Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity

Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity | 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 Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity Marianne Benoit-Marand, Sarah Chevalier, Mélina Decourt, Maureen Francheteau, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4013809/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Sep, 2024 Read the published version in npj Parkinson's Disease → Version 1 posted 11 You are reading this latest preprint version Abstract Parkinson’s disease is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations following neurodegeneration or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops. This study investigated the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity and markers of synaptic plasticity. Bilateral nigrostriatal degeneration was induced by viral-mediated expression of human mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the dorsomedial striatum (DMS) were performed and spike probability in response to OFC stimulation was measured before and after a high frequency stimulation (HFS). Post-mortem analysis included stereological assessment of nigral neurodegeneration, BDNF and TrkB protein levels. Nigrostriatal neurodegeneration led to altered firing patterns of OFC neurons that were restored by PPX. HFS of the OFC led to an increased spike probability in the DMS, while dopaminergic loss had an opposite effect. PPX led to a decreased spike probability following HFS in control rats and failed to counteract the effect of dopaminergic neurodegeneration. These alterations were associated with decreased levels of BDNF and TrkB in the DMS. This study demonstrates that nigral dopaminergic loss and PPX both contribute to alter fronstostriatal transmission, precluding adequate information processing in associative basal ganglia loops as a gateway for the development of non-motor symptoms or non-motor side-effects of DRT. Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease Biological sciences/Neuroscience/Synaptic plasticity Parkinson’s disease orbitofrontal cortex frontostriatal plasticity pramipexole Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Additional Declarations (Not answered) Cite Share Download PDF Status: Published Journal Publication published 09 Sep, 2024 Read the published version in npj Parkinson's Disease → Version 1 posted Editorial decision: revise 10 Apr, 2024 Review # 3 received at journal 03 Apr, 2024 Review # 1 received at journal 02 Apr, 2024 Review # 2 received at journal 28 Mar, 2024 Reviewer # 3 agreed at journal 19 Mar, 2024 Reviewer # 2 agreed at journal 15 Mar, 2024 Reviewer # 1 agreed at journal 12 Mar, 2024 Reviewers invited by journal 11 Mar, 2024 Editor assigned by journal 09 Mar, 2024 Submission checks completed at journal 07 Mar, 2024 First submitted to journal 04 Mar, 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-4013809","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":278545097,"identity":"dea28de8-22b4-4708-96ac-6dcab624ee24","order_by":0,"name":"Marianne Benoit-Marand","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-1380-5401","institution":"Université de Poitiers","correspondingAuthor":true,"prefix":"","firstName":"Marianne","middleName":"","lastName":"Benoit-Marand","suffix":""},{"id":278545098,"identity":"e74b20b4-be5c-403a-9f0f-822bbaf0e8e8","order_by":1,"name":"Sarah Chevalier","email":"","orcid":"","institution":"Université de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Chevalier","suffix":""},{"id":278545099,"identity":"a9a4a5a7-9f46-450a-a5e5-06b15fae5edb","order_by":2,"name":"Mélina Decourt","email":"","orcid":"","institution":"Université de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Mélina","middleName":"","lastName":"Decourt","suffix":""},{"id":278545100,"identity":"01d39ea6-7c90-4bba-8685-2a6f2f88433f","order_by":3,"name":"Maureen Francheteau","email":"","orcid":"","institution":"Université de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Maureen","middleName":"","lastName":"Francheteau","suffix":""},{"id":278545101,"identity":"e3d105ea-5625-4146-88db-4e6fc86f5d44","order_by":4,"name":"Anaïs Balbous-Gautier","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Anaïs","middleName":"","lastName":"Balbous-Gautier","suffix":""},{"id":278545102,"identity":"4fbd762b-796c-4b0a-a028-6313f07242e6","order_by":5,"name":"Pierre-Olivier Fernagut","email":"","orcid":"https://orcid.org/0000-0002-7737-5439","institution":"Université de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Pierre-Olivier","middleName":"","lastName":"Fernagut","suffix":""}],"badges":[],"createdAt":"2024-03-04 18:20:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4013809/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4013809/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41531-024-00781-4","type":"published","date":"2024-09-09T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52663018,"identity":"05c0e41b-0f91-4311-8888-48630f8bf0b1","added_by":"auto","created_at":"2024-03-14 08:19:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51425,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Stereological counts of tyrosine hydroxylase (TH) positive neurons in the SNc and representative images of the SNc in sham (top) and lesioned rats (bottom). GFP SALINE (N=17) ; GFP PPX (N=20) ; alpha-syn SALINE (N=19) ; alpha-syn PPX (N=20). (B) Fluorescence intensity of D3 mRNA in the DMS. GFP SALINE (N=4) ; GFP PPX (N=4) ; alpha-syn SALINE (N=5) ; alpha-syn PPX (N=5). ****p\u0026lt;0.0001; two-way ANOVA followed by Tukey’s post-hoc.