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. Editor's summary: Chronic pain and depression are mutually linked. Ding et al. explored the mechanistic link between chronic pain and depression in humans and rodents (see the Perspective by Beggs and Frankland). In patients and an animal model, early stages of chronic pain were found to be associated with an increase in hippocampal volume, whereas later stages were associated with decreased hippocampal volume. These changes in rats were followed by the development of depressive-like behavior. Mechanistically, the authors showed that microglial activation leads to dysregulation of hippocampal neurogenesis (producing volumetric changes), shifts in hippocampal physiology, and onset depressive-like behaviors. The study provides valuable insights into the role of the hippocampus in the development of comorbid depression in the context of chronic pain. —Mattia Maroso INTRODUCTION: Chronic pain is a leading risk factor for depression and anxiety, yet the brain mechanisms that convert persistent sensory distress into affective dysfunction remain unclear. Neuroimaging studies have implicated the hippocampus in both pain and mood regulation, but it is unknown whether hippocampal alterations precede, accompany, or result from the emergence of affective symptoms. Resolving this temporal and mechanistic relationship is essential for explaining individual vulnerability to depression in chronic pain and for identifying intervention points that can prevent this transition. RATIONALE: We hypothesized that chronic pain induces a staged remodeling process, rather than a uniform degenerative change, within the hippocampus. Specifically, we proposed that the dentate gyrus serves as a critical gate where persistent nociceptive input is initially accommodated through adaptive plasticity but later diverted into maladaptive circuit destabilization by interactions between adult-born neurons and microglia. RESULTS: Integrating longitudinal human neuroimaging data from the UK Biobank with rodent models of neuropathic pain, we identified a conserved biphasic trajectory of hippocampal remodeling. During early stages of chronic pain, hippocampal volume increased and hippocampal-dependent cognitive performance improved, consistent with an adaptive response. As pain persisted, this phase transitioned to hippocampal atrophy, cognitive decline, and the emergence of anxiety- and depression-like behaviors. At the cellular level, early chronic pain selectively increased activity of newborn neurons within the dentate gyrus and triggered targeted recruitment and remodeling of microglia in the neurogenic niche. These cell-type–specific changes progressively amplified local circuit excitability and disrupted network balance, marking a transition from adaptive hippocampal plasticity to maladaptive circuit remodeling. Functionally, distinct modes of dentate gyrus modulation produced divergent outcomes: Suppressing newborn neuron activity alleviated affective symptoms but impaired cognition, whereas microglial modulation prevented anxiety- and depression-like behaviors while preserving cognitive function. Together, these findings identify microglia as a key regulator of the pain-to-depression transition. CONCLUSION: By resolving distinct modes of dentate gyrus modulation, we show that microglia act as critical and therapeutically tractable regulators of the transition from chronic pain to affective disorders. Our findings reveal that this transition is governed not by hippocampal hyperactivity per se but rather by microglia-dependent remodeling that determines whether adaptive plasticity is sustained or diverted into maladaptive circuit states. Targeting microglial activation preserves hippocampal structure and cognitive function while preventing affective pathology, positioning microglia as a selective leverage point for interrupting the progression from chronic pain to mood disorders. Dentate gyrus–centered hippocampal remodeling during the transition from chronic pain to affective disorders.: This schematic illustrates a biphasic hippocampal response to chronic pain. Early pain induces transient hippocampal expansion and cognitive enhancement, followed by hippocampal atrophy and affective dysfunction. Dysregulated interactions between newborn neurons and microglia within the dentate gyrus drive this transition, highlighting microglial remodeling as a selective therapeutic target. E/I, excitatory-inhibitory. [ABSTRACT FROM AUTHOR]