Parvalbumin interneuron-mediated neural disruption in an animal model of postintensive care syndrome: prevention by fluoxetine

Abstract

Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness and persisting beyond hospitalization, which is associated with reduced quality of life and increased mortality. Recently, we have developed a clinically relevant animal model of PICS based on two-hit hypothesis. However, the underlying mechanism remains unclear. Accumulating evidence has demonstrated that hippocampal GABAergic interneuron dysfunction is implicated in various mood disorders induced by stress. Thus, this study investigated the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS. In addition, we tested whether fluoxetine treatment early following combined stress can prevent these anatomical and behavioral pathologies. In the present study, we confirmed our previous study 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. In summary, our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathology of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.

Post-Intensive Care Syndrome in Survivors from Critical Illness including COVID-19 Patients: A Narrative Review

“…There is not a specific medication that has been proven to be beneficial in PICS-related psychiatric symptoms, and it is not clear whether PICS-related psychiatric problems differ pathophysiologically from depression, anxiety, and PTSD not related to PICS. A recent report in a murine PICS model suggested that the GABAergic system, and in particular the parvalbumin-related interneuron dysfunction in the hippocampus, may play a significant role in PICS pathophysiology, and that the early treatment with fluoxetine, an antidepressant agent, can alleviate this pathology [151]. Relevant results from human studies are still lacking.…”

Electroacupuncture Ameliorates Chronic Inflammatory Pain-Related Anxiety by Activating PV Interneurons in the Anterior Cingulate Cortex

“…The subtypes of GABAergic interneurons mainly include parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) ( Tremblay et al, 2016 ). It has been reported that activation of PV but not SOM interneurons in the ACC had analgesic effects on inflammatory pain ( Kang et al, 2015 ), and reduction of PV but not SOM interneurons in the hippocampus led to anxiety or depression-like behavior ( Wang et al, 2021 ).…”

Human chorionic gonadotropin decreases cerebral cystic encephalomalacia and parvalbumin interneuron degeneration in a pro-inflammatory model of mouse neonatal hypoxia-ischemia

“…These changes are known to affect PV neuronal integrity and contribute to an impairment in affect and/or cognitive function (Jenkins et al, 2009;Wischhof et al, 2015). Various other studies utilizing different animal models support the notion that PV levels or PV interneuron integrity is adversely affected by increases in peripheral or central inflammation (Andersen, 2022;Ji et al, 2015;Wang et al, 2021;Zinsmaier et al, 2020). Furthermore, PV-IR neurons are decreased in the striatum and cortex of developing animals exposed to hypoxia or hyperoxia (Mallard et al, 1995;Schiavone et al, 2017).…”