Background Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness, which is associated with reduced quality of life and increased mortality. We recently have developed a clinically relevant animal model of PICS, which can mimic most features of human PICS. However, the underlying mechanism remains largely to be elucidated. Accumulating evidence has suggested that hippocampal GABAergic interneuron

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... sfunction is implicated in various mood disorders induced by stress. Methods We explored the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS based on two-hit hypothesis. In addition, we tested whether fluoxetine treatment early following combined stress can prevent subsequent anatomical and behavioral pathologies. Results Here our study further supported our previous findings that this PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments, which resembles clinical features of human PICS. This behavioral state is accompanied by hippocampal neuroinflammation, reduced parvalbumin (PV) expression, and decreased theta and gamma power. Importantly, chronic fluoxetine treatment reversed most of these abnormities. Conclusions Our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathological of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.