Depressive phenotype shapes behavioral, neuroendocrine and molecular responses to repetitive transcranial magnetic stimulation in preclinical models of depression.
8 affiliations
- 1Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
- 2Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University of ChietiPescara, Chieti, Italy.
- 3Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
- 4Department of Mental Health and Addiction, ASL Roma 5, Rome, Italy.
- 5Laboratory of Psychophysiology and Cognitive Neuroscience, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
- 6IRCCS Fondazione Santa Lucia, Rome, Italy.
- 7Department of Mental Health, ASL 2 Abruzzo Lanciano-Vasto-Chieti, Chieti, Italy.
- 8Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom.
Abstract
Introduction
Repetitive transcranial magnetic stimulation (rTMS) is an established non-invasive treatment for treatment-resistant depression (TRD), yet its neurobiological mechanisms remain only partially understood. We investigated whether rTMS recruits common or phenotype-specific adaptive mechanisms across depressive conditions.Methods
Male Wistar-Kyoto rats exposed to chronic mild stress and social isolation modeled TRD. Socially isolated Wistar rats modeled treatment-responsive depression (ISO), while socially housed Wistar rats served as non-depressed controls (CTRL). Animals received active or sham high-frequency rTMS. Behavioral batteries assessing motivation, emotionality, helplessness, and anxiety-like behavior began 1 and 14 days after the final rTMS session. Basal plasma corticosterone and Bdnf and Cnr1 mRNA expression in the prefrontal cortex and hippocampus were also assessed.Results
rTMS produced phenotype-dependent behavioral, neuroendocrine, and molecular effects. In ISO rats, active stimulation improved multiple behavioral measures and reduced basal corticosterone. In TRD rats, behavioral effects were more selective, primarily involving motivation and self-care, and occurred without corticosterone normalization. The most prominent molecular effects emerged in the prefrontal cortex of TRD rats, where rTMS increased both Bdnf and Cnr1 expression. Their expression was strongly positively correlated only in active TRD animals, suggesting coordinated engagement of plasticity-related pathways.Conclusion
rTMS did not elicit a uniform response across depressive phenotypes but recruited distinct adaptive mechanisms according to the underlying neurobiological state. Neuroendocrine normalization characterized the treatment-responsive model, whereas selective behavioral improvement in TRD was associated with coordinated engagement of prefrontal Bdnf- and Cnr1-related pathways. These findings support phenotype-informed, mechanism-guided neuromodulation strategies for depression.
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BibTeX
@article{boffa2026depressive,
title = {{Depressive phenotype shapes behavioral, neuroendocrine and molecular responses to repetitive transcranial magnetic stimulation in preclinical models of depression.}},
author = {Marta Boffa and Sara Spalletti and Francesca Martella and Carola Cerri and Beatrice Feliciani and Antonio Inserra and Luisa De Risio and Giorgio Di Lorenzo and Giovanni Martinotti and Claudio D'Addario and Mauro Pettorruso and Francesca Zoratto},
journal = {Frontiers in molecular neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnmol.2026.1939025},
url = {https://europepmc.org/article/MED/42947970},
note = {CC BY},
}
RIS
TY - JOUR
TI - Depressive phenotype shapes behavioral, neuroendocrine and molecular responses to repetitive transcranial magnetic stimulation in preclinical models of depression.
AU - Marta Boffa
AU - Sara Spalletti
AU - Francesca Martella
AU - Carola Cerri
AU - Beatrice Feliciani
AU - Antonio Inserra
AU - Luisa De Risio
AU - Giorgio Di Lorenzo
AU - Giovanni Martinotti
AU - Claudio D'Addario
AU - Mauro Pettorruso
AU - Francesca Zoratto
PY - 2026
DA - 2026/10/13
JO - Frontiers in molecular neuroscience
DO - 10.3389/fnmol.2026.1939025
UR - https://europepmc.org/article/MED/42947970
AB - Introduction Repetitive transcranial magnetic stimulation (rTMS) is an established non-invasive treatment for treatment-resistant depression (TRD), yet its neurobiological mechanisms remain only partially understood. We investigated whether rTMS recruits common or phenotype-specific adaptive mechanisms across depressive conditions.Methods Male Wistar-Kyoto rats exposed to chronic mild stress and social isolation modeled TRD. Socially isolated Wistar rats modeled treatment-responsive depression (ISO), while socially housed Wistar rats served as non-depressed controls (CTRL). Animals received active or sham high-frequency rTMS. Behavioral batteries assessing motivation, emotionality, helplessness, and anxiety-like behavior began 1 and 14 days after the final rTMS session. Basal plasma corticosterone and Bdnf and Cnr1 mRNA expression in the prefrontal cortex and hippocampus were also assessed.Results rTMS produced phenotype-dependent behavioral, neuroendocrine, and molecular effects. In ISO rats, active stimulation improved multiple behavioral measures and reduced basal corticosterone. In TRD rats, behavioral effects were more selective, primarily involving motivation and self-care, and occurred without corticosterone normalization. The most prominent molecular effects emerged in the prefrontal cortex of TRD rats, where rTMS increased both Bdnf and Cnr1 expression. Their expression was strongly positively correlated only in active TRD animals, suggesting coordinated engagement of plasticity-related pathways.Conclusion rTMS did not elicit a uniform response across depressive phenotypes but recruited distinct adaptive mechanisms according to the underlying neurobiological state. Neuroendocrine normalization characterized the treatment-responsive model, whereas selective behavioral improvement in TRD was associated with coordinated engagement of prefrontal Bdnf- and Cnr1-related pathways. These findings support phenotype-informed, mechanism-guided neuromodulation strategies for depression.
SN - 1662-5099
ER -