MiR-134-5p/BDNF/TrkB/CREB signaling pathway involved in the depression-like behaviors in mice following exposure to benzo[a]pyrene.

Abstract

Benzo[a]pyrene (B[a]P) is known to cause depression-like symptoms in mice, however, the mechanisms are still unclear. The present study aimed to establish a mouse model of depression-like behavior induced by B[a]P and to elucidate the possible underlying mechanisms. Forty robust male ICR mice were randomly categorized into 4 groups and received intraperitoneal injections (i.p.) of peanut oil or B[a]P at doses of 0.5, 2, or 10 mg/kg, 30 times over a period of 60 days. Behavioral assessments were conducted to evaluate depression-like symptoms, identify neuronal structural alterations and cellular apoptosis, and measure the protein levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), phosphorylated TrkB (p-TrkB), cAMP-response element binding protein (CREB) and phosphorylated CREB (p-CREB) in the cerebral cortex. To further explore the regulatory role of miRNA, small RNA sequencing was performed in HT22 cells treated with B[a]P at concentrations of 0.2, 2, and 20 µM, which revealed the dysregulated miRNA expression profiles. The interaction between miR-134-5p and BDNF mRNA was examined, along with its inhibitory effects in both in vivo and in vitro contexts. Findings indicated that B[a]P exposure significantly induced depression-like behavior and neuronal damage in mice in a dose-dependent manner, in contrast to the controls, and was associated with a reduction in BDNF/TrkB/CREB signaling pathway proteins in the cerebral cortex. As compared to the respective controls, B[a]P exposure notably triggered an irregular miRNA expression profile (encompassing miR-10b-5p, miR-124-3p, miR-134-5p, and miR-155-5p) in both the cerebral cortex of mice and HT22 cells. Owing to its uniform alterations in expression profiles in vivo and in vitro, miR-134-5p was chosen as the target miRNA for follow-up mechanistic research employing a miR-134-5p inhibitor (at concentrations of 100 nM) in HT22 cells. Following a 48-hour in vitro treatment with B[a]P (20 µM), there was a notable reduction in proteins linked to the BDNF/TrkB/CREB signaling pathway, in contrast to DMSO controls. This decrease was markedly ameliorated in HT22 cells that had been transfected with the miR-134-5p inhibitor. The research uncovered the pivotal function of the BDNF/TrkB/CREB signaling pathway in B[a]P-induced depressive-like behavior in vivo, and showed a regulatory role of miR-134-5p in this pathway. These findings suggest a potential intervention target against the depression-like behaviors resulting from B[a]P exposure.