Abnormal hippocampal BDNF and miR-16 expression is associated with depression-like behaviors induced by stress during early life

Abstract

Some environmental stressors lead to the onset of depression via inhibiting hippocampal BDNF expression, but other environmental stressors-induced depression exhibits no change in BDNF expression. The underlying mechanisms behind the divergence remain unknown. In this study, depression-like behaviors were induced in rats by maternal deprivation (MD) and chronic unpredictable stress (CUPS). Depression-like behaviors were tested by open field test, forced swimming test, and sucrose consumption test. BDNF and miR-16 expressions in the hippocampus were examined by real-time PCR. MD and CUPS rats crawled less distance, exhibited decreased vertical activity, and produced more fecal pellets than control rats in the open field test. However, MD rats crawled less distance and produced significantly less fecal pellets than CUPS rats. In the forced swimming and sucrose consumption tests, CUPS and MD rats exhibited longer floating time and consumed less sucrose than control rats, but MD rats exhibited shorter floating time and consumed less sucrose than CUPS rats. MD but not CUPS rats showed lower BDNF mRNA and higher miR-16 expression than control rats. In MD rats, BDNF mRNA expression negatively correlated with the expression of miR-16. BDNF expression positively correlated with the total distance rats crawled and vertical activity in the open field test while miR-16 expression negatively correlated the two behaviors. BDNF positively correlated with sucrose preference rate while miR-16 negatively correlated with sucrose preference rate of the sucrose consumption test. Our study suggests that MD and CUPS induced different depression-like behaviors in rats. Depression induced by MD but not CUPS was significantly associated with upregulation of miR-16 and possibly subsequent downregulation of BDNF in hippocampus.

Figure 1. The relationship between miR-16 and BDNF.

D) Western blot of BDNF protein levels. B) Correlation between BDNF mRNA expression and miR-16 expression. ^** p<0.01. C) The proposed binding site of miR16 at the 3'UTR of BDNF. D) The evolutionary conservation of the mir-16 binding site in BDNF.

Figure 2. Correlation between BDNF mRNA expression and depression-like behaviors.

(A) Correlation between BDNF mRNA expression and the total distance crawled. (B) Correlation between BDNF mRNA expression and the central area rate. (C) Correlation between BDNF mRNA expression and the fecal pellets. (D) Correlation between BDNF mRNA expression and the vertical activity. (E) Correlation between BDNF mRNA expression and the floating time. (F) Correlation between BDNF mRNA expression and the sucrose preference rate. ^* p<0.05,^** p<0.01.

Figure 3. Correlation between miR-16 expression and depression-like behaviors.

(A) Correlation between miR-16 expression and the total distance crawled. (B) Correlation between miR-16 expression and the central area rate. (C) Correlation between miR-16 expression and the fecal pellets. (D) Correlation between miR-16 expression and the vertical activity. (E) Correlation between miR-16 expression and the floating time. (F) Correlation between miR-16 expression and the sucrose preference rate. ^* p<0.05,^** p<0.01.