{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:07:17Z","timestamp":1787162837266,"version":"build-2736575974"},"reference-count":67,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["22K06618"],"award-info":[{"award-number":["22K06618"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["25K10188"],"award-info":[{"award-number":["25K10188"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["16K08215"],"award-info":[{"award-number":["16K08215"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer\u2019s disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-\u03b2 pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions.<\/jats:p>","DOI":"10.3390\/brainsci15111183","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:22:36Z","timestamp":1762176156000},"page":"1183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["rTg4510 Tauopathy Mice Exhibit Non-Spatial Memory Deficits Prevented by Doxycycline Treatment"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4828-1249","authenticated-orcid":false,"given":"Yasushi","family":"Kishimoto","sequence":"first","affiliation":[{"name":"Laboratory of Physical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan"},{"name":"Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Japan"},{"name":"Institute of Neuroscience, Tokushima Bunri University, Sanuki 769-2193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kubota","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Japan"},{"name":"Laboratory of Basic Pharmaceutical Education, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo 164-8530, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7881-5686","authenticated-orcid":false,"given":"Kentaro","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Japan"},{"name":"Institute of Neuroscience, Tokushima Bunri University, Sanuki 769-2193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Kirino","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1146\/annurev.neuro.24.1.1121","article-title":"Neurodegenerative tauopathies","volume":"24","author":"Lee","year":"2001","journal-title":"Annu. 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