The Effects of Propranolol and Corticosterone on Susceptibility Priming in a Mouse Model of Social Defeat Stress

The Effects of Propranolol and Corticosterone on Susceptibility Priming in a Mouse Model of Social Defeat Stress | 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 The Effects of Propranolol and Corticosterone on Susceptibility Priming in a Mouse Model of Social Defeat Stress Alessia Manganaro, Jack Zhang, Giulia Zanni, Clementine Fillinger, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8369302/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 10 You are reading this latest preprint version Abstract Animal models for stress-related mood disorders aim to mirror the diverse spectrum of stress responses observed in humans, which ultimately determine an individual's vulnerability or capacity to cope effectively with the stressor. The acute social defeat stress (ASDS) protocol allows a rapid phenotypic classification of mice subjected to social stress to interrogate the early neural patterns beyond divergent stress outcomes. While ASDS alone doesn't cause chronic depression-like behaviors, it "primes" the mouse to be highly susceptible to a subsequent, subthreshold stress (StSDS). Here, we tested whether pharmacological manipulation shortly before ASDS can counter this susceptibility priming. Specifically, we examined the β-adrenergic receptor antagonist propranolol and the glucocorticoid corticosterone. Male mice received acute intraperitoneal injections of propranolol, corticosterone, or saline prior to ASDS, followed one week later by StSDS and social interaction testing. Propranolol partially prevented the emergence of social avoidance following subsequent StSDS, without modifying the behavioral outcome of ASDS. In contrast, corticosterone administered at different doses, failed to prevent susceptibility priming to later StSDS, disrupting also the typical acute ASDS behavioral profiling at low and medium doses. The results suggest that blocking β-adrenergic signaling during an acute stressor can reduce future stress susceptibility, while underscore the complex and dose-dependent effects of glucocorticoids on stress responsivity. Biological sciences/Drug discovery/Biomarkers Biological sciences/Neuroscience/Learning and memory Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose All animals used in this study were maintained in accordance with the recommendations posed by the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. All experiments were performed in strict adherence with the guidelines established by the Institutional Animal Care and Use Committee at the Icahn School of Medicine at Mount Sinai and conducted in compliance with NIH animal care guidelines. It was approved by the Icahn School of Medicine IACUC Committee. Supplementary Files supplementarytable.png Table S1: Animal Table. Number of mice labelled as freezers or wounded per group and experiment. supplementaryFig.png Figure S1: Propranolol increases freezing behavior after ASDS but is absent after StSDS. (A) Comparisons of SI ratios after ASDS and StSDS for saline and propranolol defeated injected mice categorized as freezers during SIT following ASDS. Paired t-test reported. (B) Bar graphs of the absolute time in the IZ during no target and target sessions of SIT after ASDS for control, defeated and freezer mice in the saline and propranolol condition. One way ANOVA with post-hoc Tukey. (C) Bar graphs of the absolute time in the IZ during no target and target sessions of SIT after StSDS for the same groups in B. One way ANOVA with post-hoc Tukey. Data are presented as mean +/- SEM. Post-hoc: *P < 0.05, **P < 0.01, *** P < 0.001. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 26 Jan, 2026 Review # 2 received at journal 08 Jan, 2026 Review # 3 received at journal 22 Dec, 2025 Reviewer # 3 agreed at journal 22 Dec, 2025 Reviewer # 2 agreed at journal 22 Dec, 2025 Reviewer # 1 agreed at journal 21 Dec, 2025 Reviewers invited by journal 21 Dec, 2025 Editor assigned by journal 16 Dec, 2025 Submission checks completed at journal 16 Dec, 2025 First submitted to journal 15 Dec, 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. 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-8369302","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":563791987,"identity":"5cea5532-1ad1-4137-93d7-09205b6746c5","order_by":0,"name":"Alessia Manganaro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIie3QMUvDQBTA8Xd0PXR9gjVf4UKWQkM/yx0H6RJwzeAQCcSlsyB+BqFT54aAU2g3KTyHSMC5k2SQ4iG0tMOTjg73n96D+w3vAHy+/5npvmW8X0YAKHI3DP4inZLXyX7Bc4j4RBnXx+R34MnlY20VputAvdUt9Bmal+fifgvZ2OQMQUpMqxoK55QoMWvQLN6rAqGZsgQotcrMSCtKYSBKRzYmR1HWLAno9gur3eqEFL3Y8USRTq5yuTwhpfs0noSkbQTShk/ulsrdErlbypF+nUYcuSFtOpCT4ILsR9tn8XBBD91mezcesucftzxM+pznPp/P52P7AWX0YaQt/rEdAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9198-1750","institution":"Columbia University","correspondingAuthor":true,"prefix":"","firstName":"Alessia","middleName":"","lastName":"Manganaro","suffix":""},{"id":563791988,"identity":"a670d1b3-708a-4aa2-8b98-9c249530c306","order_by":1,"name":"Jack Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jack","middleName":"","lastName":"Zhang","suffix":""},{"id":563791989,"identity":"7b380d45-c45c-485f-8481-e40ca8956b31","order_by":2,"name":"Giulia Zanni","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Zanni","suffix":""},{"id":563791990,"identity":"2ae7ef5b-72f2-409a-a94c-b230bfd09959","order_by":3,"name":"Clementine Fillinger","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Clementine","middleName":"","lastName":"Fillinger","suffix":""},{"id":563791991,"identity":"2708a4cd-02a7-4c53-a0a1-6f1b9a16b696","order_by":4,"name":"Dani Dumitriu","email":"","orcid":"https://orcid.org/0000-0002-7873-5192","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Dani","middleName":"","lastName":"Dumitriu","suffix":""}],"badges":[],"createdAt":"2025-12-15 18:45:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8369302/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8369302/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99308777,"identity":"d12a6e40-0e53-4e70-8e49-dc4459088b4a","added_by":"auto","created_at":"2025-12-31 16:09:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1203951,"visible":true,"origin":"","legend":"","description":"","filename":"PublicationFigurespanels.