Impaired WNT3/IGF-1 Signaling in Dorsal Dentate Gyrus Contributes to Chronic Pain-Related Cognitive Impairment.

BACKGROUND: Neuropathic pain is frequently accompanied by cognitive deficits, but the neural circuits and molecular mechanisms linking nociceptive hypersensitivity to cognitive dysfunction remain incompletely understood. The hippocampal dentate gyrus (DG), a critical hub for adult neurogenesis and memory encoding, is emerging as a key substrate integrating pain processing and cognitive impairment, but how peripheral nerve injury disrupts DG homeostasis remains unclear.

METHODS: In this study, we used the spared nerve injury (SNI) mouse model to investigate the cellular and molecular mechanisms underlying comorbid neuropathic pain and cognitive deficits. Behavioral assessments, stereotaxic viral/drug delivery, Western blot, immunofluorescence staining, whole-cell patch-clamp recordings, ELISA, and primary astrocyte culture were employed to characterize phenotypic changes and regulatory pathways in the dorsal DG.

RESULTS: We found that SNI induced persistent mechanical hypersensitivity and cognitive impairment in mice, which was associated with reduced neurogenesis (decreased nestin+ radial glial-like cells, DCX+ immature neurons, and NeuroD1 expression) and diminished intrinsic excitability of dorsal DG granule cells. Mechanistically, SNI triggered a "double hit" to dorsal DG homeostasis: (1) neuron-specific insulin-like growth factor-1 (IGF-1) resistance, characterized by increased serine phosphorylation of insulin receptor substrate-1 (IRS1) at S612 in mature granule cells, reduced IGF-1 levels, and impaired PI3K/AKT signaling; (2) downregulation of astrocyte-derived WNT3, a key neurogenic regulator, which was mediated by proinflammatory cytokine TNF-α. Therapeutically, local supplementation of IGF-1 into the dorsal DG reversed SNI-induced nociceptive and cognitive deficits via IGF-1R/AKT-dependent restoration of neurogenesis and granule cell excitability. Similarly, chemogenetic activation of dorsal DG astrocytes alleviated comorbid symptoms by enhancing WNT3 secretion, while chronic inhibition of these astrocytes mimicked SNI-induced pain hypersensitivity, cognitive impairment, and disrupted neurogenesis. Exogenous administration of WNT3a recapitulated the therapeutic effects by activating AKT, independent of IGF-1R signaling.

CONCLUSION: Our findings identify that decreased WNT3 secretion from astrocytes in dorsal DG integrates nociceptive and cognitive dysfunction after nerve injury via crosstalking with the IGF-1/AKT pathway. Targeting this WNT3/IGF-1 axis may represent a promising therapeutic strategy for neuropathic pain and its cognitive sequelae.