{"paper_id":"2cde3466-c641-4efe-83ad-69f40fe3fccd","body_text":"Valence-dependent synaptic plasticity drives approach and avoidance behavior in social context | 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 Valence-dependent synaptic plasticity drives approach and avoidance behavior in social context Camilla Bellone, Pedro Espinosa, Benoit Girard, Lorena Jourdain, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6992977/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 Social interactions critically shape future decisions about engaging with or avoiding conspecifics. However, how the valence of previous social experiences translates into adaptive approach or avoidance behaviors remains unclear. Here, we identify a novel circuit from dopamine D1 receptor (D1R)-expressing neurons in the anterior insular cortex (AIC) to D1R-expressing neurons in the lateral nucleus accumbens (LNAc). We show that valence-specific firing frequencies—low-frequency for reward and high-frequency for aversion—induced distinct synaptic plasticity at these synapses. Imposing aversive-like firing patterns during rewarding interactions disrupts plasticity and subsequent social approach. Finally, we identify mGluR1 signaling as a critical molecular mechanism selectively required for positive-valence learning. Together, our findings elucidate the synaptic and molecular mechanisms by which social valence guides adaptive behavioral decisions, highlighting frequency-dependent plasticity within a single neural circuit as a dynamic regulator of social approach or avoidance. Biological sciences/Neuroscience Biological sciences/Neuroscience/Synaptic plasticity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Full Text Additional Declarations There is NO Competing Interest. All experimental procedures involving animals were conducted in accordance with the guidelines and regulations of the Swiss Federal Veterinary Office and were approved by the Geneva Cantonal Veterinary Authority. Supplementary Files NNA91523Figsuppcorrected17511071701.pdf Supplementary Figures 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. 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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-6992977\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":489330384,\"identity\":\"2dff995d-ffa0-4e36-8753-11a86ea1ff9e\",\"order_by\":0,\"name\":\"Camilla Bellone\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYJCCAw8KGBgMGJgbDwA5cgwMjA0g0QS8WhIMQFoYG0BajInSwoCsJbEBJohLNX/76USgLXYM5uyNDQc+7rBJ33C7ufnFBwa7PFxaJM7kbgBqSWaw7DnYcHDmmbTcDXcOtlnOYEguxqXFgAGshZnB4EZiw2HetsO5G24kthnzMByAuxBDC/9bkJZ6BoP7D0Fa/qcbgLT8wadFAmzLYaAtjCAtQPaNxObHDHi0SNwA23Kcx7InEeiXtmTDmUBbGHsMknFq4e/P3fzhQ0W1nDn74YMPPrbZyfPdSH/84UeFHU4tMMCDzGGTAAYLaYD5A4kaRsEoGAWjYHgDANC+Z5dvyiPWAAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0002-6774-6275\",\"institution\":\"Geneva University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Camilla\",\"middleName\":\"\",\"lastName\":\"Bellone\",\"suffix\":\"\"},{\"id\":489330385,\"identity\":\"b469374c-0580-4540-a535-523142a19588\",\"order_by\":1,\"name\":\"Pedro Espinosa\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-2202-8982\",\"institution\":\"University of Geneva\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Pedro\",\"middleName\":\"\",\"lastName\":\"Espinosa\",\"suffix\":\"\"},{\"id\":489330386,\"identity\":\"a9ab7df2-98fe-4dd7-9c26-602092294e2e\",\"order_by\":2,\"name\":\"Benoit Girard\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-3914-6483\",\"institution\":\"The University of Geneva\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Benoit\",\"middleName\":\"\",\"lastName\":\"Girard\",\"suffix\":\"\"},{\"id\":489330387,\"identity\":\"cfd85c39-d7a2-458e-b91f-24fd8bb3e669\",\"order_by\":3,\"name\":\"Lorena Jourdain\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Geneva\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Lorena\",\"middleName\":\"\",\"lastName\":\"Jourdain\",\"suffix\":\"\"},{\"id\":489330388,\"identity\":\"a999c789-df8b-4d62-8eb5-f94f84a0b933\",\"order_by\":4,\"name\":\"Mattia Lucchini\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Geneva\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mattia\",\"middleName\":\"\",\"lastName\":\"Lucchini\",\"suffix\":\"\"},{\"id\":489330389,\"identity\":\"44a90492-9a61-4cca-8fae-6922be745217\",\"order_by\":5,\"name\":\"Federica Campanelli\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Geneva\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Federica\",\"middleName\":\"\",\"lastName\":\"Campanelli\",\"suffix\":\"\"},{\"id\":489330390,\"identity\":\"0a10d4f4-f219-4186-a89f-4bdea25b21bc\",\"order_by\":6,\"name\":\"valentina Tiriticco\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Geneva\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"valentina\",\"middleName\":\"\",\"lastName\":\"Tiriticco\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-06-27 15:36:00\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6992977/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6992977/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":87717139,\"identity\":\"e4bd7291-bde6-4cfb-befa-1058c8c5ad8b\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:19:08\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":180938,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eJuvenile and CD1 experiences induce learned approach and avoidance behavior.