Depression is a major cause of disability worldwide affecting both the society and patients and, if un-treated, the disease carries a high mortality rate due suicide. The disease is vastly comlex and involves disturbances of several neurobiological mechanisms. The therapeutic intervention of depressive-like symptoms has evolved rapidly over the past two decades. Nevertheless, treatment refraction continues to represent a frequent problem in the clinic and up to 40 % fails to respond to the first line of treatment. Despite extensive research the etiology of depression is still unclear. However, emerging evidence suggests that the expression of microRNAs (miRNAs) is altered during stress in brains of behaviourally depressed animals, and in post-mortem brains of depressed patients. Hence, it is suggested that altered miRNA levels may contribute to the progression of depression. Research in the pathophysiology of depression has mainly involved the hippocampus. However, increased neuronal activity of the lateral habenula (LHb) has been observed in depressive patients and in animal models of depression. Additionally, an inhibition of the LHb shows antidepressive effects. The LHb has efferent projections to the monoaminergic system, and hyperactivity of the LHb is associated with an inhibition of this system, a condition observed in depressive patients. These findings indicate a role for LHb in the etiology of major depressive disorder (MDD).
The aim of the present study was to investigate the function of LHb in the development and treatment of MDD at the miRNA level in order to find novel disease targets and treatment regimens. Additionally, a search for biomarkers involved in treatment resistance and stress-resilience was included in the present study.
Depression-related miRNA changes were investigated in the highly validated Chronic Mild Stress Model of depression which generate the phenotypes reflecting depressive-like behavior, stress resilience, and drug response (after chronic treatment with escitalopram). Laser capture microdissection was used for a homogeneous isolation of the LHb and TaqMan® Low Density Arrays were used for large scale miRNA profiling. According to predetermined expression patterns relevant for depression miR-130b, miR-205, miR-327, miR-331-5p, and miR- 336 were associated with the induction and/or recovery from depression, miR-546 were found to be implicated in treatment resistance, and miR-331-5p and miR-409 were involved in stress resilience. Since miR-331-5p is involved in both recovery and stress resilience, it seems likely that the level of miR-331-5p is essential for the healthy state of rats exposed to the CMS model of depression.
Based on the present findings it is difficult to determine the exact role of the LHb in depression-related behaviour. However, several of the predicted mRNA targets, identified by TargetScan Version 6.1, are involved in mechanisms already associated with depression, including neuronal plasticity, neurogenesis, synaptic release, and demethylation suggesting an involvement of LHb in depression. To clarify the exact role of the LHb in the pathophysiology of depression, further investigations are needed.