Inhibiting Fear Memory Recall-induced Oligodendrogenesis Rescues PTSD-like Behaviors

Inhibiting Fear Memory Recall-induced Oligodendrogenesis Rescues PTSD-like Behaviors | 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 Article Inhibiting Fear Memory Recall-induced Oligodendrogenesis Rescues PTSD-like Behaviors Lan Xiao, Jie Feng, xin Huang, Kun Liu, chen Fan, fei Chen, bei Zhao, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7758367/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract The recurrent re-experiencing of traumatic memories is a core symptom of post-traumatic stress disorder (PTSD), and the severity of this symptom has been consistently associated with the clinical course and long-term prognosis of the disorder. Notably, some patients exhibit white matter abnormalities. Myelin, a crucial white matter component, has been shown to regulate the consolidation of remote memory in the adult brain. However, the dynamics of myelin following re-experienced traumatic stressors and their potential significance remain elusive. Here, we developed a repeated fear recall mouse model simulating PTSD re-experiencing symptoms, revealing that fear recalls profoundly reinforce remote fear memory and induce psychotic and social deficits. This pathological reinforcement coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and increased dendritic spine density, as demonstrated by cell-lineage tracing and labeling. We hypothesize that repeated recall-induced oligodendrogenesis may critically reinforce remote fear memories and contribute to these functional impairments. Strikingly, loss-of-function experiments, either inducing apoptosis of new oligodendrocytes or cell-specific Olig2 knockout, effectively relieve the abnormal reinforcement of long-term fear memory and the accompanying social impairments caused by repeated recall. Furthermore, diminished oligodendrogenesis also reduces fear recall-induced neuronal activation and attenuates dendritic spine changes within fear-related brain regions. Crucially, administering rapamycin, a potent oligodendrogenesis inhibitor, during repeated fear recalls phenocopies the beneficial effects of anti-myelination interventions on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis triggered by repeated fear recall is sufficient to drive PTSD-like behavioral progression, likely by modulating neuronal circuits underlying remote fear memories in adults. Medications targeting oligodendrogenesis during recall may prevent pathological reinforcement of long-term fear memories and mitigate psychotic and social deficits in PTSD patients. Biological sciences/Neuroscience Health sciences/Diseases Post-traumatic stress disorder Re-experiencing Oligodendrogenesis Myelination inhibitory medication Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files Supplementaryfigure0929.pdf Supplementary information Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 19 Dec, 2025 Review # 1 received at journal 02 Dec, 2025 Review # 2 received at journal 12 Nov, 2025 Reviewer # 2 agreed at journal 09 Nov, 2025 Reviewer # 1 agreed at journal 09 Nov, 2025 Reviewers invited by journal 05 Nov, 2025 Editor assigned by journal 03 Oct, 2025 Submission checks completed at journal 03 Oct, 2025 First submitted to journal 01 Oct, 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-7758367","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":540651865,"identity":"bdd5d726-1b93-4c16-944d-62a58935bb18","order_by":0,"name":"Lan 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Chen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"fei","middleName":"","lastName":"Chen","suffix":""},{"id":540651871,"identity":"c60c398a-8ff5-4922-bd7d-c4b312127539","order_by":6,"name":"bei Zhao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"bei","middleName":"","lastName":"Zhao","suffix":""},{"id":540651872,"identity":"a7d9a21b-dc49-44fb-a23d-76bf3feebcbc","order_by":7,"name":"Bin Yu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Yu","suffix":""},{"id":540651873,"identity":"bdc13a05-09a5-4302-930b-39c41c9d7823","order_by":8,"name":"Feng Mei","email":"","orcid":"https://orcid.org/0000-0003-4125-1570","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Mei","suffix":""},{"id":540651874,"identity":"d5cec716-a926-418f-abf8-e25f06539fef","order_by":9,"name":"Fei Wang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-10-01 10:05:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7758367/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7758367/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96049704,"identity":"ee37e9b5-c54f-4499-b355-9d3554178d19","added_by":"auto","created_at":"2025-11-17 06:35:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2397193,"visible":true,"origin":"","legend":"","description":"","filename":"FigureLegends0929.