Xiaochaihutang ameliorates depression-like behaviors induced via chronic social defeat stress by regulating exon-specific Bdnf transcription through H3K18 acetylation in the hippocampus of mice

Abstract

Introduction

Depression is a prevalent and persistent mental disease characterized by symptoms such as anhedonia, anxiety, and desperation. Although our previous study shows that Xiaochaihutang (XCHT) upregulates hippocampal brain-derived neurotrophic factor (BDNF) levels in depressed mice and rats, the underlying mechanism requires further clarification.

Objectives

To assess the mechanism by which XCHT regulates hippocampal BDNF expression in chronic social defeat stress (CSDS)-induced mice.

Methods

Adult C57BL/6J mice were exposed to CSDS for 10 consecutive days to establish a depression model. XCHT treatment (2.3, 7 and 21 g/kg, intragastric administration) was administered for 4 consecutive weeks. Behavioral assessments were sequentially conducted to investigate the antidepressant effects of CSDS-induced XCHT. Golgi staining, immunofluorescence, immunoblotting, real time fluorescence quantitative polymerase chain reaction and chromatin immunoprecipitation were then employed to study the mechanisms underlying the regulation of XCHT on hippocampal BDNF expression.

Results

XCHT significantly improved CSDS-induced anhedonia, social avoidance, recognition memory impairment, and anxiety/depression-like behaviors in mice. XCHT significantly promoted neuronal complexity and dendritic spine maturation in the mouse hippocampus. Furthermore, XCHT reversed the CSDS-induced reduction in the number of hippocampal BDNF⁺ cells and increased hippocampal BDNF protein and mRNA levels by upregulating the expression of specific Bdnf exons I, IV and VI. XCHT increased Bdnf transcripts by upregulating histone H3K18 acetylation at the Bdnf promoters. The administration of an acetyltransferase inhibitor reversed the effects of these changes.

Conclusion

XCHT may enhance the transcripts of specific Bdnf exons I, VI and VI by upregulating the H3K18 acetylation at the corresponding Bdnf promoters, which consequently promotes BDNF expression levels. This further promotes neuronal plasticity in the hippocampus, ultimately ameliorating anxiety/depression-like behavior in CSDS-induced mice.