{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:27:36Z","timestamp":1788362856537,"version":"build-2803163510"},"posted":{"date-parts":[[2025,7,31]]},"group-title":"Neuroscience","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 NS135830"],"award-info":[{"award-number":["R01 NS135830"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1 AG079199"],"award-info":[{"award-number":["RF1 AG079199"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["F31 AG079620"],"award-info":[{"award-number":["F31 AG079620"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32 AG052363"],"award-info":[{"award-number":["T32 AG052363"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["I01 BX005396"],"award-info":[{"award-number":["I01 BX005396"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>Ventral tegmental area (VTA) dopamine has been implicated in neuropsychiatric symptoms observed in Alzheimer\u2019s disease (AD) patients. Dopaminergic dysfunction and aberrant firing are observed in mouse AD models, but the specific roles of A\u03b2 and tau have not been determined.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    We performed electrophysiological recordings of single VTA dopamine neuron firing in the 3xTg-AD model, followed by recordings in amyloid (APP\n                    <jats:sup>NL-G-F<\/jats:sup>\n                    )- and human tau (hTau)-based models to determine the pathological triggers of impaired firing.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    <jats:italic>In vivo<\/jats:italic>\n                    dopamine neuron recordings showed fewer spikes in defined bursts in 3xTg-AD mice versus controls.\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    studies showed an impaired ability to sustain firing during depolarization, which was mimicked with depolarized current in wild type neurons. Dopamine neurons transduced with hTau reflected firing aberrations and impaired bursting, but the effects were not recapitulated in the APP\n                    <jats:sup>NL-G-F<\/jats:sup>\n                    model,\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>These results suggest that hTau specifically induces hyperexcitable states within individual dopamine neurons, disrupting burst firing. This dopaminergic dysfunction could compromise reward learning and contribute to the psychiatric symptoms observed in AD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.28.666953","type":"posted-content","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T19:45:19Z","timestamp":1753991119000},"source":"Crossref","is-referenced-by-count":2,"title":["Tau conveys intrinsic hyperactivity of VTA dopamine neurons but an inability to sustain burst firing"],"prefix":"10.64898","author":[{"given":"William M.","family":"Kennedy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Troyano-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew H.","family":"Higgs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7570-4895","authenticated-orcid":false,"given":"Harris E.","family":"Blankenship","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anu","family":"Korukonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Weinshenker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-4338","authenticated-orcid":false,"given":"Heather C.","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1574-530X","authenticated-orcid":false,"given":"Michael J.","family":"Beckstead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025080202150588000_2025.07.28.666953v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-022-06068-x"},{"key":"2025080202150588000_2025.07.28.666953v1.2","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.clinph.2020.10.028","article-title":"Motor dysfunction in mild cognitive impairment as tested by kinematic analysis and transcranial magnetic stimulation","volume":"132","year":"2021","journal-title":"Clin Neurophysiol"},{"key":"2025080202150588000_2025.07.28.666953v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-019-0272-1"},{"key":"2025080202150588000_2025.07.28.666953v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14727"},{"key":"2025080202150588000_2025.07.28.666953v1.5","doi-asserted-by":"crossref","unstructured":"Blankenship HE , Carter KA , Pham KD , Cassidy NT , Markiewicz AN , Thellmann MI , et al. 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