Vitamin B12 and pregabalin combination restored brain waves dynamics and behavior in chronic unpredictable mild stress (CUMS) model of depression.

Treatment-resistant late -life depression (TRLLD) is a major public health challenge, as older individuals present with suboptimal or partial responses to frontline therapeutic options. Chronic unpredictable mild stress (CUMS) is a well-validated preclinical paradigm that recapitulates the complex neurobiological changes and clinical symptomatology of major depression. Here, we elucidate the influence of pregabalin (PRG; 10 mg/kg) and vitamin B12 (B12; 40 µg/kg) combination on neurobiological correlates of LLD such as slow vs. fast brain rhythms, affective behavior, and oxidative stress in male C57BL/6 mice, aged 18 months. In the present study, we postulated that the modulation of oscillation synchronization in slow alpha and sleep spindle brainwaves with abnormal high beta oscillation synchronization is imperative to observed depressive-like phenotypes in CUMS-exposed mice, and this oscillatory pattern was absent in healthy control. Reciprocally, PRG + B12 combination restored thalamocortical coherence, as treated mice showed an increase in alpha (ɑ = 8.1 - 12 Hz) and sigma (Ʃ = 12.1 - 16 Hz) wave synchronization, while it reduced high beta rhythms (β = 24.1 - 30 Hz) bursting. Stressed geriatric mice exhibited reduced exploratory drive and impairments in proper cognition, while PRG + B12 chronic treatment mitigated the propagation of LLD-related behavioral dysfunction, as mice showed good performance in all conducted neurobehavioral assays (OFT, L/D, Y-maze, FST, and SPT). Furthermore, the PRG + B12 combination prompted redox homeostasis, as evidenced by reduced malondialdehyde (MDA) levels and increased antioxidant endogenous enzyme activity (superoxide dismutase; SOD and catalase; CAT). These outcomes support the use of multimodal network therapy to manipulate neurophysiological resilience in thalamocortical and corticocortical circuitry to modulate depression-like phenotypes and relapse in LLD patients.