Combined enriched environment and fluoxetine enhance myelin protein expression in the prefrontal cortex of a chronic unpredictable stress depression model

• Published in: Behavioral and brain functions Vol. 21; no. 1; pp. 16 - 11
• Main Authors: Gu, Jingyang, Liu, Cong, Li, Yan, Feng, Laipeng, Geng, Mengjun, Dong, Jiao, Han, Jinhong, Zhao, Liqin, Shao, Qiujing, Wang, Hui-Ying, Wang, Chang-Hong
• Format: Journal Article
• Language: English
• Published: England BioMed Central 11.06.2025; BMC
• Subjects: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - metabolism; Animals; Antidepressants; Antidepressive Agents, Second-Generation - pharmacology; Behavior, Animal - drug effects; Depression; Depression - drug therapy; Depression - metabolism; Depression - therapy; Disease Models, Animal; Enriched environment; Enrichment; Environment; Fluoxetine; Fluoxetine - pharmacology; Gene expression; IL-1β; Immunohistochemistry; Influenza; Male; Mental depression; Myelin; Myelin basic protein; Myelin Basic Protein - genetics; Myelin Basic Protein - metabolism; Myelin proteins; Myelin Proteins - metabolism; Pathophysiology; Phenotypes; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Rodents; Standard scores; Stress, Psychological - complications; Stress, Psychological - metabolism; Substantia alba; Sucrose; Therapeutic applications; China; Depression; Prefrontal cortex; Fluoxetine; Myelin proteins; Enriched environment
• ISSN: 1744-9081; 1744-9081
• DOI: 10.1186/s12993-025-00282-1

The primary protein components of white matter include myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Alterations in their expression are significantly implicated in depression. This study investigated changes in MBP and CNP expression associated with depressive-like behaviors induced by chronic unpredictable stress (CUS) and evaluated therapeutic interventions using fluoxetine (FLU), an enriched environment (EE), or their combination. Male Sprague Dawley rats were randomly assigned to a control group and four CUS-exposed groups undergoing 6 weeks of stress. During the final 3 weeks of CUS, rats received daily fluoxetine (CUS + FLU group), were housed in EE (CUS + EE group), or received combined EE and fluoxetine (CUS + FLU + EE group). Depression-like behaviors were assessed through sucrose preference, forced swimming, and open field tests after CUS completion and at the end of weeks 4-6. Protein and mRNA expression levels of MBP and CNP in the prefrontal cortex were quantified via immunohistochemistry, western blot, and qRT-PCR. Three weeks following CUS exposure, rats demonstrated significant depression-like behavioral phenotypes. By the fifth week, these behavioral deficits were ameliorated in the CUS + FLU + EE, whereas the CUS + FLU and CUS + EE groups exhibited comparable behavioral recovery by week 6. Parallel molecular analyses revealed diminished protein and mRNA expression levels of MBP and CNP in the prefrontal cortex of CUS-exposed animals, accompanied by a pronounced elevation in IL-1β expression. Therapeutic interventions with FLU, EE, or their combination significantly attenuated these CUS-induced molecular alterations. The antidepressant effects correlated with restored MBP, CNP, and IL-1β expression levels, suggesting that MBP/CNP deficiencies in depression may involve IL-1β elevation. In particular, combined enriched environment and fluoxetine accelerated behavioral recovery.