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Neuropathic pain leads to changes in synaptic plasticity in the anterior cingulate cortex (ACC). However, whether such changes occur in knee OA mice and their association with exercise therapy remains unclear. Therefore, this study investigated these aspects using electrophysiological and behavioral approaches. We found no induction of pre- or post-long-term potentiation (LTP) in the ACC of knee OA mice. Application of ZD7288 and zeta inhibitory peptide (ZIP) reduced the amplitude of evoked excitatory postsynaptic currents, indicating pre-existing changes in synaptic plasticity in the ACC. Microinjection of ZD7288 and ZIP improved pain-escape and anxiety-like behaviors. Voluntary running exercise induced pre- and post-LTP and improved these behaviors in knee OA mice. Exercise therapy for knee OA may alter synaptic plasticity in the ACC, contributing to behavioral improvements.<\/jats:p>","DOI":"10.1186\/s13041-025-01207-9","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T12:34:54Z","timestamp":1755866094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Voluntary running improves synaptic degeneration of the anterior cingulate cortex in knee osteoarthritis"],"prefix":"10.1186","volume":"18","author":[{"given":"Ryo","family":"Miyake","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Taniguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Nishio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Matsuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Kaimochi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terumasa","family":"Nakatsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"issue":"12","key":"1207_CR1","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1002\/acr.22897","volume":"68","author":"BR Deshpande","year":"2016","unstructured":"Deshpande BR, Katz JN, Solomon DH, Yelin EH, Hunter DJ, Messier SP, et al. 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