From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus

Chronic pain often evolves into depression and anxiety, yet mechanisms linking sensory distress to affective dysfunction remain unclear. Integrating human neuroimaging from the UK Biobank with a rodent model, we uncovered biphasic hippocampal remodeling. Hippocampal volume increased during early pain stages, with paradoxical cognitive improvements, but declined with comorbid depression. In rodents, the dentate gyrus (DG) acted as a hub governing this transition: Lesions of DG prevented affective symptoms. Elevated DG activity was linked to hyperactive newborn neurons and microglial recruitment and remodeling, leading to circuit imbalance. Whereas suppressing newborn neuron activity alleviated emotional pathology at the expense of cognition, microglial modulation selectively restored affective behavior without cognitive cost. These findings reveal microglia-mediated hippocampal remodeling as a key mechanism linking chronic pain to mood disorders.