\\u003c/strong\\u003e (A) Mice were exposed to an object, a juvenile, or CD1 mice for a 15-minute period of free social interaction. After 24 hours, the animals were placed in a new arena where, following 10 minutes of free exploration with an empty enclosure, an enclosure containing the stimuli from the previous day was introduced. (B) Time spent in the interaction zone on day 2, with *** indicating p = 0.0002, **** denoting p \\u0026lt; 0.0001, and p = 0.9130 for interactions with the object. (C) Proximity to the stimulus mouse on day 2, measured as the distance between the mouse’s nose point and the center of the enclosure; ** indicates p = 0.0013, *** represents p = 0.0001, and p = 0.3020 for the object. (D-G) Schematics showing how we manual label the contacts and their subsequent quantification. (H-I) Classification of contacts into positive and negative categories in preparation for training SimBA. (J) Classification of contacts by SimBA.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/946d6162d4fb6bff6197cd96.jpg\"},{\"id\":87716386,\"identity\":\"10a056b1-af67-4b39-a296-4471aa71bbbe\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:08\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":133965,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eD1-MSNs encode proximity to social stimuli, independent of experience valence.\\u003c/strong\\u003e (A) Schematic of injection and implantation sites (Scale 250uM). (B) Average activity during a rewarding experience aligned with the first interaction. The heatmap represents the activity of individual neurons (each row represents one neuron). (C) Average activity during an aversive experience aligned with the first interaction. The heatmap represents the activity of individual neurons (each row represents one neuron). (D) Schematic of a 3D heatmap representing the calcium activity in position relative to the stimuli. (E) Heatmap showing the activity in positions relative to juvenile stimuli. (F) Heatmap showing the activity in positions relative to CD1 stimuli. (G) Proportion of neurons that respond to social stimuli.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/81dcedeb7d96d02efd5d4a02.jpg\"},{\"id\":87716385,\"identity\":\"105adec8-b746-465c-a77a-6662b10c5014\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:08\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":205040,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of AIC-LNAc pathway. (A) Schema of the experimental protocol showing viral injection and transgenic construct activation by 4-OH tamoxifen.\\u003c/strong\\u003e (B) Quantification of cell densities from the main brain regions projecting to the LNAc, representing the overall active inputs during free social interaction. (C) Representative pictures of active neurons in various brain regions. One-way ANOVA was used as the statistical test, with the following significance levels: AIC: ****p\\u0026lt;0.0001, mIC: ****p\\u0026lt;0.0001, ***p=0.0002, pIC: ***p=0.0001. AMY: *p=0.0378, ***p=0.0004. n=4 per condition (prosocial, aversive, non-social). (D) In situ hybridization for mRNA of D1R and td-Tomato, showing high correspondence between c-fos positive cells (mRNA td-Tomato) and D1R mRNA (scale: 10 μm). n=2 for aversive and n=3 for rewarding experience. Most neurons colocalize for mRNA of td-tomato (c-fos signal) and D1R. (E) Schematic of viral injection using a bicolor retrovirus that turns green in the presence of cre-recombinase and remains red without it (scale: 500 μm). Below, the representative picture of the injection site (F). (G) Representative image from AIC illustrating the D1R projecting neuron subpopulation. The left picture shows AIC with D1 positive neurons in green and D1 negative in red. The right shows a magnified view of AIC detailing the proportion of D1 positive and negative cells. Right panel, Histogram represents the quantification of D1 positive and negative cells in AIC, using an unpaired t-test, with **p=0.0091, n=4.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/49cbcc25925aa9b20fc0c976.jpg\"},{\"id\":87716387,\"identity\":\"ff22a212-59c2-4c1a-96c3-ca7f34f8d767\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:08\",\"extension\":\"jpg\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":134573,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eD1R-AIC neurons predicts social valence. (A) Schematic of injection and implantation sites.\\u003c/strong\\u003e (B) Average activity during a rewarding experience aligned with the first interaction. The heatmap represents the activity of individual neurons (each row represents one neuron). (C) Average activity during an aversive experience aligned with the first interaction. The heatmap represents the activity of individual neurons (each row represents one neuron). (D) Schematic of a 3D heatmap representing the calcium activity in position relative to the stimuli. (E) Heatmap showing the activity in positions relative to juvenile stimuli. (F) Heatmap showing the activity in positions relative to CD1 stimuli. (G) Proportion of neurons that respond to social stimuli.