Metabolic changes in selective brain regions induced by chronic stress in mice and their involvement in emotional disturbance

Abstract

Chronic stress causes depressed mood and cognitive deficits and predisposes to mental illness. Brain metabolic changes are linked to stress pathology, but their molecular mechanism and functional significance remain unknown. In this study, we exposed C57BL/6N male mice to chronic social defeat stress and quantified the metabolites of central metabolic pathways by mass spectrometry imaging. We examined multiple stress-associated brain regions in susceptible mice, which showed stress-induced social avoidance, and resilient mice, which did not. In the medial prefrontal cortex and the hippocampus, chronic stress increased glycolytic metabolites of susceptible mice but not resilient mice. Among susceptible mice, we found a positive correlation between the glycolytic metabolite levels in the medial prefrontal cortex and social avoidance. Knockdown of glucose transporter in this region ameliorated stress-induced depressive-like behavior. In addition, knockdown of the glucose transporter specifically in the hippocampal neurons projecting to the medial prefrontal cortex suppressed stress-induced cognitive dysfunction. These findings suggest that chronic stress induces diverse metabolic alterations across multiple brain regions, with central metabolic changes in the prefrontal cortex and the hippocampus playing a crucial role in stress-related pathology associated with mental illness.