Postnatal depression-associated breastmilk extracellular vesicles mediate intergenerational effects on offspring neurodevelopment

Postnatal depression-associated breastmilk extracellular vesicles mediate intergenerational effects on offspring neurodevelopment | 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 Postnatal depression-associated breastmilk extracellular vesicles mediate intergenerational effects on offspring neurodevelopment Xi Chen, Zexu Wei, Ranran Yu, Junnan Xu, Chenyu Tao, Aixia Zhang, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9365315/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Postnatal depression (PND) increases the risk of neurodevelopmental impairments in offspring, yet the underlying mechanisms remain elusive. Here, we identify an intergenerational signaling pathway whereby maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and transmitted to offspring via breastmilk small extracellular vesicles (sEVs). Using cross-fostering models, we demonstrate that maternal depression disrupts offspring hippocampal dentate gyrus (DG) newborn neuron maturation, causing cognitive deficits and depressive-like behaviors. Strikingly, gastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these neurodevelopmental phenotypes. Mechanistically, PND-induced miRNAs are packaged into breastmilk sEVs and delivered to infant brain, where they suppress mGluR8 expression in supramammillary nucleus (SuM) neurons projecting to the DG. This presynaptic mGluR8 deficiency dysregulates glutamate release, triggers aberrant synaptic transmission and calcium overload, and ultimately drives a pathological “high-frequency, low amplitude” neuronal activation pattern that compromises the functional integration of newborn neurons into hippocampal circuits. Critically, inhibiting sEV secretion from the mammary gland or sequestering the culprit miRNAs within offspring SuM neurons rescues these neurodevelopmental deficits. These findings not only uncover a novel mechanism underlying PND-related offspring neurodevelopmental impairments, but also provide a promising therapeutic target for clinical intervention of intergenerational transmission of maternal mental disorders. Biological sciences/Molecular biology/Non-coding RNAs/miRNAs Biological sciences/Neuroscience/Molecular neuroscience Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFiles.pdf supplementary files Cite Share Download PDF Status: Under Review Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9365315","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":622436545,"identity":"4edc4c27-263c-4724-98bc-4f832b73dc1f","order_by":0,"name":"Xi 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neurodevelopment","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9365315/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9365315/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Postnatal depression (PND) increases the risk of neurodevelopmental impairments in offspring, yet \r\nthe underlying mechanisms remain elusive. Here, we identify an intergenerational signaling \r\npathway whereby maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and \r\ntransmitted to offspring via breastmilk small extracellular vesicles (sEVs). Using cross-fostering \r\nmodels, we demonstrate that maternal depression disrupts offspring hippocampal dentate gyrus (DG) \r\nnewborn neuron maturation, causing cognitive deficits and depressive-like behaviors. Strikingly, \r\ngastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these \r\nneurodevelopmental phenotypes. Mechanistically, PND-induced miRNAs are packaged into \r\nbreastmilk sEVs and delivered to infant brain, where they suppress mGluR8 expression in \r\nsupramammillary nucleus (SuM) neurons projecting to the DG. This presynaptic mGluR8 \r\ndeficiency dysregulates glutamate release, triggers aberrant synaptic transmission and calcium \r\noverload, and ultimately drives a pathological “high-frequency, low amplitude” neuronal activation \r\npattern that compromises the functional integration of newborn neurons into hippocampal circuits. \r\nCritically, inhibiting sEV secretion from the mammary gland or sequestering the culprit miRNAs \r\nwithin offspring SuM neurons rescues these neurodevelopmental deficits. These findings not only \r\nuncover a novel mechanism underlying PND-related offspring neurodevelopmental impairments, \r\nbut also provide a promising therapeutic target for clinical intervention of intergenerational \r\ntransmission of maternal mental disorders.","manuscriptTitle":"Postnatal depression-associated breastmilk extracellular vesicles mediate intergenerational \neffects on offspring neurodevelopment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 10:57:18","doi":"10.21203/rs.3.rs-9365315/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-metabolism","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natmetab","sideBox":"Learn more about [Nature Metabolism](http://www.nature.com/natmetab/)","snPcode":"","submissionUrl":"","title":"Nature Metabolism","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5fdad5f2-1a2d-4300-b905-dce31d7a6376","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-13T14:35:58+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T14:36:21+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-08T14:48:20+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-08T13:35:30+00:00","index":3,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66236985,"name":"Biological sciences/Molecular biology/Non-coding RNAs/miRNAs"},{"id":66236986,"name":"Biological sciences/Neuroscience/Molecular neuroscience"}],"tags":[],"updatedAt":"2026-04-21T10:57:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 10:57:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9365315","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9365315","identity":"rs-9365315","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}