Proactive Interference Unmasks Sex-Divergent Recognition Memory Instability and Catecholaminergic Dysfunction in Early-Stage Alzheimer’s model

Sex-Specific Catecholaminergic Dysfunction Underlie Proactive Interference deficits in APPswe/PS1dE9 Mice | 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 Sex-Specific Catecholaminergic Dysfunction Underlie Proactive Interference deficits in APPswe/PS1dE9 Mice Srishti Kushwaha, Smitha Karunakaran This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7591768/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Interference is a major contributor to early memory decline in Alzheimer’s disease (AD). We investigated whether proactive interference (PI) destabilizes recognition memory in 2-month-old APP/PS1 mice, a stage when novel object recognition (NOR) is normally intact. PI selectively impaired recognition in male, but not female, APP/PS1 mice, revealing a sex-specific vulnerability. At the neuromodulatory level, male APP/PS1 mice displayed reduced tyrosine hydroxylase–positive dopaminergic terminals in dorsal not ventral hippocampal subfields, whereas females were spared. These results identify PI as a sensitive probe of early recognition instability in AD and highlight sex-divergent mechanisms in which males not females show catecholaminergic vulnerability. Alzheimer’s disease APP/PS1 mice Proactive interference Dopaminergic dysfunction Sex differences Memory resilience Hippocampus Figures Figure 1 Figure 2 Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryTable1.docx SupplementaryFigure1.tif Figure 1: Proactive interference effects on novel object recognition in APP/PS1 mice. (A) Experimental design and timeline for novel object recognition (NOR) and proactive interference (PI) paradigms. Mice were habituated to the arena for three days. On Day 4, PI animals explored multiple novel objects for 1 h, while controls remained in home cages. On Day 5, all animals underwent NOR training by exploring two identical objects for 10 min. On Day 6, one familiar object was replaced with a novel one for a 5 min test to assess recognition memory. Schematic created using BioRender. (B) Discrimination index for male and female in NOR and PI+NOR tests, calculated as time exploring the novel object divided by total exploration time, plotted separately for NOR (left) and PI+NOR (right). (C) Total object exploration time during NOR testing. WT and APP/PS1 mice of both sexes showed intact novel object preference under baseline conditions. (D) Total exploration time during PI+NOR. WT mice retained novel object preference after PI exposure, whereas male APP/PS1 mice failed to discriminate, indicating PI-induced memory impairment. Female APP/PS1 mice retained discrimination despite PI exposure. Blue bars denote male APP/PS1, pink bars female APP/PS1, with adjacent dark bars representing sex-matched WT controls. Data shown as mean ± SEM (n=9-10/group) and analyzed by two-way ANOVA with Tukey–Kramer post hoc test (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001). Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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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Mice were habituated to the arena for three days. On Day 4, PI animals explored multiple novel objects for 1 h, while controls remained in home cages. On Day 5, all animals underwent NOR training by exploring two identical objects for 10 min. On Day 6, one familiar object was replaced with a novel one for a 5 min test to assess recognition memory. Schematic created using BioRender. (B) Discrimination index for male and female in NOR and PI+NOR tests, calculated as time exploring the novel object divided by total exploration time, plotted separately for NOR (left) and PI+NOR (right). (C) Total object exploration time during NOR testing. WT and APP/PS1 mice of both sexes showed intact novel object preference under baseline conditions. (D) Total exploration time during PI+NOR. WT mice retained novel object preference after PI exposure, whereas male APP/PS1 mice failed to discriminate, indicating PI-induced memory impairment. Female APP/PS1 mice retained discrimination despite PI exposure. Blue bars denote male APP/PS1, pink bars female APP/PS1, with adjacent dark bars representing sex-matched WT controls. Data shown as mean ± SEM (n=9-10/group) and analyzed by two-way ANOVA with Tukey–Kramer post hoc test (*\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, **\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, ***\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, ****\u003cem\u003ep\u003c/em\u003e\u0026lt; 0.0001).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7591768/v2/0230d4ab51e9999fa0a11eab.jpg"},{"id":99797965,"identity":"ca5b18df-2955-4a59-8961-c700c643aa88","added_by":"auto","created_at":"2026-01-08 13:47:00","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":9169058,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSex-specific TH\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e terminal intensity in dorsal and ventral hippocampus of WT and APP/PS1 mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Quantification of tyrosine hydroxylase-positive (TH⁺) terminal intensity in the dorsal hippocampus (dHP) and ventral hippocampus (vHP) of male (left) and female (right) WT and APP/PS1 mice. (B) Quantification of TH⁺ terminal intensity in the dHP, (C) dorsal dentate gyrus (dDG), dorsal CA1 (dCA1), and in dorsal CA3 (dCA3). These regional values (dDG, dCA1, dCA3) were averaged to calculate overall TH⁺ terminal intensity in dHP. (D) Quantification of TH⁺ terminal intensity in the vHP, (E) ventral