Depressive phenotype shapes behavioral, neuroendocrine and molecular responses to repetitive transcranial magnetic stimulation in preclinical models of depression

IntroductionRepetitive 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.MethodsMale 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.ResultsrTMS 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.ConclusionrTMS 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.