Spinal cord stimulation alleviates cognitive deficits in chronic pain by targeting the microglial lnc-PCM1/PKC/IFN-γ axis to resolve neuroinflammation

Spinal cord stimulation alleviates cognitive deficits in chronic pain by targeting the microglial lnc-PCM1/PKC/IFN-γ axis to resolve neuroinflammation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Spinal cord stimulation alleviates cognitive deficits in chronic pain by targeting the microglial lnc-PCM1/PKC/IFN-γ axis to resolve neuroinflammation Qin Li, Deshan Li, Shunxin Liu, Jiang Zou, Hui Pan, Huaiming Wang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8212646/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background: Neuroinflammation plays a pivotal role in chronic pain with cognitive dysfunction (CPCD), a debilitating condition where effective treatments are limited. While spinal cord stimulation (SCS) is an established analgesic therapy, its potential to ameliorate cognitive deficits via central immunomodulation remains largely unexplored. Methods: A rat model of CPCD was established by spared nerve injury (SNI). We employed RNA sequencing to identify SCS-regulated long non-coding RNAs (lncRNAs) in the prefrontal cortex (PFC). The functional role of a specific microglial lncRNA, lnc-PCM1, was investigated using adeno-associated virus (AAV)-mediated approaches, behavioral tests, molecular assays, and primary cell co-cultures. Results: SCS treatment significantly improved cognitive function in CPCD rats. We identified lnc-PCM1 as a key mediator, predominantly expressed in microglia, whose expression was suppressed by SCS. Mechanistically, SCS-mediated inhibition of lnc-PCM1 upregulated its target PCM1, thereby attenuating the protein kinase C (PKC) phosphorylation / interferon-gamma (IFN-γ) signaling axis. This led to a reduction in microglial M1 polarization and pro-inflammatory cytokine release. Consequently, SCS mitigated IFN-γ-driven neuronal oxidative stress, apoptosis, and synaptic damage in the PFC. Critically, the therapeutic benefits of SCS on cognition and neuroinflammation were abolished by overexpressing lnc-PCM1 or knocking down PCM1. Conclusions: Our study unveils a novel immunomodulatory mechanism of SCS: it ameliorates CPCD by resolving neuroinflammation through targeting the microglial lnc-PCM1/PKC/IFN-γ pathway. These findings position lnc-PCM1 as a promising new target for immunopharmacological interventions in chronic pain-related cognitive disorders. This cascade not only inhibited microglial pro-inflammatory activation but also restored PFC neuronal synaptic integrity, which collectively contributed to cognitive rescue. Spinal cord stimulation Neuroinflammation Cognitive dysfunction Microglia Lnc-PCM1 PKC/IFN-γ signaling Chronic pain Immunomodulation Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMethods.docx SupplementaryFile1.txt SupplementaryTable.docx TITANGuidelineChecklist20251.docx fulluncroppedGelsandBlots.pptx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 May, 2026 Reviews received at journal 10 May, 2026 Reviewers agreed at journal 08 May, 2026 Reviewers agreed at journal 05 May, 2026 Reviewers agreed at journal 03 May, 2026 Reviewers agreed at journal 01 May, 2026 Reviewers agreed at journal 30 Apr, 2026 Reviews received at journal 29 Jan, 2026 Reviewers agreed at journal 14 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 01 Dec, 2025 Submission checks completed at journal 01 Dec, 2025 First submitted to journal 26 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8212646","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":571754623,"identity":"725b6ab5-e452-4d9b-ab7b-75d4991abbf8","order_by":0,"name":"Qin Li","email":"","orcid":"","institution":"Sichuan Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Li","suffix":""},{"id":571754629,"identity":"7cf3ffa4-7157-46e1-ae00-aab55a9285a4","order_by":1,"name":"Deshan Li","email":"","orcid":"","institution":"Sichuan Cancer 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neuroinflammation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-neurobiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"moln","sideBox":"Learn more about [Molecular Neurobiology](https://www.springer.com/journal/12035)","snPcode":"12035","submissionUrl":"https://submission.nature.com/new-submission/12035/3","title":"Molecular Neurobiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer 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While spinal cord stimulation (SCS) is an established analgesic therapy, its potential to ameliorate cognitive deficits via central immunomodulation remains largely unexplored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA rat model of CPCD was established by spared nerve injury (SNI). We employed RNA sequencing to