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/0170e3fa865d48274503c0c9.pdf"},{"id":96049699,"identity":"f7f784d4-4ea3-4f29-bc8b-e42bf3c6b2bb","added_by":"auto","created_at":"2025-11-17 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06:35:32","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1605481,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfigure0929.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/cc44debd3df9a153eee9b675.pdf"},{"id":96049695,"identity":"91bd2e50-b071-4c75-b216-c8ffcdf86caa","added_by":"auto","created_at":"2025-11-17 06:35:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":317549,"visible":true,"origin":"","legend":"\u003cp\u003eRepeated fear memory recall results in behavioral deficits and increases the population of OLs. (A) Schematic diagram illustrating the experimental procedure, including single recall (Recall ×1) or multiple recalls (Recall ×4) after the establishment of contextual fear conditioning (CFC), followed by long-term behavioral and cell-sequence. (B) Long-term memory performance after single or multiple recalls. n=8, 8 and 11 mice in CFC control, recall (×1) and recall (×4) groups, respectively. (C) Total distance and time moving in the central area in the open field test. n=8, 8, 11 mice in CFC control, recall (×1) and recall (×4) groups, respectively. (D) Interaction time in sociability and social novelty test in three-chamber test. “E” is a new object, “S1” is unfamiliar mouse 1, and “S2” is unfamiliar mouse 2. Trail 1 is for mouse sociability test and trail 2 is for social novelty preference test. (E) Number of open arm entries in elevated plus maze test for three groups of mice. (F and G) Unbiased transcriptome clustering and proportions of different types of cells performed on hippocampal cells isolated from conditioned fear memory (CFC) and Recall (××4) mice. Projection (UMAP) identified clusters corresponding to OLs, OPCs, neurons, endothelial cells, pericytes, Vascular smooth muscle cells(VLMC), microglia, and astrocytes. (H) Representative images and quantification of CC1+ OLs (green) in brains of CFC and Recall (××4) mice. Scale bars: 50μμm. n = 5 independent mice for each group. (I) Representative images and quantification of PDGFRαα+ OPCs (red) in brains of CFC and Recall (×4) mice. Scale bars: 20μμm. n = 5 independent mice for each group. Data represent mean ± SEM. One-way ANOVA followed by Tukey’’s test for more than two groups or the unpaired t test for two experimental groups was used. n.s. indicates no statistical significance, * p \u0026lt; 0.05, ** p \u0026lt; 0.01. ***p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/6bc6ba9d99b263f6d5e9adaf.png"},{"id":96246195,"identity":"e453ce18-a889-45d1-9b99-efc1efd1697f","added_by":"auto","created_at":"2025-11-19 07:25:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1136370,"visible":true,"origin":"","legend":"\u003cp\u003eRepeated fear recall promotes regional-specific myelination, but has no significant impact on pre-existing myelin. (A) Schematic diagram illustrating the timeline for tamoxifen induction, repeated recall sessions, and histological analysis in NG2-CreERT; Tau-mGFP mice. (B and C) Representative images and quantification of mGFP+ newly-formed myelin following repeated recall. Right panels are enlarged images labeling in the left panels. Scale bars: 100μm (left panels) and 20μm (right panels). D The schematic diagram of MOG-DreERT; mT(loxp)/mG (rox) line labeling pre-existing myelin. (E and F) Representative images of pre-existing myelin (mGFP+ and MBP+) in mPFC (E) and quantification of pre-existing myelin in different regions (F), Scale bars: 50μm. (G) Representative images showing 3-D reconstruction of double labeling of NF200+ axons (gray) and MBP+ myelin (green) in CFC and Recall (××4) mice. Scale bars: 2μm. (H) Representative TEM images and quantification of myelinated axons in the hippocampus. Scale bars: 2 μμm. Data represent mean ± SEM. The unpaired Student’’s t test was used. n.s. indicates no statistical significance, * p\u0026lt;0.05, ** p\u0026lt;0.01. Abbreviations: mPFC, prefrontal cortex; ACC, anterior cingulate cortex; Hipp, hippocampus; VIS, visual cortex; AUD, auditory cortex; BLA, amygdala.