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/ecb3b35fd4c6303a538e334d.jpg\"},{\"id\":87717140,\"identity\":\"274912a5-0f66-4f15-a1db-e65516f3d2e1\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:19:09\",\"extension\":\"jpg\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":69160,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSocial valence induce specific long-term synaptic plasticity in AIC-LNAc pathway.\\u003c/strong\\u003e (A) Schematic representation of viral injection into the Lateral Nucleus Accumbens (LNAc) and Anterior Insular Cortex (AIC). (B) Diagrammatic representation of the behavioral paradigm. (C) Schematic of patch-clam whole cell recording protocol. (D) Bar graph showing the AMPA/NMDA ratio 24 hours post-behavioral experiment; to the right are example traces, with **** indicating p \\u0026lt; 0.0001. (E) Bar graph showing the rectification index 24 hours after free interaction; to the right are example traces, with ** denoting p = 0.0094 for Aversive vs. Prosocial and ** for Aversive vs. Object p = 0.0077.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/43751c5a02a31fd69eae4405.jpg\"},{\"id\":87716392,\"identity\":\"4d3bfd18-e986-42a9-981e-0ad8a790d460\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:09\",\"extension\":\"jpg\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":151664,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eValence-dependent synaptic plasticity in the AIC → LNAc pathway is frequency-specific\\u003c/strong\\u003e (A, B) Time course of optically evoked EPSC amplitudes recorded from D1-positive AIC-to-LNAc synapses in acute slices (whole-cell voltage clamp, –70 mV). 10 Hz (A) or 1 Hz (B) trains (gray bar) produced a long-lasting depression (LTD). (C) Summary of the AMPA/NMDA (A/N) ratio after each stimulation protocol. Representative AMPA (–70 mV) and NMDA (+40 mV) traces are shown on the right. **** p \\u0026lt; 0.0001, one-way ANOVA. (D) Rectification index (RI) for the groups in C, derived from I–V plots; example traces are shown on the right. *** p ≤ 0.0005. (E) Paired-pulse ratio (PPR, 100 ms inter-stimulus interval) before (Pre) and after (Post) the in-slice plasticity induction in the same cells shown in A-B. (F) Schematic of the in-vivo optogenetic protocol. In the ipsilateral hemisphere, AIC terminals in the LNAc received either 10 Hz or 1 Hz stimulation; the contralateral hemisphere received only 0.1 Hz test pulses. (G) Viral strategy and fibre placements: AAV-DIO-ChR2-eYFP injected into AIC of D1-Cre mice; optic fibres implanted above the LNAc. (H) AMPA/NMDA ratio measured ex-vivo 24 h after the in-vivo stimulation. ** p = 0.0036; * p = 0.0292; one-way ANOVA. (I) Rectification index 24 h after in-vivo stimulation. ** p = 0.0011; *** p = 0.0001; one-way ANOVA. Numbers in bars denote individual cells. Data are mean ± SEM. Scale bars: 50 pA, 10 ms.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"6.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/4be636a3f74d21a3f310ee4b.jpg\"},{\"id\":87716391,\"identity\":\"231489f3-d34a-4481-8ca4-410b4b0236ca\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:09\",\"extension\":\"jpg\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":135994,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eValence-dependent synaptic plasticity is essential for learned approach behavior. \\u003c/strong\\u003e(A) Schematic indicating the site of viral injection and placement of the optical fiber. (B) Diagram detailing the protocol, and the delivery of 10Hz optical stimulation during bouts of contact. (C) On Day 2, animals were placed in a new arena and, after 10 minutes of free exploration with an empty enclosure, were introduced to an enclosure containing the stimuli from the previous day. (D) Graph depicting the duration of interaction within the zone, with **** signifying p \\u0026lt; 0.0001 for animals that did not receive the stimulation and p = 0.8745 for animals that received the 10Hz stimulation. (E) Graph depicting the distance to stimuli, with ** indicating p = 0.0027 and p = 0.4030 for rewarding experiences with 10Hz stimulation. (F) Bar graph showing the AMPA/NMDA ratio, with * indicating p = 0.020. (G) Bar graph showing the rectification index, p = 0.1048. (H) A correlation graph between the rectification index and the avoidance index, calculated as the distance during the post-test divided by the distance during the pre-test, with p = 0.0055 and R² = 0.75 (each dot represents a single animal, n = 8). A paired t-test was utilized for analyses in (D) and (E). An unpaired t-test was employed for (F) and (G). The numbers inside the bars denote the number of cells in each group. Data are presented as mean ± SEM. Scale bars: 50 pA/10 ms.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"7.