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Perioperative neurocognitive disorder (PND) occurs frequently after anesthesia\/surgery and worsens patient outcome, but the neural circuit mechanisms remain unclear. This study aimed to determine the effects of the GJs\u2010Cx43\u2013mediated astrocytic network on PND and ascertain the underlying neural circuit mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male C57BL\/6 mice were treated with long\u2010term isoflurane exposure to construct a mouse model of PND. We also exposed primary mouse astrocytes to long\u2010term isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. Behavioral tests were performed using the Y\u2010maze and fear conditioning (FC) tests. Manganese\u2010enhanced magnetic resonance imaging (MEMRI) and resting\u2010state functional magnetic resonance imaging (rs\u2010fMRI) were used to investigate brain activity and functional connectivity. Western blot and flow cytometry analysis were used to assess protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Reconfiguring the astrocytic network by increasing GJs\u2010Cx43 expression can modulate 22 subregions affected by PND in three ways: reversed activation, reversed inhibition, and intensified activation. The brain functional connectivity analysis further suggests that PND is a brain network disorder that includes sleep\u2010wake rhythm\u2013related brain regions, contextual and fear memory\u2013related subregions, the hippocampal\u2010amygdala circuit, the septo\u2010hippocampal circuit, and the entorhinal\u2010hippocampal circuit. Notably, remodeling the astrocytic network by upregulation of GJs\u2010Cx43 can partially reverse the abnormalities in the above circuits. Pathophysiological degeneration in hippocampus is one of the primary hallmarks of PND pathology, and long\u2010term isoflurane anesthesia contributes to oxidative stress and neuroinflammation in the hippocampus. However, promoting the formation of GJs\u2010Cx43 ameliorated cognitive dysfunction induced by long\u2010term isoflurane anesthesia through the attenuation of oxidative stress in hippocampus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Enhancing GJs\u2010Cx43 coupling can improve brain network abnormalities and cognitive impairment induced by long\u2010term isoflurane anesthesia, its mechanisms might be associated with the regulation of oxidative stress and neuroinflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13974","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T16:15:11Z","timestamp":1664122511000},"page":"2281-2297","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Enhancement of astrocytic gap junctions Connexin43 coupling can improve long\u2010term isoflurane anesthesia\u2013mediated brain network abnormalities and cognitive impairment"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8591-0828","authenticated-orcid":false,"given":"Rui","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Anesthesiology The Affiliated Drum Tower Hospital of Nanjing University Medical School  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Radiology The Affiliated Drum Tower Hospital of Nanjing University Medical School  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqiang","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The Affiliated Drum Tower Hospital of Nanjing University Medical School  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The 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