Depression is a heterogeneous disorder, but the exact neuronal mechanisms causing the disease have not yet been discovered. We have established a chronic unpredictable mild stress (CUMS) mouse model to explore the blood oxygen level-dependent (BOLD) activity in the hippocampus, prefrontal cortex (PFC), and basolateral amygdala (BLA) using amplitude of low-frequency fluctuations (ALFF) in functional magnetic resonance imaging (fMRI). We initially studied the relationship between brain-derived neurotrophic factor (BDNF) expression and BOLD activity using BDNFtm1Krj/J mice. We found that CUMS induced depressive-like behaviours and stimulated changes in brain regions expressing a different BDNF level, which was decreased in the hippocampus and PFC but increased in the BLA. In contrast, the BOLD activity was elevated in the hippocampus and PFC but reduced in the BLA after CUMS exposure, indicating that the BDNF level negatively correlated with the BOLD activity in the WT CUMS-exposed mice. Moreover, the depressive-like behaviours and region-specific BOLD activity in BDNFtm1Krj/J mice were consistent with those in WT CUMS-exposed mice. We surmised that critical neural circuitry connects the hippocampus, PFC and BLA in mice, which was regulated by BDNF to protect against depression. These findings suggested a potential central role of BDNF expression in functional changes in the brain. Copyright © 2018 Elsevier Inc. All rights reserved.