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While PTEN's role in neuronal growth is recognized, its long\u2010term activation changes post\u2010TBI and its effects on sensory\u2010motor circuits are not well understood. Here, it is demonstrated that the neuronal knockout of PTEN (PTEN\u2010nKO) significantly enhances both structural and functional recovery over the long term after TBI. Importantly, in vivo, DTI\u2010MRI revealed that PTEN\u2010nKO promotes white matter repair post\u2010TBI. Additionally, calcium imaging and electromyographic recordings indicated that PTEN\u2010nKO facilitates cortical remapping and restores sensory\u2010motor pathways. Mechanistically, PTEN negatively regulates the Akt\/mTOR pathway by inhibiting Akt, thereby suppressing mTOR. Raptor is a key component of mTORC1 and its suppression impedes axonal regeneration. The restoration of white matter integrity and the improvements in neural function observed in PTEN\u2010nKO TBI\u2010treated mice are reversed by a PTEN\/Raptor double knockout (PTEN\/Raptor D\u2010nKO), suggesting that mTORC1 acts as a key mediator. These findings highlight persistent alterations in the PTEN\/Akt\/mTORC1 axis are critical for neural circuit remodeling and cortical remapping post\u2010TBI, offering new insights into TBI pathophysiology and potential therapeutic targets.<\/jats:p>","DOI":"10.1002\/advs.202410136","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T14:31:03Z","timestamp":1734359463000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Reversing Persistent PTEN Activation after Traumatic Brain Injury Fuels Long\u2010Term Axonal Regeneration via Akt\/mTORC1 Signaling Cascade"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0009-4225","authenticated-orcid":false,"given":"Ziyu","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology MOE Frontiers Center for Brain Science and Institutes of Brain Science Fudan 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