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/264f8fe1465c61bcdc50c9bf.png"},{"id":96049701,"identity":"8fae1dd2-70cb-4953-b1ba-80ee8b9c22f1","added_by":"auto","created_at":"2025-11-17 06:35:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":915047,"visible":true,"origin":"","legend":"\u003cp\u003eElimination of oligodendrogenesis alleviates remote fear memory and social deficits induced by repeated fear recall. (A) Schematic diagram of the experimental time course for verification of NG2-CreERT; Tau-DTR-tdTomato mice. (B) Representative images of CC1+ (green) and tdTomato+ (red) double labeling cells in vehicle and DT treatment mice. Right panels are enlarged images labeled in the left panels. Scale bars: 50μm (left) and 20μm (right). (C) Quantification of CC1 (green) and tdTomato (red) double positive cells in vehicle and DT treated mice. n=4 mice for each group. (D) The diagram illustrates the temporal dynamics of tamoxifen administration, repeated recall procedures, and DT treatment in NG2-CreERT; Tau-DTR-tdTomato transgenic mice. (E and F) Representative images (E) and quantification (F) of CC1/tdTomato double-positive cells (white arrows). n=4 independent mice for each group. (G) Long-term memory performance for vehicle and DT treated mice. n= 8 mice for each group. (H) Total distance and time moving in the central area in the open field test. n=8 mice in each group. (I) Number of open arm entries in elevated plus maze test vehicle and DT treated mice. n=8 mice for each group. (J) Interaction time in three-chamber social test for vehicle and DT treated mice. n=8 independent mice for each group. Data represent mean ± SEM. The unpaired Student’’s t test was used. n.s. indicates no statistical significance, * p\u0026lt;0.05, ** p\u0026lt;0.01, **** p\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/9fd3ac6c2542d94b318de1c8.png"},{"id":96247282,"identity":"4363f6e8-e079-4669-a84b-72cbaf17a99f","added_by":"auto","created_at":"2025-11-19 07:27:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":814285,"visible":true,"origin":"","legend":"\u003cp\u003eInhibition of oligodendrogenesis attenuates remote fear memory and related psychotic behaviors induced by repeated fear recall. (A) Schematic diagram illustrating the time course for tamoxifen induction, repeated recall and histological analysis in NG2-CreERT; Tau-mGFP; Olig2 fl/fl mice. (B and C) Representative images and quantification of mGFP+ newly-formed myelin in hippocampus (left panels) and mPFC (right panels) area of CTL and Olig2 cKO mice; n=4 independent mice for each group. Scale bars: 100μm. (D) Long-term memory performance for CTL and Olig2 cKO mice. n=17 mice in control group, and n=12 mice in Olig2 cKO group. The Mann-Whitney U test was used. (E-G) The open field test (E), elevated plus maze test (F), and three-chamber test (G) for Olig2 cKO mice and control mice. Data represent mean ± SEM. The unpaired Student’’s t test was used. n.s. indicates no statistical significance, * p\u0026lt;0.05, ** p\u0026lt;0.01, *** p\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/29c908960764c77bdd72ab6a.png"},{"id":96049706,"identity":"254ce7b5-c7d9-47b4-9793-7cab5bf038bf","added_by":"auto","created_at":"2025-11-17 06:35:32","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":695032,"visible":true,"origin":"","legend":"\u003cp\u003eRepeated fear memory recall causes fear-associated neuronal activation and dendritic plasticity. (A) Schematic diagram illustrating TRAP (Fos-CreERT; Ai9-tdTomato) mice and timeline for experiment pattern. (B and C) Representative images and quantifications of tdTomato+ cells in the hippocam- pus and mPFC of mice in the CTL and Recall (××4) mice. White arrows showing tdTomato+ cells. Scale bars: 50μm. n=3 independent mice for each group. (D and E) Representative images and quantification of c-Fos and tdTomato double-labeled reactivated engram cells in the hippocampus and mPFC of mice in the CTL and Recall (××4) groups. Yellow arrows showing tdTomato+ engram cells. Scale bar: 20μm. n=3 independent mice for each group. (F) Representative image of spines on the secondary dendrite of fear recall associated engram cell. The right