Jens Randel Nyengaard

Depression is a leading cause of disability worldwide and it can often ensue after a prolonged exposure to mild stressors. Despite intensive preclinical and clinical research, an objective test to diagnose the depression is still not available, causing suboptimal diagnosis and treatment. Recently, neuronal tracing technique and stereology showed persistent microstructural alterations in the stress sensitive brain regions such as dendritic atrophy in the hippocampus (HP), and prefrontal cortex (PFC), and hypertrophy in the amygdala (AM). These brain regions also showed consistent gliosis in cadaver brains of patients with depressive disorders as well as in an animal model of depression. However, clinically feasible methods to probe these microstructural alterations could be useful in treatment planning, and intervention. The present study employed ex-vivo diffusion MRI (dMRI) and immunohistochemistry to identify microstructural alterations in stress-sensitive brain regions of chronic mild stress (CMS) induced anhedonic rats after eight weeks of spontaneous recovery in comparison to age-matched controls. The investigation employs dMRI based neurite density model parameters (ν, Deff, and DL), traditional DKI parameters (MK, AK, and RK), kurtosis tensor parameters (MKT, WL, and WT) and diffusion tensor parameters (FA, MD, AD, RD). The neurite density (ν) parameter has shown a significant reduction in dorsal HP (dHP) in comparison to control, while immunohistochemistry (IHC) showed the significant reduction in histological neurite density (Hν) in dHP, ventral HP and in the AM. Hν also showed significant correlation with ν, which strengthens the reliability of this model parameter and provides a plausible underpinning of the diffusion signal. These stress-recovery findings are opposite to the changes observed just after CMS exposure paradigm in our recent in-vivo experiment. The study revealed long-term effects of CMS exposure, which may be due to incomplete microstructural normalization even after eight weeks of recovery or long-lasting microstructural alterations in dHP.