Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

Human depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward. Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a post-treatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in between-network FC, including amygdala - prefrontal cortex and amygdala - cingulate cortex. MRS identified metabolic alterations in CPS mice as increased inositol levels in amygdala and increased glycerophosphorylcholine levels in prefrontal cortex. Diffusion-weighted MRI detected increased fractional anisotropic values in the cingulum. This study demonstrates that chronic psychosocial stress induces FC states in the mouse brain analogous to those observed in depression, as well as cerebral metabolism and white matter pathway alterations that contribute to understanding of pathological processes. It also demonstrates the importance of brain imaging to the establishment of valid animal models in translational psychiatry.