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/8c5b290d82c67cb40822f45a.jpg\"},{\"id\":87716393,\"identity\":\"249a57d5-dff0-44af-adbf-79e775842e58\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:09\",\"extension\":\"jpg\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":98814,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003ePositive social-valence plasticity requires mGluR1 signalling. \\u003c/strong\\u003e(A) Viral strategy for conditional mGluR1 deletion: AAV-Cre was injected bilaterally into the LNAc of mGluR1cko mice to excise Grm1 locally (control animals received AAV-GFP). (B) Behavioural schematic. Day 1: 15-min free social interaction with a novel juvenile conspecific or CD-1 mouse. Day 2: 10-min habituation to an empty arena followed by 10 min with the previous stimuli in an enclosure (C). (D) Time in the interaction zone during the rewarding paradigm. mGluR1-cKO mice failed to develop a preference. (E) Aversive experience. Both genotypes displayed robust avoidance of the CD-1 on Day 2, indicating intact learning of negative valence. (F) Synaptic consequences of ablation of mGluR1 in the LNAc: AAV-Cre in the LNAc of mGluR1cko mice combined with AAV-hSyn-ChR2-eYFP in the AIC. (G) Ex-vivo synaptic read-out. Left, AMPA/NMDA ratio; right, rectification index (RI). **** p \\u0026lt; 0.0001 (t-test, non paired). Data are mean ± SEM. Scale bars and n for electrophysiology in each panel, behavior; n = 10 per group.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"8.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/781a7201d502369a28f6bd6b.jpg\"},{\"id\":87718508,\"identity\":\"bf43e2e5-9f2b-4a76-b5c1-902d73371c04\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:27:12\",\"extension\":\"pdf\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1827457,\"visible\":true,\"origin\":\"\",\"legend\":\"Article File\",\"description\":\"\",\"filename\":\"Espinosa2025Main.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1_covered_ec671861-b74a-45e6-b151-7e4948534340.pdf\"},{\"id\":87716396,\"identity\":\"82ac58ea-49d7-4882-b158-f1b39a4afc8f\",\"added_by\":\"auto\",\"created_at\":\"2025-07-28 09:11:10\",\"extension\":\"pdf\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":71856026,\"visible\":true,\"origin\":\"\",\"legend\":\"Supplementary Figures\",\"description\":\"\",\"filename\":\"NNA91523Figsuppcorrected17511071701.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6992977/v1/f5a87bf8e4f2f1ab8898a7dc.pdf\"}],\"financialInterests\":\"\\u003cp\\u003eThere is \\u003cstrong\\u003eNO\\u003c/strong\\u003e Competing Interest.\\u003c/p\\u003e\\n\\u003cp\\u003eAll experimental procedures involving animals were conducted in accordance with the guidelines and regulations of the Swiss Federal Veterinary Office and were approved by the Geneva Cantonal Veterinary Authority.\\u003c/p\\u003e\",\"formattedTitle\":\"Valence-dependent synaptic plasticity drives approach and avoidance behavior in social context\",\"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\":\"info@researchsquare.com\",\"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-6992977/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6992977/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eSocial interactions critically shape future decisions about engaging with or avoiding conspecifics. However, how the valence of previous social experiences translates into adaptive approach or avoidance behaviors remains unclear. Here, we identify a novel circuit from dopamine D1 receptor (D1R)-expressing neurons in the anterior insular cortex (AIC) to D1R-expressing neurons in the lateral nucleus accumbens (LNAc). We show that valence-specific firing frequencies—low-frequency for reward and high-frequency for aversion—induced distinct synaptic plasticity at these synapses.\\u003c/p\\u003e\\n\\u003cp\\u003eImposing aversive-like firing patterns during rewarding interactions disrupts plasticity and subsequent social approach. Finally, we identify mGluR1 signaling as a critical molecular mechanism selectively required for positive-valence learning. Together, our findings elucidate the synaptic and molecular mechanisms by which social valence guides adaptive behavioral decisions, highlighting frequency-dependent plasticity within a single neural circuit as a dynamic regulator of social approach or avoidance.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Valence-dependent synaptic plasticity drives approach and avoidance behavior in social context\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-28 09:11:04\",\"doi\":\"10.21203/rs.3.rs-6992977/v1\",\"editorialEvents\":[],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"nature-neuroscience\",\"isNatureJournal\":true,\"hasQc\":false,\"allowDirectSubmit\":false,\"externalIdentity\":\"neuro\",\"sideBox\":\"Learn more about [Nature Neuroscience](http://www.nature.com/neuro/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Nature Neuroscience\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"ejp\",\"reportingPortfolio\":\"Nature Research\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"f5ba64a4-d3c4-4e1a-ab6c-a9de6f386e0f\",\"owner\":[],\"postedDate\":\"July 28th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[{\"id\":51949987,\"name\":\"Biological sciences/Neuroscience\"},{\"id\":51949988,\"name\":\"Biological sciences/Neuroscience/Synaptic plasticity\"}],\"tags\":[],\"updatedAt\":\"2025-10-08T07:50:10+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-07-28 09:11:04\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6992977\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6992977\",\"identity\":\"rs-6992977\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}