1: Mechanical–Molecular Remodeling of Hippocampal ECM in Neuropathic Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Developing methodology/technology

Background and Aims: Peripheral nerve injury induces neuropathic pain characterized by persistent mechanical hypersensitivity and long-lasting central nervous system remodeling. Although neuronal plasticity has been extensively investigated, the contribution of extracellular microenvironment remodeling to pain chronification remains insufficiently understood. The hippocampus, involved in cognitive dimensions of pain, exhibits structural and synaptic plasticity in chronic pain states. Emerging evidence suggests that extracellular matrix (ECM) remodeling regulates synaptic stabilization, neuro–immune signaling, and tissue biomechanics; however, its spatial biomechanical–molecular organization during neuropathic pain progression remains unclear. This study aimed to establish a correlative multimodal platform to define region-specific hippocampal ECM remodeling during pain chronification.

Methods: Neuropathic pain was induced using the spared nerve injury (SNI) model. Longitudinal behavioral assessments confirmed sustained mechanical hypersensitivity. To enable accurate ECM characterization, multiple hippocampal decellularization protocols were systematically evaluated to optimize preservation of ECM architecture and molecular integrity while minimizing cellular contamination. The optimized workflow was applied to spatially matched hippocampal sections. Atomic force microscopy (AFM) was used to generate high-resolution stiffness maps. These biomechanical measurements were integrated with liquid chromatography–mass spectrometry (LC–MS) proteomics and MALDI mass spectrometry imaging to characterize region-specific ECM composition and glycosylation profiles within identical anatomical subregions.

Results: The correlative multimodal platform successfully enabled spatially matched integration of AFM-based stiffness mapping with LC–MS proteomics and MALDI mass spectrometry imaging in hippocampal tissue. Spared nerve injury (SNI) induced progressive and region-specific alterations in extracellular matrix (ECM) stiffness across hippocampal subregions. These biomechanical changes were accompanied by distinct remodeling of ECM protein composition and glycosylation profiles. Notably, spatial patterns of mechanical heterogeneity corresponded with localized molecular remodeling signatures within the same anatomical regions, demonstrating a tight coupling between ECM mechanical properties and biochemical composition during neuropathic pain persistence.

Conclusions: This study establishes a novel correlative framework linking ECM structure, mechanics, and molecular composition in intact brain tissue. The findings indicate that neuropathic pain is associated with coordinated biomechanical and biochemical remodeling of the hippocampal extracellular microenvironment, supporting a non-neuronal contribution to pain maintenance. Beyond chronic neuropathic pain, this integrative platform provides a broadly applicable approach for investigating ECM remodeling in diverse neurological and neuroinflammatory conditions, including neurodegeneration, brain injury, epilepsy, and psychiatric disorders.

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Presenting Author: Chuang Ge
Submitting Author: Chuang Ge

Senior Author: Maral Tajerian

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Jiazhang Chen: PhD - The Advanced Science Research Center, CUNY
• Lele Xu: PhD Candidate - The Advanced Science Research Center, CUNY
• Rinat Abzalimov: PhD - The Advanced Science Research Center, CUNY
• Ye He: PhD - The Advanced Science Research Center, CUNY
• Taide Li: PhD - The Advanced Science Research Center, CUNY