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

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.

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.

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.

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.