ORIGINAL RESEARCH article
Front. Comput. Neurosci.
Population-Level Neural Rejuvenation Dynamics in Addiction: A Computational Framework for Understanding Developmental Plasticity Reactivation
Provisionally accepted
- 1Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
- 2International Centre for Translational Eye Research (ICTER), Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
- 3Hochschule fur Technik und Wirtschaft Berlin, Berlin, Germany
- 4Urmia University of Technology, Urmia, Iran
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Background: The neural rejuvenation hypothesis proposes that drugs of abuse reactivate developmental plasticity mechanisms to create abnormally persistent addiction memories. While individual molecular components have been characterized experimentally, the population-level dynamics and their collective contribution to addiction pathophysiology remain poorly understood. Objectives: To develop a computational framework tracking theoretical synaptic population dynamics during simulated drug exposure and withdrawal, and to demonstrate how coordinated population-level transitions could account for key experimental observations in addiction neuroscience. Methods: We constructed a mathematical model tracking four theoretical synaptic populations (adult, juvenile, silent, and matured synapses) using differential equations. The model simulated conversion from adult to juvenile-like synapses during exposure, silent synapse generation, and subsequent maturation driving craving incubation during withdrawal. Rate constants were selected based on experimental time scales, and simulations involved five intermittent exposures followed by extended withdrawal. Results: The model demonstrated coordinated synaptic population transformations that qualitatively paralleled experimental observations. Results revealed distinct phases of neural rejuvenation with characteristic population dynamics: adult-to-juvenile conversion during exposure (reaching ∼500 juvenile synapses), silent synapse generation (∼300 synapses), and progressive maturation during withdrawal (∼280 matured synapses). NMDA receptor composition shifted from 80% GluN2A to 80% GluN2B during exposure. Memory strength increased continuously through biphasic mechanisms, reaching 25-fold enhancement. Plasticity capacity remained elevated at 1.5-fold above baseline throughout withdrawal. Conclusion: This computational framework demonstrates how neural rejuvenation might operate as a population-level phenomenon, with sequential recruitment of different plasticity mechanisms creating robust addiction-related memories. The model generates testable hypotheses and provides a foundation for understanding potential therapeutic intervention windows targeting different phases of rejuvenation.
Keywords: Neural rejuvenation, Addiction, synaptic plasticity, silent synapses, NMDAreceptors, computational modeling
Received: 24 Nov 2025; Accepted: 26 Jan 2026.
Copyright: © 2026 Borjkhani, Borjkhani and Sharif. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mehdi Borjkhani
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