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4013809/v1/fd5fc7c627e14b7ac5c5badd.jpg"},{"id":52663651,"identity":"a970eaae-02ea-492e-9fa1-c4907f62d284","added_by":"auto","created_at":"2024-03-14 08:27:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":87877,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Representative electrophysiological trace of an OFC neuron, the inset represents the action potential shape (averaged over 2 minutes recording), the action potential duration is measured from rising up to the hyperpolarization peak (grey window). (B) Distribution of spike durations (ms), the dashed lines indicate the limits of inclusion criteria for putative pyramidal neurons. (C) Density of spontaneously active putative pyramidal neurons per mm. (D) Spike frequency (Hz). (E) Proportion of neurons exhibiting burst firing activity (%). (F) Bursting frequency (Bursts per minute). (G) Burst duration (seconds). (H) Percentage of spikes in burst. GFP SALINE (n=157 neurons ; N=6 rats) ; GFP PPX (n=162 ; N=8) ; alpha-syn SALINE (n= 191; N=8) ; alpha-syn PPX (n= 158; N=7). *p\u0026lt;0.05 ; **p\u0026lt;0.01 ; two-way ANOVA followed by Tukey’s post-hoc.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4013809/v1/7c66b50fb6ef24a01a3b6fab.jpg"},{"id":52663016,"identity":"1f240702-5155-4784-9af6-57fbc6b50862","added_by":"auto","created_at":"2024-03-14 08:19:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":81484,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Schematic representation of stimulation and recording sites. (B) Representative electrophysiological trace of spike responses evoked in a DMS neuron by OFC stimulation. Black traces represent trials that do not exhibit spike responses to OFC stimulations and colored traces represent trials exhibiting spike response to OFC stimulation both before (baseline, blue) and after (post HFS, green) high frequency stimulation of the OFC-DMS pathway. Spike probability was measured as the number of responding trials over 5 minutes. (C) Spike probability (% of baseline) 15 before and 30-45 minutes after HFS. Delta change of response probability after HFS compared to baseline (%). GFP SALINE (N=6) ; GFP PPX (N=6) ; alpha-syn SALINE (N=6) ; alpha-syn PPX (N=6); ****p\u0026lt;0.0001 ; two-way ANOVA followed by Tukey’s post-hoc.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4013809/v1/6f2f1b8085be41a7a622b0a0.jpg"},{"id":52663019,"identity":"dde5e018-6aae-47ad-9227-899aa0415403","added_by":"auto","created_at":"2024-03-14 08:19:05","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":47627,"visible":true,"origin":"","legend":"\u003cp\u003e(A) BDNF immunoblot levels and (B) TrkB immunoblot levels in the DMS. GFP SALINE (N=5) ; GFP PPX (N=5) ; alpha-syn SALINE (N=5) ; alpha-syn PPX (N=6). *p\u0026lt;0.05 ; **p\u0026lt;0.01 ; two-way ANOVA followed by Tukey’s post-hoc.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4013809/v1/89f8f2e35f576705f70f622f.jpg"},{"id":64777518,"identity":"91136aeb-a3e9-4a88-ba97-9dd06dc3a06c","added_by":"auto","created_at":"2024-09-18 18:32:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":563744,"visible":true,"origin":"","legend":"","description":"","filename":"ChevalierSetalNPJPD03042024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4013809/v1_covered_a0a4da28-47e3-48ee-99f0-7df36f2d092b.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, orbitofrontal cortex, frontostriatal plasticity, pramipexole","lastPublishedDoi":"10.21203/rs.3.rs-4013809/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4013809/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Parkinson’s disease is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations following neurodegeneration or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops. This study investigated the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity and markers of synaptic plasticity. Bilateral nigrostriatal degeneration was induced by viral-mediated expression of human mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the dorsomedial striatum (DMS) were performed and spike probability in response to OFC stimulation was measured before and after a high frequency stimulation (HFS). Post-mortem analysis included stereological assessment of nigral neurodegeneration, BDNF and TrkB protein levels. Nigrostriatal neurodegeneration led to altered firing patterns of OFC neurons that were restored by PPX. HFS of the OFC led to an increased spike probability in the DMS, while dopaminergic loss had an opposite effect. PPX led to a decreased spike probability following HFS in control rats and failed to counteract the effect of dopaminergic neurodegeneration. These alterations were associated with decreased levels of BDNF and TrkB in the DMS. 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