panels showing dendritic spines in CTL and Recall (××4) brains. (G) Quantifications of total dendritic spines and “mushroom” like spines in CTL and Recall (××4) mice. n=3 independent mice for each group. Data represent mean ± SEM. The unpaired Student’’s t test was used. n.s. indicates no statistical significance, * p\u0026lt;0.05, ** p\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/0c5ad39ac6f0c1e7d8c9712f.png"},{"id":96049702,"identity":"63503d38-6db1-4987-a80e-816c643c663c","added_by":"auto","created_at":"2025-11-17 06:35:32","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":535748,"visible":true,"origin":"","legend":"\u003cp\u003eOligodendrogenesis modulates fear-associated neuronal activation and dendritic plasticity following repeated fear recall. (A and B) Representative images and quantification of c-Fos+ (red) cells in Vehicle and DT treated mice after long-term fear memory test. Scale bar: 50μm. n=4 independent mice for each group. (C and D) Representative images and quantification of c-Fos+ (red) cells in Olig2 control and Olig2 cKO mice. Scale bar: 50μm. n=4 independent mice for each group. (E, F and G) Golgi staining revealed dendritic spines on secondary dendrites of neurons in mPFC area of both vehicle and DT-treated mice (E) and quantification of total dendritic spines (F) and “mushroom” like dendritic spines (G). n=4 independent mice for each group. (H and I) Golgi staining revealed dendritic spines on secondary dendrites of neurons in mPFC area of CTL or Olig2 cKO mice (H) and quantification of total dendritic spines and “mushroom” like dendritic spines (I). n=3 independent mice for each group. Data represent mean ± SEM. The unpaired Student’’s t test was used. n.s. indicates no statistical significance, * p\u0026lt;0.05, ** p\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/8800e415adea0ebb2ce09545.png"},{"id":96247318,"identity":"7d23c79e-776a-404e-a00b-3f3f92f46ff5","added_by":"auto","created_at":"2025-11-19 07:27:22","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":964195,"visible":true,"origin":"","legend":"\u003cp\u003eRapamycin inhibits oligodendrogenesis and alleviate reinforcement of remote fear memory induced by repeated fear recall. (A) The Schematic diagram illustrates the time course of tamoxifen induction, rapamycin treatment, behavioral tests and histological analysis in NG2-CreERT; Tau-mGFP mice. (B) Representative images of mGFP+ new myelin in the hippocampus of Vehicle or rapamycin-treated mice after repeated fear recall. Scale bar: 200μm. (C) Quantification of mGFP+ (green) new myelin in the hippocampus, mPFC and BLA of Vehicle or rapamycin-treated mice upon repeated fear recall. n=4 independent mice for each group. (D) Long-term memory performance for vehicle and rapamycin treated mice. n=8 independent mice for vehicle group and n=9 independent mice for rapamycin treated group. (E-G) The open field test (E), elevated plus maze test (F), and three-chamber test (G) for vehicle and rapamycin-treated mice following repeated fear recall. n=9 independent mice for vehicle group and n=8 independent mice for rapamycin-treated group. (H) Schematic diagram of the time patterns for fear memory retrieval, tamoxifen induction, rapamycin administration, and tissue collection in Fos-CreERT2; Ai9-tdTomato mice. (I) Representative images of tdTomato+ (red), and c-Fos/tdTomato double positive (yellow) cells in the hippocampus of vehicle and rapamycin-treated mice. Scale bar: 50μμm. Yellow arrow indicating reactivated engram cells. (J and K) Quantification of tdTomato+ (J), and c-Fos/tdTomato double positive (K) cells in the hippocampus of vehicle and rapamycin treated mice. (L) Representative images of tdToamto+ cells and quantification of total dendritic spines on secondary dendrites in hippocampus of vehicle and rapamycin-treated mice. Yellow arrows indicating dendritic spines. Data represent mean ± SEM. The unpaired Student’’s t test was used. n.s. indicates no statistical significance, * p\u0026lt;0.05, ** p\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/ce8915408aa159a4d0a12803.png"},{"id":96256078,"identity":"f3490979-2df0-4a44-bf45-62d0840938eb","added_by":"auto","created_at":"2025-11-19 07:49:26","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1382857,"visible":true,"origin":"","legend":"Article File","description":"","filename":"fengmanuscript1001.