dentate gyrus (vDG), ventral CA1 (vCA1), and in ventral CA3 (vCA3). These regional values (vDG, vCA1, vCA3) were averaged to calculate overall TH⁺ terminal intensity in vHP. (F) Representative 40X confocal images showing TH⁺ terminals (green) with DAPI (cyan) in DG/CA1 and CA3 regions of dorsal and ventral hippocampus of 2-month-old WT and APP/PS1 mice. Scale bar: 50 µm. Blue bars denote male APP/PS1, pink bars female APP/PS1, with adjacent dark bars representing sex-matched WT controls. Data shown as mean ± SEM (n=5/group) and analyzed by two-way ANOVA with Tukey–Kramer post hoc test (*\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05, **\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, ***\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, ****\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001).Top of Form\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7591768/v2/861111e3dc90a037e6e0f4be.jpg"},{"id":99805629,"identity":"5ee62d71-0852-4c80-90c7-edde4d9ff5f2","added_by":"auto","created_at":"2026-01-08 14:16:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":16873348,"visible":true,"origin":"","legend":"","description":"","filename":"KushwahaKarunakaran2025V6.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7591768/v2_covered_910a90c3-07cb-4012-ac6e-80b44d039aa5.pdf"},{"id":99797892,"identity":"f78727b0-7c65-47af-bfa7-3291e5ce497c","added_by":"auto","created_at":"2026-01-08 13:46:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16656,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7591768/v2/d1f62ee3bab7ce3f07415ba5.docx"},{"id":99734474,"identity":"72737cad-57e8-40a8-b1e9-7917b70178b6","added_by":"auto","created_at":"2026-01-07 18:57:34","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3942312,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 1: Proactive interference effects on novel object recognition in APP/PS1 mice\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e(A) Experimental design and timeline for novel object recognition (NOR) and proactive interference (PI) paradigms. Mice were habituated to the arena for three days. On Day 4, PI animals explored multiple novel objects for 1 h, while controls remained in home cages. On Day 5, all animals underwent NOR training by exploring two identical objects for 10 min. On Day 6, one familiar object was replaced with a novel one for a 5 min test to assess recognition memory. Schematic created using BioRender. (B) Discrimination index for male and female in NOR and PI+NOR tests, calculated as time exploring the novel object divided by total exploration time, plotted separately for NOR (left) and PI+NOR (right). (C) Total object exploration time during NOR testing. WT and APP/PS1 mice of both sexes showed intact novel object preference under baseline conditions. (D) Total exploration time during PI+NOR. WT mice retained novel object preference after PI exposure, whereas male APP/PS1 mice failed to discriminate, indicating PI-induced memory impairment. Female APP/PS1 mice retained discrimination despite PI exposure. Blue bars denote male APP/PS1, pink bars female APP/PS1, with adjacent dark bars representing sex-matched WT controls. Data shown as mean ± SEM (n=9-10/group) and analyzed by two-way ANOVA with Tukey–Kramer post hoc test (*\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, **\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, ***\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, ****\u003cem\u003ep\u003c/em\u003e\u0026lt; 0.0001).\u003c/p\u003e","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7591768/v2/31ef06030ad64aeffe401b36.tif"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSex-Specific Catecholaminergic Dysfunction Underlie Proactive Interference deficits in APPswe/PS1dE9 Mice\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, APP/PS1 mice, Proactive interference, Dopaminergic dysfunction, Sex differences, Memory resilience, Hippocampus","lastPublishedDoi":"10.21203/rs.3.rs-7591768/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7591768/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInterference is a major contributor to early memory decline in Alzheimer’s disease (AD). We investigated whether proactive interference (PI) destabilizes recognition memory in 2-month-old APP/PS1 mice, a stage when novel object recognition (NOR) is normally intact. PI selectively impaired recognition in male, but not female, APP/PS1 mice, revealing a sex-specific vulnerability. At the neuromodulatory level, male APP/PS1 mice displayed reduced tyrosine hydroxylase–positive dopaminergic terminals in dorsal not ventral hippocampal subfields, whereas females were spared. These results identify PI as a sensitive probe of early recognition instability in AD and highlight sex-divergent mechanisms in which males not females show catecholaminergic vulnerability.\u003c/p\u003e","manuscriptTitle":"Sex-Specific Catecholaminergic Dysfunction Underlie Proactive Interference deficits in APPswe/PS1dE9 Mice","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-01-07 18:57:29","doi":"10.21203/rs.3.rs-7591768/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-09-12 10:39:26","doi":"10.21203/rs.3.rs-7591768/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5a5242ed-b6d7-412d-b5e2-a93d323549dd","owner":[],"postedDate":"January 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-17T03:53:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-07 18:57:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-7591768","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7591768","identity":"rs-7591768","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}