NR1H4 and major depressive disorder: Chen et al. similarly found that chronic unpredictable mild stress (CUMS) completely enhanced the expression of FXR protein and mRNA in the hippocampus, and overexpression of FXR in the hippocampus caused significant depression-like behavior and decreased expression of brain-derived neurotrophic factor (BDNF), while knockdown of FXR in the hippocampus completely inhibited the effects of CUMS on rat behavior and hippocampal BDNF expression (Chen et al., 2018).