Cofilin 1 overexpression in the ventral hippocampus partially alleviates depressive-like behaviors in postmenopausal depression model mice through the dynamics of dendrites/dendritic spines in relevant brain regions.

INTRODUCTION: The ventral hippocampus (vHPC) itself or its input pathways can directly influence behaviors related to anxiety and depression. Cofilin 1, as a member of the actin-depolymerizing factor/cofilin (ADF/cofilin) family, participates in dendritic spine remodeling, thereby influencing depression-like behaviors. METHODS: To investigate the effects of Cofilin 1 on neural circuits related to depression, this study utilized Thy1-YFP-H transgenic mice to create an ovariectomized (OVX) + chronic restraint stress (CRS)-induced depression model. Recombinant virus AAV2/9 was bilaterally injected into the vHPC CA1 region using stereotactic surgery to knock down or overexpress Cofilin 1. The sucrose preference test (SPT), tail suspension test (TST), elevated plus maze test (EPM), and novel inhibition feeding test (NSFT) were used to assess depression-like behaviors. Meanwhile, ImageJ and Imaris software were employed to analyze the density and morphology of dendrites and dendritic spines of excitatory neurons in the HPC and related brain regions. RESULTS: The results showed that OVX + CRS induced depression-like behaviors in mice. Overexpression of vCA1 Cofilin 1 rescued a subset of depression-like behavioral phenotypes, increased dendritic density in the mPFC and vHPC, and upregulated dendritic spine density in the vHPC CA1 region. It also decreased dendritic density in the aBLA and nucleus accumbens core while increasing dendritic density in the pBLA and AcbSh. These findings suggest that overexpression of vHPC Cofilin 1 may influence depression-related neural structure by altering dendritic and dendritic spine density and connectivity, thereby improving depression-like behaviors. However, although knockdown of vCA1 Cofilin 1 did not significantly affect depression-like behaviors in mice, it reduced dendritic density and overall dendritic spine density in vHPC region, and increase negative changes in these brain regions including mPFC, BLA and NAc. CONCLUSION: Overexpression of Cofilin 1 in the vHPC CA1 subregion exerts antidepressant-like effects in mice, yet this intervention only ameliorates a subset of depression-related behavioral phenotypes. In contrast, knockdown of endogenous Cofilin 1 in vCA1 exacerbates OVX + CRS-induced dendritic and dendritic spine atrophy in the vCA1, and further aggravates adverse structural remodeling across downstream regions including the mPFC, BLA and NAc. Notably, these widespread neuronal morphological deficits triggered by vCA1 Cofilin 1 knockdown are insufficient to produce statistically significant worsening of depression-like behaviors in the model mice.