MicroRNA Expression Profile Is Altered by Short-Term and Chronic Lithium Treatment in a Rat Model of Depression

Abstract

Depression is a common disease that affects 3.8% of the global population. Despite various antidepressant treatments, one-third of patients do not respond to antidepressants, therefore augmentation with mood stabilizers such as lithium may be required in this group. One of the suggested pathomechanisms of depression is the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and recent reports showed that microRNAs (miRNA) can impact its activity by epigenetic regulation. We aimed to explore the miRNA expression profile in the depression model and its changes upon short-term and chronic lithium treatment in the rat brain (pituitary, hypothalamus, and hippocampus). We used a chronic mild stress rat model of depression and short- and long-term lithium treatment. The behavior was assessed by an open-field test. The miRNA expression profile in the pituitary was estimated by sequencing and validated in the hypothalamus and hippocampus with qPCR. We found several miRNAs in the pituitary that were significantly altered between CMS-exposed and control rats as well as after short- and long-term lithium treatment. MicroRNAs chosen for validation in the hypothalamus and hippocampus (rno-miR-146a-5p, rno-miR-127-3p) showed no significant changes in expression. We performed in silico analysis and estimated potential pathways involved in lithium action for miRNAs differentially expressed in the pituitary at different time points. Specific microRNA subsets showed altered expression in the pituitary in depression model upon short- and long-term lithium treatment. We identified that biological pathways of target genes for these altered miRNAs differ, with the Foxo pathway potentially involved in disease development.