Stress-Induced Microstructural Alterations Correlate With the Cognitive Performance of Rats: A Longitudinal in vivo Diffusion Tensor Imaging Study

Abstract

Background: Stress-induced cellular changes in limbic brain structures contribute to the development of various psychopathologies. In vivo detection of these microstructural changes may help us to develop objective biomarkers for psychiatric disorders. Diffusion tensor imaging (DTI) is an advanced neuroimaging technique that enables the non-invasive examination of white matter integrity and provides insights into the microstructure of pathways connecting brain areas. Objective: Our aim was to examine the temporal dynamics of stress-induced structural changes with repeated in vivo DTI scans and correlate them with behavioral alterations. Methods: Out of 32 young adult male rats, 16 were exposed to daily immobilization stress for 3 weeks. Four DTI measurements were done: one before the stress exposure (baseline), two scans during the stress (acute and chronic phases), and a last one 2 weeks after the end of the stress protocol (recovery). We used a 4.7T small-animal MRI system and examined 18 gray and white matter structures calculating the following parameters: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). T2-weighted images were used for volumetry. Cognitive performance and anxiety levels of the animals were assessed in the Morris water maze, novel object recognition, open field, and elevated plus maze tests. Results: Reduced FA and increased MD and RD values were found in the corpus callosum and external capsule of stressed rats. Stress increased RD in the anterior commissure and reduced MD and RD in the amygdala. We observed time-dependent changes in several DTI parameters as the rats matured, but we found no evidence of Nagy et al. Stress-Induced DTI Changes and Behavior stress-induced volumetric alterations in the brains. Stressed rats displayed cognitive impairments and we found numerous correlations between the cognitive performance of the animals and between various DTI metrics of the inferior colliculus, corpus callosum, anterior commissure, and amygdala. Conclusions: Our data provide further support to the translational value of DTI studies and suggest that chronic stress exposure results in similar white matter microstructural alterations that have been documented in stress-related psychiatric disorders. These DTI findings imply microstructural abnormalities in the brain, which may underlie the cognitive deficits that are often present in stress-related mental disorders.

White Matter Changes Following Chronic Restraint Stress and Neuromodulation: A Diffusion Magnetic Resonance Imaging Study in Young Male Rats

“…However, the DTI and DKI results are less clear-cut. Microstructural disruption in WM, axonal degeneration, and demyelination in depression are generally believed to produce higher RD and MD and lower FA in both patients with depression ( 11 , 59 , 60 , 61 ) and animal models of depression ( 62 , 63 ), such as the Wistar–Kyoto strain genetic model ( 14 ) and chronic unpredicted mild stress model ( 13 ). Keeping in mind that relating DTI and DKI measures to tissue microstructure is difficult, our observation of higher FA values being driven by a decrease in RD and MD contradicts the above-mentioned studies.…”

Frontal white matter association with sleep quality and the role of stress

“…Several studies have also evaluated the relationship between measurements of stress and measurements of brain structure such as grey matter volume and white matter integrity with differing findings. In an animal model, stress has been associated with reduced FA in the corpus callosum and external capsule (Nagy et al, 2020) but there were no such findings in another study (Henckens et al, 2015). Some studies in humans showed that clinically severe stress such as a diagnosis of PTSD in adolescents with history of childhood adverse events was associated with lower FA in white matter tracts (Huang, Gundapuneedi, & Rao, 2012) although whether stress experienced by an otherwise healthy population would have a substantial effect on white matter is less clear.…”

Germinal matrix hemorrhage induces immune responses, brain injury, and motor impairment in neonatal rats

“…53 After intracerebral hemorrhage, hemoglobin changes from oxyhemoglobin to deoxyhemoglobin and hemosiderin and iron are released, which can be detected by MRI. 54 It has been found that cognitive impairments in stressed rats correlate with various DTI metrics of the corpus callosum and amygdala, 55 and experienceinduced differences in white matter and grey matter structures have also been observed by DTI in adult rats. 56 In this study, we first used DTI to evaluate the different brain regions after hemorrhage.…”