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/6b4bd90e11928b9fb57d2a83.pdf"},{"id":99308759,"identity":"ef9761c0-b345-45c2-a5c3-e55a565bf73d","added_by":"auto","created_at":"2025-12-31 16:09:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":217312,"visible":true,"origin":"","legend":"","description":"","filename":"TranslationalPsychiatrysubmissionmanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/50b9c8b8f45dae4b1ab79a67.pdf"},{"id":98846771,"identity":"22fa2104-9452-4610-9d51-68e6f68f5456","added_by":"auto","created_at":"2025-12-23 04:46:01","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6744,"visible":true,"origin":"","legend":"","description":"","filename":"2025TP003095.json","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/d9ce49d22eb9de238ac021c5.json"},{"id":98846765,"identity":"56af01f9-4f65-48e0-98d4-83118d0b277d","added_by":"auto","created_at":"2025-12-23 04:46:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":359102,"visible":true,"origin":"","legend":"\u003cp\u003eExperimental design of the Propranolol and Corticosterone experiments. (A) Experimental Timeline (B) Schematic representation of the two consecutive trials of SIT, without and with target (non-aggressive CD1) in the interactor. The “interaction zone” and the “corners zone” are depicted in green and red respectively. (C). Examples of mean occupancy heatmaps for two mice showing approaching and social avoidant behavior respectively during the SIT Target session.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/754ff3b88402d64d5bf1ea25.png"},{"id":98846766,"identity":"5be89139-f6e8-4dd3-abf5-991777d484a8","added_by":"auto","created_at":"2025-12-23 04:46:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":272036,"visible":true,"origin":"","legend":"\u003cp\u003ePropranolol administration reduces ASDS-induced stress priming to StSDS. Experimental timeline of the propranolol experiment on top. (A) Violin dot plot graph showing SI ratios in control (CTR) and defeated (DEF) groups following ASDS and StSDS in saline (SAL) and propranolol (PROP) treatment groups. Dashed line denotes the threshold for social avoidance (SI ratio = 1). (B) Bar graph of the absolute time animals spent in the interaction zone (IZ) during SI after ASDS, showing no difference between groups when the CD1 target is not present (left panel) and in the presence of the CD1 target (right panel). (C) Bar graph of the time the animal spent exploring the IZ during SIT after StSDS in absence (left) and in presence (right) of the CD1 target. (D) Bar graph of the time the animal spent exploring the corners zone (CZ) during SIT after ASDS. (E) Bar graph of the time the animal spent exploring the CZ during SI after StSDS. Data are presented as mean +/- SEM. Main effect # P \u0026lt; 0.05, ## P \u0026lt; 0.001, ### P \u0026lt; 0.0001. Post-hoc: *P \u0026lt; 0.05, **P \u0026lt; 0.01, *** P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/d54da219dfa579c7522c4c2d.png"},{"id":98846772,"identity":"f02e2ab9-9024-42c3-9176-0405886e6158","added_by":"auto","created_at":"2025-12-23 04:46:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":287986,"visible":true,"origin":"","legend":"\u003cp\u003eCorticosterone administration interferes with ASDS social avoidance. Experimental timeline of the corticosterone experiment on top. (A) Violin dot plot graph showing SI ratios in control (CTR) and defeated (DEF) groups following ASDS and StSDS in the three mice groups injected, low dose (LOW CORT), medium dose (MED CORT) and high dose (HI CORT) of corticosterone. Dashed line denotes the threshold for social avoidance (SI ratio = 1). (B) Bar graph of the absolute time animals spent in the interaction zone (IZ) during SIT following ASDS, in the no target and target sessions. (C) Bar graph of the absolute time animals spent in IZ during SI after StSDS without the CD1 target (left panel) and in the presence of the CD1 target (right panel). (D) Bar graph of the time the animals spent exploring the corner zone (CZ) during SI after ASDS, in the no target and target sessions. (E) Bar graph of the time the animal spent exploring the CZ during SI following StSDS without CD1 target and with CD1 target. Data are presented as mean +/- SEM. Main effect # P \u0026lt; 0.05, ## P \u0026lt; 0.001, ### P \u0026lt; 0.0001. Post-hoc: *P \u0026lt; 0.05, **P \u0026lt; 0.01, *** P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/fc0000c3a31a0bf36b5e933e.png"},{"id":99322628,"identity":"8efbfbfd-fc46-4e4a-8bbc-ffe47a84b5e5","added_by":"auto","created_at":"2025-12-31 16:43:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1014984,"visible":true,"origin":"","legend":"Article File","description":"","filename":"TranslationalPsychiatrysubmissionmanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1_covered_7ba0de5b-3808-4ee2-b52e-0c1bb9d63c94.pdf"},{"id":99308458,"identity":"861c7747-0e21-4764-aacc-630c394c86df","added_by":"auto","created_at":"2025-12-31 16:08:36","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38235,"visible":true,"origin":"","legend":"\u003cp\u003eTable S1: Animal Table. Number of mice labelled as freezers or wounded per group and experiment.