: depression, 1 reference

[6] doi:10.1093/psyrad/kkag025

White matter functional connectome topology and its clinical correlations in adolescent major depressive disorder.

Journal: Psychoradiology

In common: depression, 1 reference

[7] doi:10.1017/s0033291726104711

Cell-type and spatiotemporal transcriptional signatures of white matter morphometric similarity network alterations in major depressive disorder.

Journal: Psychological medicine

In common: depression, 1 reference

[8] doi:10.3390/e28080893

Structured Fluctuations and the Information Dynamics of Self-Maintenance in Growing Neural Cellular Automata.

Journal: Entropy (Basel, Switzerland)

In common: 1 reference

[9] doi:10.1186/s13020-026-01445-6

Electroacupuncture enhances anti-tumor immunity in TNBC by reducing NE release and blocking α2-AR-mediated NGF/Hippo signaling.

Journal: Chinese medicine

In common: 1 reference

[10] doi:10.1038/s41467-026-74215-5 [code]

Multi-metric evaluations of acute psychedelic effects on fMRI brain entropy.

Journal: Nature communications

In common: 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.