Effects of stress on behavior and resting-state fMRI in rats and evaluation of Telmisartan therapy in a stress-induced depression model

Abstract

Background: The etiology of depression and its effective therapeutic treatment have not been clearly identified. Using behavioral phenotyping and resting-state functional magnetic resonance imaging (r-fMRI), we investigated the behavioral impact and cerebral alterations of chronic unpredictable mild stress (CUMS) in the rat. We also evaluated the efficacy of telmisartan therapy in this rodent model of depression. Methods: Thirty-two rats were divided into 4 groups: a control group(C group), a stress group(S group), a stress + telmisartan(0.5 mg/kg)group (T-0.5 mg/kg group) and a stress + telmisartan(1 mg/kg) group (T-1 mg/kg group). A behavioral battery, including an open field test (OFT), a sucrose preference test (SPT), and an object recognition test (ORT), as well as r-fMRI were conducted after 4 weeks of CUMS and telmisartan therapy. The r-fMRI data were analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) approach. The group differences in the behavior and r-fMRI test results as well as the correlations between these 2 approaches were examined. Results: CUMS reduced the number of rearings and the total moved distance in OFT, the sucrose preference in SPT, and novel object recognition ability in ORT. The telmisartan treatment (1 mg/kg) significantly improved B-A/B + A in the ORT and improved latency scores in the OFT and SPT. The S group exhibited a decreased ReHo in the motor cortex and pons, but increased ReHo in the thalamus, visual cortex, midbrain, cerebellum, hippocampus, hypothalamus, and olfactory cortex compared to the C group. Telmisartan (1 mg/kg)reversed or attenuated the stress-induced changes in the motor cortex, midbrain, thalamus, hippocampus, hypothalamus, visual cortex, and olfactory cortex. A negative correlation was found between OFT rearing and ReHo values in the thalamus. Two positive correlations were found between ORT B-A and the ReHo values in the olfactory cortexand pons. Conclusions: Telmisartan may be an effective complementary drug for individuals with depression who also exhibit memory impairments. Stress induced widespread regional alterations in the cerebrum in ReHo measures while telmissartan can reverse part of theses alterations. These data lend support for future research on the pathology of depression and provide a new insight into the effects of telmisartan on brain function in depression.