Chronic Pain, Depression Linked Through Hippocampal Remodeling, With Xiao Xiao, PhD

New research showed that chronic pain can alter the hippocampal structure, increasing the risk for depression.1

This study, led by Fudan University investigators Ming Ding and Shitong Xiang, examined how chronic pain affects the hippocampus, integrating human neuroimaging data from the UK Biobank and rodent models of neuropathic pain. Chronic pain particularly altered the dentate gyrus, known for tasks related to memory, spatial orientation, and spatial navigation.2

“Chronic pain and depression are not simply 2 conditions that happen together, but may be linked through a structural process,” explained Xiao Xiao, PhD, from the Behavioral and Cognitive Neuroscience Center at Fudan University, in an interview with HCPLive. “Microglia are directly involved in shaping this process. From a clinical perspective, these [findings suggest] that [the] development of depression in chronic pain patients may depend on how the brain responds and adapts… so the depression is not a fixed consequence. This opens a possibility [of identifying] earlier changes before the condition becomes fully established.

Early stages of chronic pain were associated with increased hippocampal volume and improved memory and learning.1 Over time, hippocampal shrinkage occurs, coinciding with cognitive decline and depression- and anxiety-like behaviors.

Preclinical work suggests that overactive newborn neurons in the dentate gyrus trigger microglia to remodel neural circuits.1 Diminishing neuron activity can reduce depressive-like symptoms but may impair cognition. Targeting microglia, rather than neurons, can protect cognition while preventing depression and anxiety, making microglia a potential therapeutic target.

Xiao emphasized that resilience and vulnerability in patients with chronic pain are dynamic states rather than fixed outcomes.

“Our findings suggest that resilience is not simply the absence of symptoms, but also an active process in which these brain circuits remain adaptive regulation under this system and distress or pain,” Xiao said. “In other words, some individuals are able to sustain functional plasticity…. while others transition more rapidly into [a] maladaptive sedation state. This shift may reflect the differences [in] how neural systems, such as [the] hippocampus, respond to this long-lasting pain clinically. This helps explain how and why these patients [with] similar levels of pain can have very different emotional outcomes.”

References

1. Ding M, Xiang S, Zhang Y, et al. From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus. Science. 2026;391(6791):eaee6177. doi:10.1126/science.aee6177

2. Know Your Brain: Dentate Gyrus. Neuro Scientifically Challenged. Accessed on March 23, 2026. https://neuroscientificallychallenged.com/posts/know-your-brain-dentate-gyrus.