{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T04:47:17Z","timestamp":1785646037255,"version":"3.56.0"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2025ZD1801202"],"award-info":[{"award-number":["2025ZD1801202"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lingang Laboratory","award":["LGL-2614-14"],"award-info":[{"award-number":["LGL-2614-14"]}]},{"DOI":"10.13039\/501100007162","name":"Department of Science and Technology of Guangdong Province","doi-asserted-by":"crossref","award":["2024TX08A283"],"award-info":[{"award-number":["2024TX08A283"]}],"id":[{"id":"10.13039\/501100007162","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2024TX08A283"],"award-info":[{"award-number":["2024TX08A283"]}],"id":[{"id":"https:\/\/ror.org\/00tjzgn92","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"crossref","award":["24ZR1477800"],"award-info":[{"award-number":["24ZR1477800"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"crossref"}]},{"award":["24ZR1477800"],"award-info":[{"award-number":["24ZR1477800"]}],"id":[{"id":"https:\/\/ror.org\/03kt66j61","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017291","name":"Zhongshan Municipal Bureau of Science and Technology","doi-asserted-by":"crossref","award":["CXTD2022013"],"award-info":[{"award-number":["CXTD2022013"]}],"id":[{"id":"10.13039\/501100017291","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CXTD2022013"],"award-info":[{"award-number":["CXTD2022013"]}],"id":[{"id":"https:\/\/ror.org\/01b7ss333","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is associated with progressive hippocampal circuit dysfunction, but electrophysiological measures of state-dependent abnormalities and treatment responsiveness remain incompletely characterized. We examined hippocampal theta\u2013gamma coupling in 5xFAD mice across behavioral states and after donepezil. Methods: Local field potentials were recorded from CA1 in freely behaving wild-type (WT) and 5xFAD mice during home-cage activity, open-field exploration, and Y-maze testing. Power spectral density and theta\u2013gamma phase\u2013amplitude coupling (PAC) were quantified at the animal level at baseline and after seven days of donepezil. Results: Untreated 5xFAD mice showed reduced theta\u2013low-gamma coupling during home-cage and open-field activity, but not Y-maze exploration, and elevated theta\u2013high-gamma coupling in all three contexts. Donepezil increased theta\u2013low-gamma coupling during open-field and Y-maze exploration and produced a partial numerical shift toward WT levels in the home cage. For theta\u2013high-gamma coupling, the treated group did not differ significantly from either comparator. Untreated 5xFAD mice also showed reduced center exploration and distance traveled in the open field, while Y-maze spontaneous alternation was unchanged. Theta\u2013high-gamma coupling correlated positively with open-field center time in WT mice only. Conclusions: Hippocampal theta\u2013gamma coupling shows frequency- and context-dependent abnormalities in 5xFAD mice. Theta\u2013low-gamma coupling is sensitive to short-term cholinergic modulation during exploration, whereas donepezil\u2019s effect on theta\u2013high-gamma coupling remains inconclusive. Animal-level PAC may provide a candidate functional readout, but longitudinal and cross-model validation is required before biomarker claims are justified.<\/jats:p>","DOI":"10.3390\/brainsci16080816","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["State-Dependent Alterations of Hippocampal Theta\u2013Gamma Coupling in 5xFAD Mice and Their Differential Modulation by Donepezil"],"prefix":"10.3390","volume":"16","author":[{"given":"Haodong","family":"Wang","sequence":"first","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of New Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyang","family":"Lv","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"School of Pharmacy, Zunyi Medical University, Zunyi 563000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueting","family":"Deng","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"School of Pharmacy, University of Chinese Academy of Sciences, Beijing 101408, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Pan","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Li","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zikai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"},{"name":"School of New Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"School of Pharmacy, University of Chinese Academy of Sciences, Beijing 101408, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2024). 2024 Alzheimer\u2019s disease facts and figures. 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