identify SCS-regulated long non-coding RNAs (lncRNAs) in the prefrontal cortex (PFC). The functional role of a specific microglial lncRNA, lnc-PCM1, was investigated using adeno-associated virus (AAV)-mediated approaches, behavioral tests, molecular assays, and primary cell co-cultures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eSCS treatment significantly improved cognitive function in CPCD rats. We identified lnc-PCM1 as a key mediator, predominantly expressed in microglia, whose expression was suppressed by SCS. Mechanistically, SCS-mediated inhibition of lnc-PCM1 upregulated its target PCM1, thereby attenuating the protein kinase C (PKC) phosphorylation / interferon-gamma (IFN-γ) signaling axis. This led to a reduction in microglial M1 polarization and pro-inflammatory cytokine release. Consequently, SCS mitigated IFN-γ-driven neuronal oxidative stress, apoptosis, and synaptic damage in the PFC. Critically, the therapeutic benefits of SCS on cognition and neuroinflammation were abolished by overexpressing lnc-PCM1 or knocking down PCM1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur study unveils a novel immunomodulatory mechanism of SCS: it ameliorates CPCD by resolving neuroinflammation through targeting the microglial lnc-PCM1/PKC/IFN-γ pathway. These findings position lnc-PCM1 as a promising new target for immunopharmacological interventions in chronic pain-related cognitive disorders. This cascade not only inhibited microglial pro-inflammatory activation but also restored PFC neuronal synaptic integrity, which collectively contributed to cognitive rescue.\u003c/p\u003e","manuscriptTitle":"Spinal cord stimulation alleviates cognitive deficits in chronic pain by targeting the microglial lnc-PCM1/PKC/IFN-γ axis to resolve neuroinflammation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-09 07:01:41","doi":"10.21203/rs.3.rs-8212646/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-11T03:07:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T02:15:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148471660086994189131926524739768840548","date":"2026-05-08T05:54:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"337633679999729086676593925702746989272","date":"2026-05-05T16:56:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335224104737578133720645859806143303634","date":"2026-05-03T05:30:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178570194558101231188823581982585643755","date":"2026-05-01T06:34:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"112169027704780530965418320964358472804","date":"2026-05-01T01:21:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-29T11:19:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229309768200552380216514072386090595861","date":"2026-01-14T15:39:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334215347036405633462862419685940344707","date":"2026-01-12T06:49:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T18:52:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-02T00:42:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-02T00:41:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Neurobiology","date":"2025-11-26T11:35:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-neurobiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"moln","sideBox":"Learn more about [Molecular Neurobiology](https://www.springer.com/journal/12035)","snPcode":"12035","submissionUrl":"https://submission.nature.com/new-submission/12035/3","title":"Molecular Neurobiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"599344a9-e77f-425d-bd02-e5666dbc9f13","owner":[],"postedDate":"January 9th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-11T03:07:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T02:15:47+00:00","index":112,"fulltext":""},{"type":"reviewerAgreed","content":"148471660086994189131926524739768840548","date":"2026-05-08T05:54:51+00:00","index":111,"fulltext":""},{"type":"reviewerAgreed","content":"337633679999729086676593925702746989272","date":"2026-05-05T16:56:51+00:00","index":108,"fulltext":""},{"type":"reviewerAgreed","content":"335224104737578133720645859806143303634","date":"2026-05-03T05:30:09+00:00","index":107,"fulltext":""},{"type":"reviewerAgreed","content":"178570194558101231188823581982585643755","date":"2026-05-01T06:34:06+00:00","index":104,"fulltext":""},{"type":"reviewerAgreed","content":"112169027704780530965418320964358472804","date":"2026-05-01T01:21:19+00:00","index":103,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T15:53:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-09 07:01:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8212646","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8212646","identity":"rs-8212646","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}