{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:31:34Z","timestamp":1789648294868,"version":"4.0.0"},"reference-count":41,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870969"],"award-info":[{"award-number":["81870969"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010cell patch\u2010clamp recordings, ELISA, and primary astrocyte culture were employed to characterize phenotypic changes and regulatory pathways in the dorsal DG.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that SNI induced persistent mechanical hypersensitivity and cognitive impairment in mice, which was associated with reduced neurogenesis (decreased nestin\n                      <jats:sup>+<\/jats:sup>\n                      radial glial\u2010like cells, DCX\n                      <jats:sup>+<\/jats:sup>\n                      immature neurons, and NeuroD1 expression) and diminished intrinsic excitability of dorsal DG granule cells. Mechanistically, SNI triggered a \u201cdouble hit\u201d to dorsal DG homeostasis: (1) neuron\u2010specific insulin\u2010like growth factor\u20101 (IGF\u20101) resistance, characterized by increased serine phosphorylation of insulin receptor substrate\u20101 (IRS1) at S612 in mature granule cells, reduced IGF\u20101 levels, and impaired PI3K\/AKT signaling; (2) downregulation of astrocyte\u2010derived WNT3, a key neurogenic regulator, which was mediated by proinflammatory cytokine TNF\u2010\n                      <jats:italic>\u03b1<\/jats:italic>\n                      . Therapeutically, local supplementation of IGF\u20101 into the dorsal DG reversed SNI\u2010induced nociceptive and cognitive deficits via IGF\u20101R\/AKT\u2010dependent 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\u2010induced pain hypersensitivity, cognitive impairment, and disrupted neurogenesis. Exogenous administration of WNT3a recapitulated the therapeutic effects by activating AKT, independent of IGF\u20101R signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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\u20101\/AKT pathway. Targeting this WNT3\/IGF\u20101 axis may represent a promising therapeutic strategy for neuropathic pain and its cognitive sequelae.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70714","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:56:33Z","timestamp":1766127393000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impaired\n                    <scp>WNT3<\/scp>\n                    \/\n                    <scp>IGF<\/scp>\n                    \u20101 Signaling in Dorsal Dentate Gyrus Contributes to Chronic Pain\u2010Related Cognitive Impairment"],"prefix":"10.1002","volume":"31","author":[{"given":"Yajie","family":"An","sequence":"first","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyong","family":"Li","sequence":"additional","affiliation":[{"name":"Infectious Department The Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taihe","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, the First Affiliated Hospital Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Physiology, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Pain Research Center, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"issue":"4","key":"e_1_2_12_2_1","first-page":"469","article-title":"Evidences of Memory Dysfunction and Maladaptive Coping in Chronic Low Back Pain and Rheumatoid Arthritis Patients: Challenges for Rehabilitation","volume":"45","author":"Jorge L. 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