Role of DNA hypomethylation in lateral habenular nucleus in the development of depressive-like behavior in rats

Abstract

Background: Lateral habenula nucleus (LHb) has recently been noted for its role in stress-induced depressive disorder. Yet little is known about the mechanisms by which external stimuli or depression induces pathological alteration in the LHb.

Methods: Chronic unpredictable mild stress (CUMS) was employed to model depressive-like behaviors in adult rats. We examined expressions of DNA methyltransferases (Dnmts) mRNA and protein and global DNA methylation levels in LHb of CUMS-induced depressive rats. Then 5-aza-2'-deoxycytidine (5-aza), a Dnmts inhibitor, was infused into the LHb of native rats to test the effects of hypomethylation in the LHb. The gene expressions in the LHb and the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe nucleus (DRN) were examined in 5-aza infusion rats by quantitative real-time PCR and high performance liquid chromatography, respectively.

Results: Rats were exposed to CUMS for 21 days and depressive-like behaviors were induced as expected. We observed significant decrease in mRNA and protein expressions of Dnmt1 and DNA hypomethylation in LHb of depressive rats. These phenomenon suggests that CUMS-induced depressive-like behaviors are related with DNA hypomethylation in the LHb. Local 5-aza infusion into LHb of native rat resulted in global DNA hypomethylation in the LHb and induced depressive-like behaviors which are featured with lack of interest and investment in the environment, behavioral despair and anhedonia. Moreover, DNA hypomethylation in the LHb increased transcription of β calcium/calmodulin dependent protein kinase II and glutamate receptor 1 in the LHb and attenuated the levels of 5-HT and 5-HIAA in the DRN. Our data suggested that alteration of DNA methylation in the LHb may control 5-HT neuronal activity in the DRN to regulate emotional state.

Conclusions: DNA hypomethylation in the LHb is involved in the development of depressive-like behavior and suitable methylation state contributes to the emotional stabilization.

Keywords: 5-aza; Chronic unpredictable mild stress; DNA hypomethylation; DNA methyltransferases; Depressive-like behaviors; Lateral habenular nucleus.