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However, the pathophysiology of SAE is complex and unclear. Here, we investigated the role of hippocampus (HPC)\u2010prefrontal cortex (PFC) in cognitive dysfunction in sepsis induced by cecal ligation puncture (CLP) in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The neural projections from the HPC to PFC were first identified via retrograde tracing and viral expression. Chemogenetic activation of the HPC\u2010PFC pathway was shown via immunofluorescent staining of c\u2010Fos\u2010positive neurons in PFC. Morris Water Maze (MWM) and Barnes maze (BM) were used to evaluate cognitive function. Western blotting analysis was used to determine the expression of glutamate receptors and related molecules in PFC and HPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Chemogenetic activation of the HPC\u2010PFC pathway enhanced cognitive dysfunction in CLP\u2010induced septic mice. Glutamate receptors mediated the effects of HPC\u2010PFC pathway activation in CLP mice. The activation of the HPC\u2010PFC pathway resulted in significantly increased levels of NMDAR, AMPAR, and downstream signaling molecules including CaMKIIa, pCREB, and BDNF in PFC. However, inhibition of glutamate receptors using 2,3\u2010dihydroxy\u20106\u2010nitro\u20107\u2010sulphamoyl\u2010benzo (F)quinoxaline (NBQX), which is an \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptor (AMPAR inhibitor), or D\u20102\u2010amino\u20105\u2010phosphonopentanoate (D\u2010AP5), which is an NMDA receptor antagonist abolished this increase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study reveals the important role of the HPC\u2010PFC pathway in improving cognitive dysfunction in a mouse model of CLP sepsis and provides a novel pathogenetic mechanism for SAE.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14013","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T08:50:44Z","timestamp":1668502244000},"page":"390-401","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Hippocampus\u2010prefrontal cortex inputs modulate spatial learning and memory in a mouse model of sepsis induced by cecal ligation puncture"],"prefix":"10.1111","volume":"29","author":[{"given":"Cheng\u2010Long","family":"Ge","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine Xiangya Hospital, Central South University  Changsha Hunan Province China"},{"name":"National Clinical Research Center for Geriatric Disorders  Changsha Hunan Province China"},{"name":"Hunan Provincial Clinical Research Center for Critical Care Medicine  Changsha Hunan Province 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