Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations

Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations | 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 Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations Janet Wang, William Schupp, Kazuko Sakata This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5027446/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 May, 2025 Read the published version in Molecular Medicine → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Brain-derived neurotrophic factor (BDNF) expression is reduced in the brain of various central nervous system (CNS) disorders, but its relation to peripheral expression remains unclear. This study aimed to determine peripheral BDNF expression affected by BDNF promoter IV defect and enriched environment treatment (EET). Promoter IV defect is associated with CNS disorders and chronic stress, whereas EET increases hippocampal BDNF expression and ameliorates CNS dysfunctions. Methods: Enzyme-linked immunosorbent assay was conducted to measure BDNF protein levels in eleven regions (hippocampus, frontal cortex, heart, lung, liver, spleen, intestine, kidney, intestine, thymus, muscle, serum) in wild-type and knock-in promoter IV (KIV) mice with or without 3 weeks of EET provided after weaning. Results: Knock-in promoter IV resulted in BDNF levels significantly decreased in muscle, but significantly increased in intestine, liver, thymus, and serum, which suggests compensatory upregulation of other promoters in those tissues. EET increased BDNF levels in muscle and serum of KIV mice and thymus of wild-type mice, along with significant positive serum-muscle and serum-thymus correlations of BDNF levels, suggesting EET’s beneficial effects in muscle motor and adaptive immune regulation. EET increased hippocampal BDNF levels in both genotypes and showed a significant negative correlation with intestine BDNF levels, suggesting its role in the brain-gut axis. EET reduced wild-type heart BDNF levels, possibly through parasympathetic regulation. BDNF levels were also significantly positively correlated between lung and spleen and between intestine and liver, suggesting inter-organ interaction and regulation of BDNF. Conclusion: This is the first study to not only demonstrate how these specific genetic and environmental factors affect BDNF expression in peripheral tissues, but also highlight the complex regulatory interplay of BDNF expression across organ systems. Elucidation of BDNF’s role and regulatory mechanisms in peripheral organ systems may help better our understanding of its connection to CNS disorders and their treatments. BDNF peripheral tissues enriched environmental treatment promoter IV knock-in mice inter-organ correlations Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigures14.pdf SupplementaryTable1statistics.xlsx Cite Share Download PDF Status: Published Journal Publication published 01 May, 2025 Read the published version in Molecular Medicine → Version 1 posted Editorial decision: Revision requested 16 Jan, 2025 Reviews received at journal 18 Dec, 2024 Reviewers agreed at journal 06 Dec, 2024 Reviewers agreed at journal 29 Oct, 2024 Reviews received at journal 05 Oct, 2024 Reviewers agreed at journal 27 Sep, 2024 Reviewers agreed at journal 21 Sep, 2024 Reviewers agreed at journal 21 Sep, 2024 Reviewers invited by journal 06 Sep, 2024 Editor assigned by journal 06 Sep, 2024 Submission checks completed at journal 06 Sep, 2024 First submitted to journal 03 Sep, 2024 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-5027446","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":362657811,"identity":"3637ecee-c2b9-4701-a3e0-19508a2f4ee0","order_by":0,"name":"Janet Wang","email":"","orcid":"","institution":"University of Tennessee Health Science Center","correspondingAuthor":false,"prefix":"","firstName":"Janet","middleName":"","lastName":"Wang","suffix":""},{"id":362657812,"identity":"fee55cf9-1f9a-4a5f-a8ea-bad78724ac32","order_by":1,"name":"William Schupp","email":"","orcid":"","institution":"University of Tennessee Health Science 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This study aimed to determine peripheral BDNF expression affected by BDNF promoter IV defect and enriched environment treatment (EET). Promoter IV defect is associated with CNS disorders and chronic stress, whereas EET increases hippocampal BDNF expression and ameliorates CNS dysfunctions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eEnzyme-linked immunosorbent assay was conducted to measure BDNF protein levels in eleven regions (hippocampus, frontal cortex, heart, lung, liver, spleen, intestine, kidney, intestine, thymus, muscle, serum) in wild-type and knock-in promoter IV (KIV) mice with or without 3 weeks of EET provided after weaning.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eKnock-in promoter IV resulted in BDNF levels significantly decreased in muscle, but significantly increased in intestine, liver, thymus, and serum, which suggests compensatory upregulation of other promoters in those tissues. EET increased BDNF levels in muscle and serum of KIV mice and thymus of wild-type mice, along with significant positive serum-muscle and serum-thymus correlations of BDNF levels, suggesting EET’s beneficial effects in muscle motor and adaptive immune regulation. EET increased hippocampal BDNF levels in both genotypes and showed a significant negative correlation with intestine BDNF levels, suggesting its role in the brain-gut axis. EET reduced wild-type heart BDNF levels, possibly through parasympathetic regulation. BDNF levels were also significantly positively correlated between lung and spleen and between intestine and liver, suggesting inter-organ interaction and regulation of BDNF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis is the first study to not only demonstrate how these specific genetic and environmental factors affect BDNF expression in peripheral tissues, but also highlight the complex regulatory interplay of BDNF expression across organ systems. Elucidation of BDNF’s role and regulatory mechanisms in peripheral organ systems may help better our understanding of its connection to CNS disorders and their treatments.\u003c/p\u003e","manuscriptTitle":"Peripheral tissue BDNF expression is affected by promoter IV defect and enriched environments in mice: negative hippocampus-intestine and positive thymus-serum-muscle correlations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-09 15:34:35","doi":"10.21203/rs.3.rs-5027446/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-16T19:31:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-18T11:12:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"155794705746836262778657907308072519891","date":"2024-12-06T15:49:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334070369784796171245914156365713720915","date":"2024-10-29T12:22:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-05T22:36:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217701922353495701203989664804114969358","date":"2024-09-27T04:19:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"244688085205443335022642201082553089921","date":"2024-09-21T19:30:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"126535328135339897526405363074489177647","date":"2024-09-21T19:28:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-06T16:33:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-06T04:25:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-06T04:23:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Medicine","date":"2024-09-03T22:08:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mome","sideBox":"Learn more about [Molecular Medicine](https://molmed.biomedcentral.com)","snPcode":"10020","submissionUrl":"https://submission.springernature.com/new-submission/10020/3","title":"Molecular Medicine","twitterHandle":"@MolecularMedic1","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6f96d404-cd38-462f-8537-5cb0aae35cce","owner":[],"postedDate":"October 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-05T13:24:11+00:00","versionOfRecord":{"articleIdentity":"rs-5027446","link":"https://doi.org/10.1186/s10020-025-01196-4","journal":{"identity":"molecular-medicine","isVorOnly":false,"title":"Molecular Medicine"},"publishedOn":"2025-05-02 00:00:00","publishedOnDateReadable":"May 2nd, 2025"},"versionCreatedAt":"2024-10-09 15:34:35","video":"","vorDoi":"10.1186/s10020-025-01196-4","vorDoiUrl":"https://doi.org/10.1186/s10020-025-01196-4","workflowStages":[]},"version":"v1","identity":"rs-5027446","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5027446","identity":"rs-5027446","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}