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.

Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia

“…25 While specific upstream regulators of cortical miR16 expression have yet to be investigated, damaging DNA increases miR16 expression in human fibroblasts 48,49 and maternal deprivation increases miR16 in the hippocampus. 50 Although our findings are consistent with miR16 as an upstream factor accounting for lower RGS4 levels in schizophrenia, RGS4 levels can be lowered through other mechanisms. For example, genetic ablation of brain-derived neurotrophic factor (BDNF) during adulthood reduces RGS4 levels, 51 and findings consistent with lower BDNF signaling in the DLPFC have been reported in schizophrenia.…”

Divergent anomaly in mesocorticolimbic dopaminergic circuits might be associated with different depressive behaviors, an animal study

“…Recent studies reported that merely 37–50% of individuals diagnosed with depression experience clinically significant anhedonia (Bogdan, Nikolova, & Pizzagalli, 2013; Pelizza & Ferrari, 2009). Our previous study in rats also demonstrated that the depressive phenotype induced by maternal deprivation (MD), a well‐verified depressogenic stressor, was characterized by severe anhedonia while the depressive phenotype triggered by chronic unpredictable stress (CUPS), another well‐established depressogenic stressor, primarily exhibited anxiety and passive coping behavior (Bai et al., 2012; Bai, Zhang, et al., 2014; Bai, Zhu, et al., 2014). However, the precise neurobiological basis of different depressive phenotypes remains unclear.…”

Epigenetics and depression: return of the repressed

“…Infusion of fluoxetine into the raphe nucleus, a major source of ascending serotonergic projections in the brain, resulted in a decrease in miR-16 and a two-fold reduction in binding of serotonin transporter (Baudry et al, 2010). Fluoxetine applied at the raphe, also appears to affect miRNA expression in the locus coeruleus (Baudry et al, 2010) and hippocampus (Launay et al, 2011) causing a reduction in miR-16 and a subsequent increase in serotonin transporter levels in both brain regions. Furthermore, neutralisation of miR-16 in the hippocampus by application of anti-miR16 results in antidepressant-like behavioural effects highlighting the importance of its role in the downstream effects of fluoxetine (Launay et al, 2011).…”

“…Studies examining the expression of miR-16, which targets the serotonin transporter, have provided insight into the mechanism of action of fluoxetine in the mouse brain (Baudry et al, 2010;Launay et al, 2011). Infusion of fluoxetine into the raphe nucleus, a major source of ascending serotonergic projections in the brain, resulted in a decrease in miR-16 and a two-fold reduction in binding of serotonin transporter (Baudry et al, 2010).…”