Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Clinical and experimental studies show that spinal cord injury (SCI) can cause cognitive impairment and depression that can significantly impact outcomes. Thus, identifying mechanisms responsible for these less well-examined, important SCI consequences may provide targets for more effective therapeutic intervention. To determine whether cognitive and depressive-like changes correlate with injury severity, we exposed mice to sham, mild, moderate, or severe SCI using the Infinite Horizon Spinal Cord Impactor and evaluated performance on a variety of neurobehavioral tests that are less dependent on locomotion. Cognitive impairment in Y-maze, novel objective recognition, and step-down fear conditioning tasks were increased in moderate- and severe-injury mice that also displayed depressive-like behavior as quantified in the sucrose preference, tail suspension, and forced swim tests. Bromo-deoxyuridine incorporation with immunohistochemistry revealed that SCI led to a long-term reduction in the number of newly-generated immature neurons in the hippocampal dentate gyrus, accompanied by evidence of greater neuronal endoplasmic reticulum (ER) stress. Stereological analysis demonstrated that moderate/severe SCI reduced neuronal survival and increased the number of activated microglia chronically in the cerebral cortex and hippocampus. The potent microglial activator cysteine-cysteine chemokine ligand 21 (CCL21) was elevated in the brain sites after SCI in association with increased microglial activation. These findings indicate that SCI causes chronic neuroinflammation that contributes to neuronal loss, impaired hippocampal neurogenesis and increased neuronal ER stress in important brain regions associated with cognitive decline and physiological depression. Accumulation of CCL21 in brain may subserve a pathophysiological role in cognitive changes and depression after SCI.