Structural abnormality of the hippocampus and depressive symptoms in a rat model of heart failure

Abstract

Purpose: Heart failure (HF) affects almost all organs in our body through reduced organ perfusion and resultant neurohumoral alterations. Major depression is more prevalent in HF patients as compared with normal subjects, suggesting the possible interaction between the heart and the brain in HF. However, the mechanism of depressive symptoms in HF remains largely unclear. Several reports showed the association between major depression and structural abnormality of the hippocampus such as grey matter reduction and decreased neurogenesis. In the present study, we thus investigated whether hippocampal grey matter reduction and decreased neurogenesis were observed in association with depressive symptoms in a rat model of HF using magnetic resonance (MR) imaging and histological analysis. Methods: Male Wistar rats were divided into two groups: HF group with permanent ligation of the left coronary artery (n=28) and sham-operated control group (n=25). Four months after the procedure, the following two studies were performed. In the first study, the HF group (n=20) and the sham group (n=17) underwent behavioral tests (open-field test and elevated plus maze test) for assessment of depressive symptoms, followed by structural brain MR image acquisition. The obtained MR images were analyzed to detect regional alterations in grey matter between the two groups as measured by grey matter probability values (a maximum value of 1). In the second study, brains of the both groups (n=8, each) were fixed for histological analysis of neurogenesis by counting the number of bromodeoxyuridine (BrdU)-immunopositive cells in the hippocampus. Results: The HF group showed significantly greater depressive symptoms as compared with the sham group, including decreased time spent in the inner zone (HF group, 4.2±0.7% vs. sham group, 8.7±1.8%, P<0.05) in open-field test and decreased time spent in the open arm (HF group, 2.5±0.6% vs. sham group, 6.6±1.5%, P<0.05) in elevated plus maze test. Analysis of structural brain MR images revealed grey matter reduction in the HF group than in the sham group in several brain regions including the bilateral hippocampus (HF group, 0.480±0.002 vs. sham group, 0.505±0.002, P<0.001). Moreover, the number of BrdU-immunopositive cells in the hippocampus was decreased in the HF group than in the sham group (HF group, 18.3±1.5 vs. sham group, 23.0±1.3, P<0.05). Conclusions: The present study demonstrates for the first time that HF induces structural abnormality of the hippocampus such as grey matter reduction and decreased neurogenesis in association with depressive symptoms.