Duration-dependent transition from reversible to persistent depressive-like behaviors following chronic circadian misalignment: Involvement of impaired BDNF-TrkB signaling and myelin loss.

Chronic circadian misalignment (CM) is increasingly implicated in the development of depression. However, the temporal progression of CM-induced neural dysfunction and the reversibility of associated myelin pathology remain poorly understood. This study aimed to investigate how different durations of CM influence depressive-like behaviors, myelination, and oligodendrocyte (OL) development in mice, with particular emphasis on recovery potential and the involvement of brain-derived neurotrophic factor (BDNF) signaling. Male C57BL/6 mice were exposed to a long-term variable photoperiod (L-VP) paradigm for 18, 36, or 54 days, followed by recovery under a normal light-dark cycle for 18 or 54 days. During recovery, a subset of mice received the BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF). Behavioral and molecular analyses were used to assess depressive-like behaviors, OL lineage dynamics, myelination status, and BDNF-TrkB downstream signaling in the prefrontal cortex and hippocampus. CM induced duration-dependent depressive-like behaviors, reduced BDNF expression, impaired OL maturation, and myelin loss. Deficits caused by short- to intermediate-term CM (18 and 36 days) were largely reversible after circadian restoration, whereas prolonged CM (54 days) resulted in persistent myelin basic protein (MBP) reduction and sustained behavioral impairments, indicating a transition toward irreversible pathology. Activation of TrkB signaling via 7,8-DHF partially restored OL. This study elucidates the temporal dynamics of CM-induced depressive behaviors and myelin injury, and suggests that prolonged CM drives a transition from reversible dysfunction to persistent pathology. Targeting BDNF-TrkB signaling may represent a potential chronotherapeutic strategy for mood disorders associated with long-term circadian misalignment.