\u003c/p\u003e","description":"","filename":"supplementarytable.png","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/239b8ef99534e392524b4117.png"},{"id":99308608,"identity":"6f6bbe4d-b752-48e5-8f2f-55bd0ca0e1da","added_by":"auto","created_at":"2025-12-31 16:08:49","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":104842,"visible":true,"origin":"","legend":"\u003cp\u003eFigure S1: Propranolol increases freezing behavior after ASDS but is absent after StSDS. (A) Comparisons of SI ratios after ASDS and StSDS for saline and propranolol defeated injected mice categorized as freezers during SIT following ASDS. Paired t-test reported. (B) Bar graphs of the absolute time in the IZ during no target and target sessions of SIT after ASDS for control, defeated and freezer mice in the saline and propranolol condition. One way ANOVA with post-hoc Tukey. (C) Bar graphs of the absolute time in the IZ during no target and target sessions of SIT after StSDS for the same groups in B. One way ANOVA with post-hoc Tukey. Data are presented as mean +/- SEM. Post-hoc: *P \u0026lt; 0.05, **P \u0026lt; 0.01, *** P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"supplementaryFig.png","url":"https://assets-eu.researchsquare.com/files/rs-8369302/v1/90e6c4e9a6feb1a3738081b9.png"}],"financialInterests":"\u003cp\u003eThe authors have declared there is \u003cstrong\u003eNO\u003c/strong\u003e conflict of interest to disclose\u003c/p\u003e\n\u003cp\u003eAll animals used in this study were maintained in accordance with the recommendations posed by the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. All experiments were performed in strict adherence with the guidelines established by the Institutional Animal Care and Use Committee at the Icahn School of Medicine at Mount Sinai and conducted in compliance with NIH animal care guidelines. It was approved by the Icahn School of Medicine IACUC Committee.\u003c/p\u003e","formattedTitle":"The Effects of Propranolol and Corticosterone on Susceptibility Priming in a Mouse Model of Social Defeat Stress","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":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8369302/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8369302/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Animal models for stress-related mood disorders aim to mirror the diverse spectrum of stress responses observed in humans, which ultimately determine an individual's vulnerability or capacity to cope effectively with the stressor. The acute social defeat stress (ASDS) protocol allows a rapid phenotypic classification of mice subjected to social stress to interrogate the early neural patterns beyond divergent stress outcomes. While ASDS alone doesn't cause chronic depression-like behaviors, it \"primes\" the mouse to be highly susceptible to a subsequent, subthreshold stress (StSDS). Here, we tested whether pharmacological manipulation shortly before ASDS can counter this susceptibility priming. Specifically, we examined the β-adrenergic receptor antagonist propranolol and the glucocorticoid corticosterone. Male mice received acute intraperitoneal injections of propranolol, corticosterone, or saline prior to ASDS, followed one week later by StSDS and social interaction testing. Propranolol partially prevented the emergence of social avoidance following subsequent StSDS, without modifying the behavioral outcome of ASDS. In contrast, corticosterone administered at different doses, failed to prevent susceptibility priming to later StSDS, disrupting also the typical acute ASDS behavioral profiling at low and medium doses. The results suggest that blocking β-adrenergic signaling during an acute stressor can reduce future stress susceptibility, while underscore the complex and dose-dependent effects of glucocorticoids on stress responsivity.","manuscriptTitle":"The Effects of Propranolol and Corticosterone on Susceptibility Priming in a Mouse Model of Social Defeat Stress","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-23 04:45:57","doi":"10.21203/rs.3.rs-8369302/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-01-26T09:44:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-01-08T08:25:30+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-12-22T20:13:32+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-22T14:21:39+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-22T07:40:18+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-22T02:34:02+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-12-22T01:49:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-16T12:13:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-16T12:13:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Translational Psychiatry","date":"2025-12-15T18:41:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"df572749-4042-4898-96f6-53d3f05a0900","owner":[],"postedDate":"December 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":60031376,"name":"Biological sciences/Drug discovery/Biomarkers"},{"id":60031377,"name":"Biological sciences/Neuroscience/Learning and memory"}],"tags":[],"updatedAt":"2026-05-12T15:31:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-23 04:45:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8369302","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8369302","identity":"rs-8369302","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}