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1_covered_b2b4272a-0c7b-4c41-8a27-b63fe7278508.pdf"},{"id":96049698,"identity":"4ec3d94a-3788-4b41-99f9-b4b2f4868bf0","added_by":"auto","created_at":"2025-11-17 06:35:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1605481,"visible":true,"origin":"","legend":"Supplementary information","description":"","filename":"Supplementaryfigure0929.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7758367/v1/f4b51f3282e629f6ea5fd2a6.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Inhibiting Fear Memory Recall-induced Oligodendrogenesis Rescues PTSD-like Behaviors","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-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Post-traumatic stress disorder, Re-experiencing, Oligodendrogenesis, Myelination inhibitory medication","lastPublishedDoi":"10.21203/rs.3.rs-7758367/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7758367/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The recurrent re-experiencing of traumatic memories is a core symptom of post-traumatic stress disorder (PTSD), and the severity of this symptom has been consistently associated with the clinical course and long-term prognosis of the disorder. Notably, some patients exhibit white matter abnormalities. Myelin, a crucial white matter component, has been shown to regulate the consolidation of remote memory in the adult brain. However, the dynamics of myelin following re-experienced traumatic stressors and their potential significance remain elusive. Here, we developed a repeated fear recall mouse model simulating PTSD re-experiencing symptoms, revealing that fear recalls profoundly reinforce remote fear memory and induce psychotic and social deficits. This pathological reinforcement coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and increased dendritic spine density, as demonstrated by cell-lineage tracing and labeling. We hypothesize that repeated recall-induced oligodendrogenesis may critically reinforce remote fear memories and contribute to these functional impairments. Strikingly, loss-of-function experiments, either inducing apoptosis of new oligodendrocytes or cell-specific Olig2 knockout, effectively relieve the abnormal reinforcement of long-term fear memory and the accompanying social impairments caused by repeated recall. Furthermore, diminished oligodendrogenesis also reduces fear recall-induced neuronal activation and attenuates dendritic spine changes within fear-related brain regions. Crucially, administering rapamycin, a potent oligodendrogenesis inhibitor, during repeated fear recalls phenocopies the beneficial effects of anti-myelination interventions on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis triggered by repeated fear recall is sufficient to drive PTSD-like behavioral progression, likely by modulating neuronal circuits underlying remote fear memories in adults. Medications targeting oligodendrogenesis during recall may prevent pathological reinforcement of long-term fear memories and mitigate psychotic and social deficits in PTSD patients.","manuscriptTitle":"Inhibiting Fear Memory Recall-induced Oligodendrogenesis Rescues PTSD-like Behaviors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 06:35:27","doi":"10.21203/rs.3.rs-7758367/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-12-19T10:13:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-12-02T11:22:46+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-11-12T07:31:09+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-09T13:18:29+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-09T08:50:59+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-11-05T23:25:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-03T10:48:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-03T10:41:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Psychiatry","date":"2025-10-01T10:00:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5e7ed7f3-18c0-4cc0-a958-cd56124be735","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":57514654,"name":"Biological sciences/Neuroscience"},{"id":57514655,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2026-04-23T10:31:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 06:35:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7758367","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7758367","identity":"rs-7758367","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}